Epigenetics

<div class="hatnote" >For the unfolding of an organism or the theory that plants and animals (including humans) develop in this way, see <a href="http://en.wikipedia.org/wiki/Epigenesis_(biology)" title="Epigenesis (biology)" >epigenesis (biology)</a>. For epigenetics in robotics, see <a href="http://en.wikipedia.org/wiki/Developmental_robotics" title="Developmental robotics" >developmental robotics</a>.</div>

In <a href="http://en.wikipedia.org/wiki/Biology" title="Biology" >biology</a>, and specifically <a href="http://en.wikipedia.org/wiki/Genetics" title="Genetics" >genetics</a>, epigenetics is the study of <a href="http://en.wikipedia.org/wiki/Heritable" title="Heritable" class="mw-redirect" >heritable</a> changes in <a href="http://en.wikipedia.org/wiki/Gene" title="Gene" >gene</a> activity that are not caused by changes in the <a href="http://en.wikipedia.org/wiki/DNA" title="DNA" >DNA</a> sequence; it also can be used to describe the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. Unlike simple <a href="http://en.wikipedia.org/wiki/Genetics" title="Genetics" >genetics</a> based on changes to the DNA sequence (the <a href="http://en.wikipedia.org/wiki/Genotype" title="Genotype" >genotype</a>), the changes in <a href="http://en.wikipedia.org/wiki/Gene_expression" title="Gene expression" >gene expression</a> or <a href="http://en.wikipedia.org/wiki/Cell_(biology)" title="Cell (biology)" >cellular</a> <a href="http://en.wikipedia.org/wiki/Phenotype" title="Phenotype" >phenotype</a> of epigenetics have other causes, thus use of the term epi- (Greek: επί- over, outside of, around) -<a href="http://en.wikipedia.org/wiki/Genetics" title="Genetics" >genetics</a>.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-1" >[1]</a>

The term also refers to the changes themselves: functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Examples of mechanisms that produce such changes are <a href="http://en.wikipedia.org/wiki/DNA_methylation" title="DNA methylation" >DNA methylation</a> and <a href="http://en.wikipedia.org/wiki/Histone_modification" title="Histone modification" class="mw-redirect" >histone modification</a>, each of which alters how genes are expressed without altering the underlying <a href="http://en.wikipedia.org/wiki/DNA_sequence" title="DNA sequence" class="mw-redirect" >DNA sequence</a>. Gene expression can be controlled through the action of repressor proteins that attach to <a href="http://en.wikipedia.org/wiki/Silencer_(DNA)" title="Silencer (DNA)" >silencer</a> regions of the DNA. These epigenetic changes may last through <a href="http://en.wikipedia.org/wiki/Cell_division" title="Cell division" >cell divisions</a> for the duration of the cell's life, and may also last for multiple generations even though they do not involve changes in the underlying <a href="http://en.wikipedia.org/wiki/DNA" title="DNA" >DNA</a> sequence of the organism;<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid17522671-2" >[2]</a> instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-3" >[3]</a> (There are objections to the use of the term epigenetic to describe chemical modification of histone, since it remains unclear whether or not histone modifications are heritable.)<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-nature2008-4" >[4]</a>

One example of an epigenetic change in <a href="http://en.wikipedia.org/wiki/Eukaryotic" title="Eukaryotic" class="mw-redirect" >eukaryotic</a> biology is the process of <a href="http://en.wikipedia.org/wiki/Cellular_differentiation" title="Cellular differentiation" >cellular differentiation</a>. During <a href="http://en.wikipedia.org/wiki/Morphogenesis" title="Morphogenesis" >morphogenesis</a>, <a href="http://en.wikipedia.org/wiki/Totipotent" title="Totipotent" class="mw-redirect" >totipotent</a> <a href="http://en.wikipedia.org/wiki/Stem_cells" title="Stem cells" class="mw-redirect" >stem cells</a> become the various <a href="http://en.wikipedia.org/wiki/Pluripotent" title="Pluripotent" class="mw-redirect" >pluripotent</a> <a href="http://en.wikipedia.org/wiki/Cell_line" title="Cell line" class="mw-redirect" >cell lines</a> of the <a href="http://en.wikipedia.org/wiki/Embryo" title="Embryo" >embryo</a>, which in turn become fully differentiated cells. In other words, as a single fertilized egg cell – the <a href="http://en.wikipedia.org/wiki/Zygote" title="Zygote" >zygote</a> – continues to <a href="http://en.wikipedia.org/wiki/Mitosis" title="Mitosis" >divide</a>, the resulting daughter cells change into all the different cell types in an organism, including <a href="http://en.wikipedia.org/wiki/Neurons" title="Neurons" class="mw-redirect" >neurons</a>, <a href="http://en.wikipedia.org/wiki/Muscle_cells" title="Muscle cells" class="mw-redirect" >muscle cells</a>, <a href="http://en.wikipedia.org/wiki/Epithelium" title="Epithelium" >epithelium</a>, <a href="http://en.wikipedia.org/wiki/Endothelium" title="Endothelium" >endothelium</a> of <a href="http://en.wikipedia.org/wiki/Blood_vessels" title="Blood vessels" class="mw-redirect" >blood vessels</a>, etc., by activating some genes while inhibiting the expression of others.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid17522676-5" >[5]</a>

In 2011, it was demonstrated that the <a href="http://en.wikipedia.org/wiki/Methylation" title="Methylation" >methylation</a> of <a href="http://en.wikipedia.org/wiki/Messenger_RNA" title="Messenger RNA" >mRNA</a> plays a critical role in human <a href="http://en.wikipedia.org/wiki/Energy_balance_(biology)" title="Energy balance (biology)" class="mw-redirect" >energy homeostasis</a>. The obesity-associated <a href="http://en.wikipedia.org/wiki/FTO_gene" title="FTO gene" >FTO gene</a> is shown to be able to <a href="http://en.wikipedia.org/wiki/Demethylate" title="Demethylate" class="mw-redirect" >demethylate</a> <a href="http://en.wikipedia.org/wiki/N6-methyladenosine" title="N6-methyladenosine" class="mw-redirect" >N6-methyladenosine</a> in RNA. This discovery launched the subfield of RNA epigenetics.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-6" >[6]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-7" >[7]</a>

<h2 >Contents</h2>

[<a href="http://en.wikipedia.org/wiki/Epigenetics#" class="internal" id="togglelink" >hide</a>] </div>

<ul >

<li class="toclevel-1 tocsection-1" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Historical_usage_of_term" >1 Historical usage of term</a></li>

<li class="toclevel-1 tocsection-2" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Contemporary_usage_of_term" >2 Contemporary usage of term</a></li>

<li class="toclevel-1 tocsection-3" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Molecular_basis" >3 Molecular basis</a></li>

<li class="toclevel-1 tocsection-4" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Mechanisms" >4 Mechanisms</a>

<ul >

<li class="toclevel-2 tocsection-5" ><a href="http://en.wikipedia.org/wiki/Epigenetics#DNA_methylation_and_chromatin_remodeling" >4.1 DNA methylation and chromatin remodeling</a></li>

<li class="toclevel-2 tocsection-6" ><a href="http://en.wikipedia.org/wiki/Epigenetics#RNA_transcripts_and_their_encoded_proteins" >4.2 RNA transcripts and their encoded proteins</a></li>

<li class="toclevel-2 tocsection-7" ><a href="http://en.wikipedia.org/wiki/Epigenetics#MicroRNAs" >4.3 MicroRNAs</a></li>

<li class="toclevel-2 tocsection-8" ><a href="http://en.wikipedia.org/wiki/Epigenetics#sRNAs" >4.4 sRNAs</a></li>

<li class="toclevel-2 tocsection-9" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Prions" >4.5 Prions</a></li>

<li class="toclevel-2 tocsection-10" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Structural_inheritance_systems" >4.6 Structural inheritance systems</a></li>

</ul>

</li>

<li class="toclevel-1 tocsection-11" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Functions_and_consequences" >5 Functions and consequences</a>

<ul >

<li class="toclevel-2 tocsection-12" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Development" >5.1 Development</a></li>

<li class="toclevel-2 tocsection-13" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Medicine" >5.2 Medicine</a></li>

<li class="toclevel-2 tocsection-14" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Evolution" >5.3 Evolution</a></li>

<li class="toclevel-2 tocsection-15" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Current_research_findings_and_examples_of_effects" >5.4 Current research findings and examples of effects</a></li>

</ul>

</li>

<li class="toclevel-1 tocsection-16" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Epigenetic_effects_in_humans" >6 Epigenetic effects in humans</a>

<ul >

<li class="toclevel-2 tocsection-17" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Genomic_imprinting_and_related_disorders" >6.1 Genomic imprinting and related disorders</a></li>

<li class="toclevel-2 tocsection-18" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Transgenerational_epigenetic_observations" >6.2 Transgenerational epigenetic observations</a></li>

<li class="toclevel-2 tocsection-19" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Cancer_and_developmental_abnormalities" >6.3 Cancer and developmental abnormalities</a>

<ul >

<li class="toclevel-3 tocsection-20" ><a href="http://en.wikipedia.org/wiki/Epigenetics#DNA_methylation_in_cancer" >6.3.1 DNA methylation in cancer</a></li>

<li class="toclevel-3 tocsection-21" ><a href="http://en.wikipedia.org/wiki/Epigenetics#DNA_repair_epigenetics_in_cancer" >6.3.2 DNA repair epigenetics in cancer</a></li>

<li class="toclevel-3 tocsection-22" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Variant_histones_H2A_in_cancer" >6.3.3 Variant histones H2A in cancer</a></li>

<li class="toclevel-3 tocsection-23" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Cancer_treatment" >6.3.4 Cancer treatment</a></li>

</ul>

</li>

<li class="toclevel-2 tocsection-24" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Twin_studies" >6.4 Twin studies</a></li>

</ul>

</li>

<li class="toclevel-1 tocsection-25" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Epigenetics_in_microorganisms" >7 Epigenetics in microorganisms</a></li>

<li class="toclevel-1 tocsection-27" ><a href="http://en.wikipedia.org/wiki/Epigenetics#Notes_and_references" >9 Notes and references</a></li>

<li class="toclevel-1 tocsection-28" ><a href="http://en.wikipedia.org/wiki/Epigenetics#External_links" >10 External links</a></li>

</ul>

</div>

<h2 >Historical usage of term[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=1" title="Edit section: Historical usage of term" >edit</a>]</h2>

Epigenetics (as in "epigenetic landscape") was coined by <a href="http://en.wikipedia.org/wiki/Conrad_Hal_Waddington" title="Conrad Hal Waddington" >C. H. Waddington</a> in 1942 as a <a href="http://en.wikipedia.org/wiki/Portmanteau" title="Portmanteau" >portmanteau</a> of the words <a href="http://en.wikipedia.org/wiki/Epigenesis(biology)" title="Epigenesis (biology)" >epigenesis</a> and <a href="http://en.wikipedia.org/wiki/Genetics" title="Genetics" >genetics</a>.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-waddington-8" >[8]</a> Epigenesis is an old<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-OED1-9" >[9]</a> word that has more recently been used (see <a href="http://en.wikipedia.org/wiki/Preformationism" title="Preformationism" >preformationism</a> for historical background) to describe the differentiation of cells from their initial <a href="http://en.wikipedia.org/wiki/Totipotent" title="Totipotent" class="mw-redirect" >totipotent</a> state in embryonic development. When Waddington coined the term the physical nature of genes and their role in heredity was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a <a href="http://en.wikipedia.org/wiki/Phenotype" title="Phenotype" >phenotype</a>; he used the phrase "epigenetic landscape" as a metaphor for <a href="http://en.wikipedia.org/wiki/Morphogenesis" title="Morphogenesis" >biological development</a>. Waddington held that <a href="http://en.wikipedia.org/wiki/Cell(biology)" title="Cell (biology)" >cell</a> fates were established in development much like a marble rolls down to the point of <a href="http://en.wikipedia.org/wiki/Local_optimum" title="Local optimum" >lowest local elevation</a>.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-10" >[10]</a> Waddington suggested visualising increasing irreversibility of cell type differentiation as ridges rising between the valleys where the marbles (cells) are travelling.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-11" >[11]</a> In recent times Waddington's notion of the epigenetic landscape has been rigorously formalized in the context of the <a href="http://en.wikipedia.org/wiki/System_dynamics" title="System dynamics" >systems dynamics</a> state approach to the study of cell-fate.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-12" >[12]</a>

The term "epigenetics" has also been used in <a href="http://en.wikipedia.org/wiki/Developmental_psychology" title="Developmental psychology" >developmental psychology</a> to describe psychological development as the result of an ongoing, bi-directional interchange between heredity and the environment.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-13" >[13]</a> Interactivist ideas of development have been discussed in various forms and under various names throughout the 19th and 20th centuries. An early version was proposed, among the founding statements in <a href="http://en.wikipedia.org/wiki/Embryology" title="Embryology" >embryology</a>, by <a href="http://en.wikipedia.org/wiki/Karl_Ernst_von_Baer" title="Karl Ernst von Baer" >Karl Ernst von Baer</a> and popularized by <a href="http://en.wikipedia.org/wiki/Ernst_Haeckel" title="Ernst Haeckel" >Ernst Haeckel</a>. A radical epigenetic view (physiological epigenesis) was developed by <a href="http://en.wikipedia.org/wiki/Paul_Wintrebert" title="Paul Wintrebert" >Paul Wintrebert</a>. Another variation, probabilistic epigenesis, was presented by <a href="http://en.wikipedia.org/wiki/Gilbert_Gottlieb" title="Gilbert Gottlieb" >Gilbert Gottlieb</a> in 2003.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-14" >[14]</a> This view encompasses all of the possible developing factors on an organism and how they not only influence the organism and each other but how the organism also influences its own development.

Noted developmental psychologist <a href="http://en.wikipedia.org/wiki/Erik_Erikson" title="Erik Erikson" >Erik Erikson</a> used the term epigenetic principle in his book <a href="http://en.wikipedia.org/wiki/Erik_Erikson#Bibliography" title="Erik Erikson" >Identity: Youth and Crisis (1968)</a>, and used it to encompass the notion that we develop through an unfolding of our personality in predetermined stages, and that our environment and surrounding culture influence how we progress through these stages. This biological unfolding in relation to our socio-cultural settings is done in <a href="http://en.wikipedia.org/wiki/Erikson%27s_stages_of_psychosocial_development" title="Erikson's stages of psychosocial development" >stages of psychosocial development</a>, where "progress through each stage is in part determined by our success, or lack of success, in all the previous stages."<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Boeree1997-15" >[15]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-16" >[16]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-17" >[17]</a>

<h2 >Contemporary usage of term[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=2" title="Edit section: Contemporary usage of term" >edit</a>]</h2>

Epigenetic mechanisms</div>

</div>

<a href="http://en.wikipedia.org/wiki/Robin_Holliday" title="Robin Holliday" >Robin Holliday</a> defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid2265224-18" >[18]</a> Thus epigenetic can be used to describe anything other than DNA sequence that influences the development of an organism.

The more recent usage of the word in science has a stricter definition. It is, as defined by <a href="http://en.wikipedia.org/wiki/Arthur_Riggs_(geneticist)" title="Arthur Riggs (geneticist)" >Arthur Riggs</a> and colleagues, "the study of <a href="http://en.wikipedia.org/wiki/Mitosis" title="Mitosis" >mitotically</a> and/or <a href="http://en.wikipedia.org/wiki/Meiosis" title="Meiosis" >meiotically</a>heritable changes in gene function that cannot be explained by changes in DNA sequence."<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-isbn0-87969-490-4-19" >[19]</a> The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" genetics; thus epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.

The term "epigenetics", however, has been used to describe processes which have not been demonstrated to be heritable such as histone modification; there are therefore attempts to redefine it in broader terms that would avoid the constraints of requiring heritability. For example, <a href="http://en.wikipedia.org/wiki/Adrian_Peter_Bird" title="Adrian Peter Bird" class="mw-redirect" >Sir Adrian Bird</a> defined epigenetics as "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states."<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid17522671-2" >[2]</a> This definition would be inclusive of transient modifications associated with <a href="http://en.wikipedia.org/wiki/DNA_repair" title="DNA repair" >DNA repair</a> or <a href="http://en.wikipedia.org/wiki/Cell-cycle" title="Cell-cycle" class="mw-redirect" >cell-cycle</a> phases as well as stable changes maintained across multiple cell generations, but exclude others such as templating of membrane architecture and <a href="http://en.wikipedia.org/wiki/Prions" title="Prions" class="mw-redirect" >prions</a> unless they impinge on chromosome function. Such redefinitions however are not universally accepted and are still subject to dispute.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-nature2008-4" >[4]</a> The NIH "Roadmap Epigenomics Project," ongoing as of 2013, uses the following definition: "Epigenetics is an emerging frontier of science that involves the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence. For purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome."<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-20" >[20]</a>

In 2008, a consensus definition of the epigenetic trait, "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence", was made at a <a href="http://en.wikipedia.org/wiki/Cold_Spring_Harbor_Laboratory" title="Cold Spring Harbor Laboratory" >Cold Spring Harbor</a>meeting.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid19339683-21" >[21]</a>

The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "<a href="http://en.wikipedia.org/wiki/Genome" title="Genome" >genome</a>", and refers to the overall epigenetic state of a cell. The phrase "<a href="http://en.wikipedia.org/wiki/Genetic_code" title="Genetic code" >genetic code</a>" has also been adapted—the "<a href="http://en.wikipedia.org/wiki/Epigenetic_code" title="Epigenetic code" >epigenetic code</a>" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for in an epigenomic map, a diagrammatic representation of the gene expression, DNA methylation and histone modification status of a particular genomic region. More typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the <a href="http://en.wikipedia.org/wiki/Histone_code_hypothesis" title="Histone code hypothesis" class="mw-redirect" >histone code</a> or<a href="http://en.wikipedia.org/wiki/DNA_methylation" title="DNA methylation" >DNA methylation</a> patterns.

<h2 >Molecular basis[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=3" title="Edit section: Molecular basis" >edit</a>]</h2>

Epigenetic changes can modify the activation of certain genes, but not the sequence of <a href="http://en.wikipedia.org/wiki/DNA" title="DNA" >DNA</a>. Additionally, the <a href="http://en.wikipedia.org/wiki/Chromatin" title="Chromatin" >chromatin</a> proteins associated with DNA may be activated or silenced. This is why the differentiated cells in a multi-cellular organism express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if gene inactivation occurs in a sperm or egg cell that results in fertilization, then some epigenetic changes can be transferred to the next generation.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid17320501-22" >[22]</a> This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA (see <a href="http://en.wikipedia.org/wiki/Epigenetics#Evolution" >Evolution, below</a>), a form of <a href="http://en.wikipedia.org/wiki/Lamarckism" title="Lamarckism" >Lamarckism</a>.

Specific epigenetic processes include <a href="http://en.wikipedia.org/wiki/Paramutation" title="Paramutation" >paramutation</a>, <a href="http://en.wikipedia.org/wiki/Bookmarking" title="Bookmarking" >bookmarking</a>, <a href="http://en.wikipedia.org/wiki/Imprinting(genetics)" title="Imprinting (genetics)" class="mw-redirect" >imprinting</a>, <a href="http://en.wikipedia.org/wiki/Gene_silencing" title="Gene silencing" >gene silencing</a>, <a href="http://en.wikipedia.org/wiki/X-inactivation" title="X-inactivation" >X chromosome inactivation</a>, <a href="http://en.wikipedia.org/wiki/Position_effect" title="Position effect" >position effect</a>, <a href="http://en.wikipedia.org/wiki/Reprogramming" title="Reprogramming" >reprogramming</a>, <a href="http://en.wikipedia.org/wiki/Transvection(genetics)" title="Transvection (genetics)" >transvection</a>, <a href="http://en.wikipedia.org/wiki/Maternal_effect" title="Maternal effect" >maternal effects</a>, the progress of<a href="http://en.wikipedia.org/wiki/Carcinogenesis" title="Carcinogenesis" >carcinogenesis</a>, many effects of <a href="http://en.wikipedia.org/wiki/Teratogen" title="Teratogen" class="mw-redirect" >teratogens</a>, regulation of <a href="http://en.wikipedia.org/wiki/Histone" title="Histone" >histone</a> modifications and <a href="http://en.wikipedia.org/wiki/Heterochromatin" title="Heterochromatin" >heterochromatin</a>, and technical limitations affecting <a href="http://en.wikipedia.org/wiki/Parthenogenesis" title="Parthenogenesis" >parthenogenesis</a> and <a href="http://en.wikipedia.org/wiki/Cloning" title="Cloning" >cloning</a>.

DNA damage can also cause epigenetic changes.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-23" >[23]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-24" >[24]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-25" >[25]</a> DNA damages are very frequent, occurring on average about 10,000 times a day per cell of the human body (see <a href="http://en.wikipedia.org/wiki/DNA_damage_(naturally_occurring)" title="DNA damage (naturally occurring)" >DNA damage (naturally occurring)</a>). These damages are largely repaired, but at the site of a DNA repair, epigenetic changes can remain.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-26" >[26]</a> In particular, a double strand break in DNA can initiate unprogrammed epigenetic gene silencing both by causing DNA methylation as well as by promoting silencing types of histone modifications (chromatin remodeling) (see next section).<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-27" >[27]</a> In addition, the enzyme <a href="http://en.wikipedia.org/wiki/Poly_ADP_ribose_polymerase" title="Poly ADP ribose polymerase" >Parp1 (poly(ADP)-ribose polymerase)</a> and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-28" >[28]</a> This accumulation, in turn, directs recruitment and activation of the chromatin remodeling protein ALC1 that can cause nucleosome remodeling.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-29" >[29]</a> Nucleosome remodeling has been found to cause, for instance, epigenetic silencing of DNA repair gene MLH1.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-isbn0-87969-490-4-19" >[19]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-30" >[30]</a> DNA damaging chemicals, such as <a href="http://en.wikipedia.org/wiki/Benzene" title="Benzene" >benzene</a>, <a href="http://en.wikipedia.org/wiki/Hydroquinone" title="Hydroquinone" >hydroquinone</a>, <a href="http://en.wikipedia.org/wiki/Styrene" title="Styrene" >styrene</a>, <a href="http://en.wikipedia.org/wiki/Carbon_tetrachloride" title="Carbon tetrachloride" >carbon tetrachloride</a> and <a href="http://en.wikipedia.org/wiki/Trichloroethylene" title="Trichloroethylene" >trichloroethylene</a>, cause considerable hypomethylation of DNA, some through the activation of oxidative stress pathways.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-31" >[31]</a>

Foods are known to alter the epigenetics of rats on different diets.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-32" >[32]</a> Some food components epigenetically increase the levels of DNA repair enzymes such as <a href="http://en.wikipedia.org/wiki/O-6-methylguanine-DNA_methyltransferase" title="O-6-methylguanine-DNA methyltransferase" >MGMT</a> and <a href="http://en.wikipedia.org/wiki/MLH1" title="MLH1" >MLH1</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-33" >[33]</a> and <a href="http://en.wikipedia.org/wiki/P53" title="P53" >p53</a>.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-34" >[34]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-35" >[35]</a> Other food components can reduce DNA damage, such as soy <a href="http://en.wikipedia.org/wiki/Isoflavones" title="Isoflavones" >isoflavones</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-36" >[36]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-37" >[37]</a> and bilberry anthocyanins.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-38" >[38]</a>

Epigenetic research uses a wide range of molecular biologic techniques to further our understanding of epigenetic phenomena, including <a href="http://en.wikipedia.org/wiki/Chromatin_immunoprecipitation" title="Chromatin immunoprecipitation" >chromatin immunoprecipitation</a> (together with its large-scale variants <a href="http://en.wikipedia.org/wiki/ChIP-on-chip" title="ChIP-on-chip" >ChIP-on-chip</a> and <a href="http://en.wikipedia.org/wiki/ChIP-Seq" title="ChIP-Seq" class="mw-redirect" >ChIP-Seq</a>), <a href="http://en.wikipedia.org/wiki/Fluorescent_in_situ_hybridization" title="Fluorescent in situ hybridization" class="mw-redirect" >fluorescent in situ hybridization</a>, methylation-sensitive <a href="http://en.wikipedia.org/wiki/Restriction_enzymes" title="Restriction enzymes" class="mw-redirect" >restriction enzymes</a>, DNA adenine methyltransferase identification (<a href="http://en.wikipedia.org/wiki/DamID" title="DamID" >DamID</a>) and <a href="http://en.wikipedia.org/wiki/Bisulfite_sequencing" title="Bisulfite sequencing" >bisulfite sequencing</a>. Furthermore, the use of <a href="http://en.wikipedia.org/wiki/Bioinformatic" title="Bioinformatic" class="mw-redirect" >bioinformatic</a> methods is playing an increasing role (<a href="http://en.wikipedia.org/wiki/Computational_epigenetics" title="Computational epigenetics" >computational epigenetics</a>).

Computer simulations and molecular dynamics approaches revealed the atomistic motions associated with the molecular recognition of the histone tail through an allosteric mechanism.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid22802671-39" >[39]</a>

<h2 >Mechanisms[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=4" title="Edit section: Mechanisms" >edit</a>]</h2>

Several types of epigenetic inheritance systems may play a role in what has become known as cell memory,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-jablonka92-40" >[40]</a> note however that not all of these are universally accepted to be examples of epigenetics.

<h3 >DNA methylation and chromatin remodeling[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=5" title="Edit section: DNA methylation and chromatin remodeling" >edit</a>]</h3>

Because DNA methylation and chromatin remodeling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid17407749-41" >[41]</a>

DNA associates with histone proteins to form chromatin.</div>

</div>

Because the <a href="http://en.wikipedia.org/wiki/Phenotype" title="Phenotype" >phenotype</a> of a cell or individual is affected by which of its genes are transcribed, heritable <a href="http://en.wikipedia.org/wiki/Transcription_(genetics)" title="Transcription (genetics)" >transcription states</a> can give rise to epigenetic effects. There are several layers of regulation of <a href="http://en.wikipedia.org/wiki/Gene_expression" title="Gene expression" >gene expression</a>. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the <a href="http://en.wikipedia.org/wiki/Histone" title="Histone" >histone</a>proteins with which it associates. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:

<ol >

<li >The first way is <a href="http://en.wikipedia.org/wiki/Post_translational_modification" title="Post translational modification" class="mw-redirect" >post translational modification</a> of the amino acids that make up histone proteins. Histone proteins are made up of long chains of amino acids. If the amino acids that are in the chain are changed, the shape of the histone might be modified. DNA is not completely unwound during replication. It is possible, then, that the modified histones may be carried into each new copy of the DNA. Once there, these histones may act as templates, initiating the surrounding new histones to be shaped in the new manner. By altering the shape of the histones around it, these modified histones would ensure that a lineage-specific transcription program is maintained after cell division.</li>

<li >The second way is the addition of methyl groups to the DNA, mostly at <a href="http://en.wikipedia.org/wiki/CpG_site" title="CpG site" >CpG sites</a>, to convert <a href="http://en.wikipedia.org/wiki/Cytosine" title="Cytosine" >cytosine</a> to <a href="http://en.wikipedia.org/wiki/5-methylcytosine" title="5-methylcytosine" class="mw-redirect" >5-methylcytosine</a>. 5-Methylcytosine performs much like a regular cytosine, pairing with a guanine in double-standed DNA. However, some areas of the genome are methylated more heavily than others, and highly methylated areas tend to be less transcriptionally active, through a mechanism not fully understood. Methylation of cytosines can also persist from the germ line of one of the parents into the zygote, marking the chromosome as being inherited from one parent or the other (<a href="http://en.wikipedia.org/wiki/Genetic_imprinting" title="Genetic imprinting" class="mw-redirect" >genetic imprinting</a>).</li>

</ol>

Mechanisms of heritability of histone state are not well understood, however much is known about the mechanism of heritability of DNA methylation state during cell division and differentiation. Heritability of methylation state depends on certain enzymes (such as <a href="http://en.wikipedia.org/wiki/DNA_methyltransferase" title="DNA methyltransferase" >DNMT1</a>) that have a higher affinity for 5-methylcytosine than for cytosine. If this enzyme reaches a "hemimethylated" portion of DNA (where 5-methylcytosine is in only one of the two DNA strands) the enzyme will methylate the other half.

Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include <a href="http://en.wikipedia.org/wiki/Acetylation" title="Acetylation" >acetylation</a>,<a href="http://en.wikipedia.org/wiki/Methylation" title="Methylation" >methylation</a>, <a href="http://en.wikipedia.org/wiki/Ubiquitylation" title="Ubiquitylation" class="mw-redirect" >ubiquitylation</a>, <a href="http://en.wikipedia.org/wiki/Phosphorylation" title="Phosphorylation" >phosphorylation</a>, <a href="http://en.wikipedia.org/wiki/Sumoylation" title="Sumoylation" class="mw-redirect" >sumoylation</a>, ribosylation and citrullination. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 <a href="http://en.wikipedia.org/wiki/Lysine" title="Lysine" >lysines</a> of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally related to transcriptional competence.

One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. When this occurs, complexes like <a href="http://en.wikipedia.org/wiki/SWI/SNF" title="SWI/SNF" >SWI/SNF</a> and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of epigenetic function. In other words, changes to the histone tails have a direct effect on the DNA itself.

Another model of epigenetic function is the "trans" model. In this model changes to the histone tails act indirectly on the DNA. For example, lysine acetylation may create a binding site for chromatin modifying enzymes (or transcription machinery as well). This chromatin remodeler can then cause changes to the state of the chromatin. Indeed, a bromodomain — a protein domain that specifically binds acetyl-lysine — is found in many enzymes that help activate transcription, including the <a href="http://en.wikipedia.org/wiki/SWI/SNF" title="SWI/SNF" >SWI/SNF</a> complex. It may be that acetylation acts in this and the previous way to aid in transcriptional activation.

The idea that modifications act as docking modules for related factors is borne out by <a href="http://en.wikipedia.org/wiki/Histone_methylation" title="Histone methylation" >histone methylation</a> as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive <a href="http://en.wikipedia.org/wiki/Heterochromatin" title="Heterochromatin" >heterochromatin</a>). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein <a href="http://en.wikipedia.org/wiki/Heterochromatin_Protein_1" title="Heterochromatin Protein 1" class="mw-redirect" >HP1</a>recruits HP1 to K9 methylated regions. One example that seems to refute this biophysical model for methylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.

It has been shown that the histone lysine methyltransferase (KMT) is responsible for this methylation activity in the pattern of histones H3 & H4. This enzyme utilizes a catalytically active site called the SET domain (Suppressor of variegation, Enhancer of zeste, Trithorax). The SET domain is a 130-amino acid sequence involved in modulating gene activities. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid9487389-42" >[42]</a>

Differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently from acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the <a href="http://en.wikipedia.org/wiki/Histone_code" title="Histone code" >histone code</a>, although the idea that histone state can be read linearly as a digital information carrier has been largely debunked. One of the best-understood systems that orchestrates chromatin-based silencing is the <a href="http://en.wikipedia.org/wiki/SIR_protein" title="SIR protein" >SIR protein</a> based silencing of the yeast hidden mating type loci <a href="http://en.wikipedia.org/wiki/HML" title="HML" >HML</a> and <a href="http://en.wikipedia.org/wiki/HMR" title="HMR" >HMR</a>.

DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of '<a href="http://en.wikipedia.org/wiki/Transposable_elements" title="Transposable elements" class="mw-redirect" >transposable elements</a>':<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-slotkin2007-43" >[43]</a> Because <a href="http://en.wikipedia.org/wiki/5-methylcytosine" title="5-methylcytosine" class="mw-redirect" >5-methylcytosine</a> can be spontaneously deaminated (replacing nitrogen by oxygen) to <a href="http://en.wikipedia.org/wiki/Thymidine" title="Thymidine" >thymidine</a>, CpG sites are frequently mutated and become rare in the genome, except at <a href="http://en.wikipedia.org/wiki/CpG_islands" title="CpG islands" class="mw-redirect" >CpG islands</a> where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. <a href="http://en.wikipedia.org/wiki/DNA_methylation" title="DNA methylation" >DNA methylation</a> patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent <a href="http://en.wikipedia.org/wiki/DNA_methyltransferase" title="DNA methyltransferase" >DNA methyltransferases</a>, DNMT1, DNMT3A, and DNMT3B, the loss of any of which is lethal in mice.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-li92-44" >[44]</a> DNMT1 is the most abundant methyltransferase in somatic cells,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-robertson99-45" >[45]</a> localizes to replication foci,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-leonhardt92-46" >[46]</a> has a 10–40-fold preference for hemimethylated DNA and interacts with the <a href="http://en.wikipedia.org/wiki/Proliferating_cell_nuclear_antigen" title="Proliferating cell nuclear antigen" >proliferating cell nuclear antigen</a> (PCNA).<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-chuang97-47" >[47]</a>

By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after <a href="http://en.wikipedia.org/wiki/DNA_replication" title="DNA replication" >DNA replication</a>, and therefore is often referred to as the ‘maintenance' methyltransferase.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-robertson00-48" >[48]</a> DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-li92-44" >[44]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-li93-49" >[49]</a> To emphasize the difference of this molecular mechanism of inheritance from the canonical Watson-Crick base-pairing mechanism of transmission of genetic information, the term 'Epigenetic templating' was introduced.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-50" >[50]</a> Furthermore, in addition to the maintenance and transmission of methylated DNA states, the same principle could work in the maintenance and transmission of histone modifications and even cytoplasmic (<a href="http://en.wikipedia.org/wiki/Structural_inheritance" title="Structural inheritance" >structural</a>) heritable states.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-51" >[51]</a>

Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identified enzyme has a catalytically active site called the Jumonji domain (JmjC). The demethylation occurs when JmjC utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. JmjC is capable of demethylating mono-, di-, and tri-methylated substrates.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid19234061-52" >[52]</a>

Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative<a href="http://en.wikipedia.org/wiki/Covalent_modification" title="Covalent modification" class="mw-redirect" >covalent modifications</a> of histones.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Rosenfeld_2009-53" >[53]</a> The stability and heritability of states of larger chromosomal regions are suggested to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-54" >[54]</a> A simplified stochastic model for this type of epigenetics is found here.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-55" >[55]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid17512413-56" >[56]</a>

It has been suggested that chromatin-based transcriptional regulation could be mediated by the effect of small RNAs. <a href="http://en.wikipedia.org/wiki/Small_interfering_RNA" title="Small interfering RNA" >Small interfering RNAs</a> can modulate transcriptional gene expression via epigenetic modulation of targeted <a href="http://en.wikipedia.org/wiki/Promoter_(biology)" title="Promoter (biology)" class="mw-redirect" >promoters</a>.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Morris-57" >[57]</a>

<h3 >RNA transcripts and their encoded proteins[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=6" title="Edit section: RNA transcripts and their encoded proteins" >edit</a>]</h3>

Sometimes a gene, after being turned on, transcribes a product that (directly or indirectly) maintains the activity of that gene. For example, <a href="http://en.wikipedia.org/wiki/Hnf4" title="Hnf4" class="mw-redirect" >Hnf4</a> and <a href="http://en.wikipedia.org/wiki/MyoD" title="MyoD" >MyoD</a> enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the <a href="http://en.wikipedia.org/wiki/Transcription_factor" title="Transcription factor" >transcription factor</a> activity of the <a href="http://en.wikipedia.org/wiki/Proteins" title="Proteins" class="mw-redirect" >proteins</a> they encode. RNA signalling includes differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid19154003-58" >[58]</a> Other epigenetic changes are mediated by the production of <a href="http://en.wikipedia.org/wiki/Alternative_splicing" title="Alternative splicing" >different splice forms</a> of <a href="http://en.wikipedia.org/wiki/RNA" title="RNA" >RNA</a>, or by formation of double-stranded RNA (<a href="http://en.wikipedia.org/wiki/RNAi" title="RNAi" class="mw-redirect" >RNAi</a>). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are often turned on or off by <a href="http://en.wikipedia.org/wiki/Signal_transduction" title="Signal transduction" >signal transduction</a>, although in some systems where <a href="http://en.wikipedia.org/wiki/Syncytia" title="Syncytia" class="mw-redirect" >syncytia</a> or <a href="http://en.wikipedia.org/wiki/Gap_junctions" title="Gap junctions" class="mw-redirect" >gap junctions</a> are important, RNA may spread directly to other cells or nuclei by<a href="http://en.wikipedia.org/wiki/Diffusion" title="Diffusion" >diffusion</a>. A large amount of RNA and protein is contributed to the <a href="http://en.wikipedia.org/wiki/Zygote" title="Zygote" >zygote</a> by the mother during <a href="http://en.wikipedia.org/wiki/Oogenesis" title="Oogenesis" >oogenesis</a> or via <a href="http://en.wikipedia.org/wiki/Nurse_cell" title="Nurse cell" >nurse cells</a>, resulting in <a href="http://en.wikipedia.org/wiki/Maternal_effect" title="Maternal effect" >maternal effect</a> phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-choi06-59" >[59]</a>

<h3 >MicroRNAs[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=7" title="Edit section: MicroRNAs" >edit</a>]</h3>

<a href="http://en.wikipedia.org/wiki/MicroRNA" title="MicroRNA" >MicroRNAs</a> (miRNAs) are members of <a href="http://en.wikipedia.org/wiki/Non-coding_RNA" title="Non-coding RNA" >non-coding RNAs</a> that range in size from 17 to 25 nucleotides. As indicated by Wang et al.,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Wang-60" >[60]</a> miRNAs regulate a large variety of biological functions in plants and animals. So far, in 2013, about 2000 miRNAs have been discovered in humans and these can be found online in an miRNA database.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-61" >[61]</a> Each miRNA expressed in a cell may target about 100 to 200 messenger RNAs that it downregulates.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-62" >[62]</a> Most of the downregulation of mRNAs occurs by causing the decay of the targeted mRNA, while some downregulation occurs at the level of translation into protein.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-63" >[63]</a>

It appears that about 60% of human protein coding genes are regulated by miRNAs.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-64" >[64]</a> Many miRNAs are epigenetically regulated. About 50% of miRNA genes are associated with <a href="http://en.wikipedia.org/wiki/CpG_island" title="CpG island" class="mw-redirect" >CpG islands</a>,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Wang-60" >[60]</a> that may be repressed by epigenetic methylation. Transcription from methylated CpG islands is strongly and heritably repressed.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-65" >[65]</a> Other miRNAs are epigenetically regulated by either histone modifications or by combined DNA methylation and histone modification.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Wang-60" >[60]</a>

<h3 >sRNAs[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=8" title="Edit section: sRNAs" >edit</a>]</h3>

<a href="http://en.wikipedia.org/wiki/Bacterial_small_RNA" title="Bacterial small RNA" >sRNAs</a> are small (50-250 nucleotides), highly-structured, non-coding RNA fragments found in bacteria. They control gene expression including <a href="http://en.wikipedia.org/wiki/Virulence" title="Virulence" >virulence</a> genes in pathogens and are viewed as new targets in the fight against drug-resistant bacteria.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-66" >[66]</a> They play an important role in many biological processes, binding to mRNA and protein targets in prokaryotes. Their phylogenetic analyses, for example through sRNA–mRNA target interactions or protein <a href="http://en.wikipedia.org/wiki/Hfq_binding_sRNA" title="Hfq binding sRNA" >binding properties</a>, are used to build comprehensive databases.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-67" >[67]</a> sRNA-<a href="http://en.wikipedia.org/wiki/Gene_map" title="Gene map" >gene maps</a> based on their targets in microbial genomes are also constructed.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-68" >[68]</a>

<h3 >Prions[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=9" title="Edit section: Prions" >edit</a>]</h3>

<div class="hatnote boilerplate seealso" >For more details on this topic, see <a href="http://en.wikipedia.org/wiki/Fungal_prions" title="Fungal prions" class="mw-redirect" >Fungal prions</a>.</div>

<a href="http://en.wikipedia.org/wiki/Prion" title="Prion" >Prions</a> are <a href="http://en.wikipedia.org/wiki/Infection" title="Infection" >infectious</a> forms of <a href="http://en.wikipedia.org/wiki/Protein" title="Protein" >proteins</a>. In general, proteins fold into discrete units that perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of <a href="http://en.wikipedia.org/wiki/Transmissible_spongiform_encephalopathy" title="Transmissible spongiform encephalopathy" >infectious disease</a>, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-69" >[69]</a>

<a href="http://en.wikipedia.org/wiki/Fungal_prion" title="Fungal prion" >Fungal prions</a> are considered by some to be epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. <a href="http://en.wikipedia.org/wiki/PSI_(prion)" title="PSI (prion)" class="mw-redirect" >PSI+</a> and URE3, discovered in <a href="http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae" title="Saccharomyces cerevisiae" >yeast</a> in 1965 and 1971, are the two best studied of this type of prion.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-70" >[70]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid5573734-71" >[71]</a> Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop <a href="http://en.wikipedia.org/wiki/Codon" title="Codon" class="mw-redirect" >codons</a>, an effect that results in suppression of <a href="http://en.wikipedia.org/wiki/Nonsense_mutation" title="Nonsense mutation" >nonsense mutations</a> in other genes.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid225301-72" >[72]</a> The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to <a href="http://en.wikipedia.org/wiki/Evolutionary_capacitance" title="Evolutionary capacitance" >switch into a PSI+ state</a> and express dormant genetic features normally terminated by stop codon mutations.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid11028992-73" >[73]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid15931169-74" >[74]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-75" >[75]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-76" >[76]</a>

<h3 >Structural inheritance systems[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=10" title="Edit section: Structural inheritance systems" >edit</a>]</h3>

<div class="hatnote boilerplate seealso" >For more details on this topic, see <a href="http://en.wikipedia.org/wiki/Structural_inheritance" title="Structural inheritance" >Structural inheritance</a>.</div>

In <a href="http://en.wikipedia.org/wiki/Ciliate" title="Ciliate" >ciliates</a> such as <a href="http://en.wikipedia.org/wiki/Tetrahymena" title="Tetrahymena" >Tetrahymena</a> and <a href="http://en.wikipedia.org/wiki/Paramecium" title="Paramecium" >Paramecium</a>, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid1804215-77" >[77]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-isbn0-19-515619-6-78" >[78]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-isbn0-262-65063-0-79" >[79]</a>

<h2 >Functions and consequences[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=11" title="Edit section: Functions and consequences" >edit</a>]</h2>

<h3 >Development[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=12" title="Edit section: Development" >edit</a>]</h3>

Somatic epigenetic inheritance through <a href="http://en.wikipedia.org/wiki/Epigenetic_modifications" title="Epigenetic modifications" class="mw-redirect" >epigenetic modifications</a>, particularly through DNA methylation and chromatin remodeling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate into many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, <a href="http://en.wikipedia.org/wiki/Morphogen" title="Morphogen" >morphogens</a> activate or silence genes in an epigenetically heritable fashion, giving cells a "memory". In mammals, most cells terminally differentiate, with only <a href="http://en.wikipedia.org/wiki/Stem_cells" title="Stem cells" class="mw-redirect" >stem cells</a> retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In <a href="http://en.wikipedia.org/wiki/Mammal" title="Mammal" >mammals</a>, some stem cells continue producing new differentiated cells throughout life, such as in<a href="http://en.wikipedia.org/wiki/Epigenetic_Regulation_of_Neurogenesis" title="Epigenetic Regulation of Neurogenesis" class="mw-redirect" >neurogenesis</a>, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as <a href="http://en.wikipedia.org/wiki/Chromatin_remodeling" title="Chromatin remodeling" >chromatin remodeling</a>, it has been hypothesised that some kinds of plant cells do not use or require "cellular memories", resetting their gene expression patterns using positional information from the environment and surrounding cells to determine their fate.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid17194589-80" >[80]</a>

Epigenetics can be divided into predetermined and probabilistic epigenesis. Predetermined epigenesis is a unidirectional movement from structural development in DNA to the functional maturation of the protein. "Predetermined" here means that development is scripted and predictable. Probabilistic epigenesis on the other hand is a bidirectional structure-function development with experiences and external molding development.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Griesemer_2005-81" >[81]</a>

<h3 >Medicine[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=13" title="Edit section: Medicine" >edit</a>]</h3>

Epigenetics has many and varied potential medical applications as it tends to be multidimensional in nature.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid21447282-82" >[82]</a> Congenital genetic disease is well understood, and it is also clear that epigenetics can play a role, for example, in the case of <a href="http://en.wikipedia.org/wiki/Angelman_syndrome" title="Angelman syndrome" >Angelman syndrome</a> and <a href="http://en.wikipedia.org/wiki/Prader-Willi_syndrome" title="Prader-Willi syndrome" class="mw-redirect" >Prader-Willi syndrome</a>. These are normal genetic diseases caused by gene deletions or inactivation of the genes, but are unusually common because individuals are essentially <a href="http://en.wikipedia.org/wiki/Hemizygous" title="Hemizygous" class="mw-redirect" >hemizygous</a> because of <a href="http://en.wikipedia.org/wiki/Genomic_imprinting" title="Genomic imprinting" >genomic imprinting</a>, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-83" >[83]</a>

<h3 >Evolution[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=14" title="Edit section: Evolution" >edit</a>]</h3>

Epigenetics can impact evolution when epigenetic changes are heritable. A sequestered germ line or <a href="http://en.wikipedia.org/wiki/Weismann_barrier" title="Weismann barrier" >Weismann barrier</a> is specific to animals, and epigenetic inheritance is more common in plants and microbes. <a href="http://en.wikipedia.org/wiki/Eva_Jablonka" title="Eva Jablonka" >Eva Jablonka</a> and <a href="http://en.wikipedia.org/wiki/Marion_Lamb" title="Marion Lamb" class="mw-redirect" >Marion Lamb</a> have argued that these effects may require enhancements to the standard conceptual framework of the <a href="http://en.wikipedia.org/wiki/Modern_evolutionary_synthesis" title="Modern evolutionary synthesis" >modern evolutionary synthesis</a>.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-isbn0-262-10107-6-84" >[84]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-85" >[85]</a> Other evolutionary biologists have incorporated epigenetic inheritance into <a href="http://en.wikipedia.org/wiki/Population_genetics" title="Population genetics" >population genetics</a> models<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-86" >[86]</a> or are openly skeptical.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-87" >[87]</a>

Two important ways in which epigenetic inheritance can be different from traditional genetic inheritance, with important consequences for evolution, are that rates of epimutation can be much faster than rates of mutation<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-rando_and_verstrepen-88" >[88]</a> and the epimutations are more easily reversible.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-89" >[89]</a> An epigenetically inherited element such as the <a href="http://en.wikipedia.org/wiki/PSI_(prion)" title="PSI (prion)" class="mw-redirect" >PSI+</a> system can act as a "stop-gap", good enough for short-term adaptation that allows the lineage to survive for long enough for mutation and/or recombination to <a href="http://en.wikipedia.org/wiki/Genetic_assimilation" title="Genetic assimilation" >genetically assimilate</a> the adaptive phenotypic change.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-90" >[90]</a> The existence of this possibility increases the <a href="http://en.wikipedia.org/wiki/Evolvability" title="Evolvability" >evolvability</a> of a species.

<h3 >Current research findings and examples of effects[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=15" title="Edit section: Current research findings and examples of effects" >edit</a>]</h3>

Epigenetic changes have been observed to occur in response to environmental exposure—for example, mice given some dietary supplements have epigenetic changes affecting expression of the <a href="http://en.wikipedia.org/wiki/Agouti_gene" title="Agouti gene" >agouti gene</a>, which affects their fur color, weight, and propensity to develop cancer.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid12163699-91" >[91]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-waterland-92" >[92]</a>

One study indicates that traumatic experiences can produce fearful memories which are passed to future generations via epigenetics. A study carried out on mice in 2013 found that mice could produce offspring which had an aversion to certain items which had been the source of negative experiences for their ancestors.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-93" >[93]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-94" >[94]</a> Reports stated that:

For the study, author Brian Dias and co-author Kerry Ressler trained mice, using foot shocks, to fear an odour that resembles cherry blossoms. Later, they tested the extent to which the animals' offspring startled when exposed to the same smell. The younger generation had not even been conceived when their fathers underwent the training, and had never smelt the odour before the experiment.

The offspring of trained mice were "able to detect and respond to far less amounts of odour... suggesting they are more sensitive" to it, Ressler told AFP of the findings published in the journal Nature Neuroscience. They did not react the same way to other odours, and compared to the offspring of non-trained mice, their reaction to the cherry blossom whiff was about 200 percent stronger, he said.

The scientists then looked at a gene, M71, that governs the functioning of an odour receptor in the nose that responds specifically to the cherry blossom smell. The gene, inherited through the sperm of trained mice, had undergone no change to its DNA encoding, the team found. But the gene did carry epigenetic marks that could alter its behaviour and cause it to be "expressed more" in descendants, said Dias. This in turn caused a physical change in the brains of the trained mice, their sons and grandsons, who all had a larger glomerulus—a section in the olfactory (smell) unit of the brain.</blockquote>

In the case of humans with different environmental exposures, Fraga et al.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-95" >[95]</a> studied young monozygotic (identical) twins and older monozygotic twins. They found that although such twins were epigenetically indistinguishable during their early years, older twins had remarkable differences in the overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation. The twin pairs who had spent less of their lifetime together and/or had greater differences in their medical histories were those who showed the largest differences in their levels of 5methylcytosine DNA and acetylation of histones H3 and H4.

More than 100 cases of transgenerational epigenetic inheritance phenomena have been reported in a wide range of organisms, including prokaryotes, plants, and animals.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Jablonka09-96" >[96]</a> For instance, <a href="http://en.wikipedia.org/wiki/Nymphalis_antiopa" title="Nymphalis antiopa" >Mourning Cloak butterflies</a> will change color through hormone changes in response to experimentation of varying temperatures.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-97" >[97]</a>

Recent analyses have suggested that members of the APOBEC/AID family of cytosine deaminases are capable of simultaneously mediating genetic and epigenetic inheritance using similar molecular mechanisms.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid20800313-98" >[98]</a>

<h2 >Epigenetic effects in humans[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=16" title="Edit section: Epigenetic effects in humans" >edit</a>]</h2>

<h3 >Genomic imprinting and related disorders[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=17" title="Edit section: Genomic imprinting and related disorders" >edit</a>]</h3>

Some human disorders are associated with <a href="http://en.wikipedia.org/wiki/Genomic_imprinting" title="Genomic imprinting" >genomic imprinting</a>, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their <a href="http://en.wikipedia.org/wiki/Germ_cells" title="Germ cells" class="mw-redirect" >germ cells</a>.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid17121465-99" >[99]</a> The best-known case of imprinting in human disorders is that of <a href="http://en.wikipedia.org/wiki/Angelman_syndrome" title="Angelman syndrome" >Angelman syndrome</a> and <a href="http://en.wikipedia.org/wiki/Prader-Willi_syndrome" title="Prader-Willi syndrome" class="mw-redirect" >Prader-Willi syndrome</a>—both can be produced by the same genetic mutation, <a href="http://en.wikipedia.org/wiki/Chromosome_15q_partial_deletion" title="Chromosome 15q partial deletion" >chromosome 15q partial deletion</a>, and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid2564739-100" >[100]</a> This is due to the presence of genomic imprinting in the region. <a href="http://en.wikipedia.org/wiki/Beckwith-Wiedemann_syndrome" title="Beckwith-Wiedemann syndrome" class="mw-redirect" >Beckwith-Wiedemann syndrome</a> is also associated with genomic imprinting, often caused by abnormalities in maternal genomic imprinting of a region on chromosome 11.

<h3 >Transgenerational epigenetic observations[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=18" title="Edit section: Transgenerational epigenetic observations" >edit</a>]</h3>

See main article <a href="http://en.wikipedia.org/wiki/Transgenerational_epigenetics" title="Transgenerational epigenetics" >Transgenerational epigenetics</a>

In the <a href="http://en.wikipedia.org/wiki/%C3%96verkalix_study" title="Överkalix study" >Överkalix study</a>, Marcus Pembrey and colleagues observed that the paternal (but not maternal) grandsons<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-paternal-grandson-101" >[101]</a> of Swedish men who were exposed during preadolescence to famine in the 19th century were less likely to die of cardiovascular disease. If food was plentiful, then <a href="http://en.wikipedia.org/wiki/Diabetes" title="Diabetes" class="mw-redirect" >diabetes</a> mortality in the grandchildren increased, suggesting that this was a transgenerational epigenetic inheritance.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid16391557-102" >[102]</a>The opposite effect was observed for females—the paternal (but not maternal) granddaughters of women who experienced famine while in the womb (and therefore while their eggs were being formed) lived shorter lives on average.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-103" >[103]</a>

<h3 >Cancer and developmental abnormalities[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=19" title="Edit section: Cancer and developmental abnormalities" >edit</a>]</h3>

A variety of compounds are considered as epigenetic <a href="http://en.wikipedia.org/wiki/Carcinogens" title="Carcinogens" class="mw-redirect" >carcinogens</a>—they result in an increased incidence of tumors, but they do not show <a href="http://en.wikipedia.org/wiki/Mutagenic" title="Mutagenic" class="mw-redirect" >mutagen</a> activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include <a href="http://en.wikipedia.org/wiki/Diethylstilbestrol" title="Diethylstilbestrol" >diethylstilbestrol</a>, <a href="http://en.wikipedia.org/wiki/Arsenite" title="Arsenite" >arsenite</a>, <a href="http://en.wikipedia.org/wiki/Hexachlorobenzene" title="Hexachlorobenzene" >hexachlorobenzene</a>, and <a href="http://en.wikipedia.org/wiki/Nickel" title="Nickel" >nickel</a> compounds.

Many teratogens exert specific effects on the fetus by epigenetic mechanisms.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-bishop97-104" >[104]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-gurvich04-105" >[105]</a> While epigenetic effects may preserve the effect of a teratogen such as <a href="http://en.wikipedia.org/wiki/Diethylstilbestrol" title="Diethylstilbestrol" >diethylstilbestrol</a> throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-smithells98-106" >[106]</a> However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-friedler96-107" >[107]</a> FDA label information for Vidaza, a formulation of <a href="http://en.wikipedia.org/wiki/5-azacytidine" title="5-azacytidine" class="mw-redirect" >5-azacitidine</a> (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss, and abnormal embryo development.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-108" >[108]</a> In rats, endocrine differences were observed in offspring of males exposed to morphine.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-cicero91-109" >[109]</a> In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-newbold06-110" >[110]</a>

Recent studies have shown that the <a href="http://en.wikipedia.org/wiki/MLL_(gene)" title="MLL (gene)" >mixed-lineage leukemia</a> (MLL) gene causes <a href="http://en.wikipedia.org/wiki/Leukemia" title="Leukemia" >leukemia</a> by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid20236314-111" >[111]</a>

Other investigations have concluded that alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Li2005-112" >[112]</a> Gene expression in the prostate can be modulated by nutrition and lifestyle changes.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid18559852-113" >[113]</a>

In 2008, the National Institutes of Health announced that $190 million had been earmarked for epigenetics research over the next five years. In announcing the funding, government officials noted that epigenetics has the potential to explain mechanisms of aging, human development, and the origins of cancer, heart disease, mental illness, as well as several other conditions. Some investigators, like<a href="http://en.wikipedia.org/wiki/Randy_Jirtle" title="Randy Jirtle" >Randy Jirtle</a>, PhD, of Duke University Medical Center, think epigenetics may ultimately turn out to have a greater role in disease than genetics.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-114" >[114]</a>

<h4 >DNA methylation in cancer[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=20" title="Edit section: DNA methylation in cancer" >edit</a>]</h4>

<a href="http://en.wikipedia.org/wiki/DNA_methylation" title="DNA methylation" >DNA methylation</a> is an important regulator of gene transcription and a large body of evidence has demonstrated that aberrant DNA methylation is associated with unscheduled gene silencing, and the genes with high levels of 5-methylcytosine in their promoter region are transcriptionally silent. DNA methylation is essential during embryonic development, and in somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with a high fidelity. Aberrant DNA methylation patterns have been associated with a large number of human malignancies and found in two distinct forms: hypermethylation and hypomethylation compared to normal tissue. Hypermethylation is one of the major epigenetic modifications that repress transcription via promoter region of tumour suppressor genes. Hypermethylation typically occurs at CpG islands in the promoter region and is associated with gene inactivation. Global hypomethylation has also been implicated in the development and progression of cancer through different mechanisms.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-CraigJMWongNC-115" >[115]</a>

<h4 >DNA repair epigenetics in cancer[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=21" title="Edit section: DNA repair epigenetics in cancer" >edit</a>]</h4>

Germ line (familial) mutations have been identified in 34 different DNA repair genes that cause a high risk of cancer, including, for example <a href="http://en.wikipedia.org/wiki/BRCA1" title="BRCA1" >BRCA1</a> and <a href="http://en.wikipedia.org/wiki/Ataxia_telangiectasia_mutated" title="Ataxia telangiectasia mutated" >ATM</a>. These are listed in the article <a href="http://en.wikipedia.org/wiki/DNA_repair-deficiency_disorder" title="DNA repair-deficiency disorder" >DNA repair-deficiency disorder</a>. However, cancers caused by such germ line mutations make up only a very small proportion of cancers. For instance, germ line mutations cause only 2% to 5% of colon cancer cases.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-116" >[116]</a>

Epigenetic reductions in expression of DNA repair genes, however, are very frequent in sporadic (non-germ line) cancers, as shown among some representative cancers in the table in this section, while mutations in DNA repair genes in sporadic cancer are very rare.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-117" >[117]</a>

<caption >Epigenetic changes in DNA repair genes in sporadic cancers</caption>

<tbody>

<tr>

<th >Cancer</th>

<th >Epigenetic change</th>

<th >Frequency</th>

</tr>

<tr>

<th rowspan="2" >Breast</th>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<th rowspan="4" >Ovarian</th>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<td ><a href="http://en.wikipedia.org/wiki/Fanconi_anemia" title="Fanconi anemia" >FANCF</a></td>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<th rowspan="6" >Colorectal</th>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<td >epigenetic type unknown</td>

</tr>

<tr>

<td >epigenetic type unknown</td>

</tr>

<tr>

<th rowspan="6" >Head

and

neck</th>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<td ><a href="http://en.wikipedia.org/wiki/Fanconi_anemia" title="Fanconi anemia" >FANCB</a></td>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

<tr>

<td >CpG island methylation</td>

</tr>

</tbody></table>

References in the table are given here: 1,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-118" >[118]</a> 2,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-119" >[119]</a> 3,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-120" >[120]</a> 4,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-121" >[121]</a> 5,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-122" >[122]</a> 6,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-123" >[123]</a> 7,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-124" >[124]</a> 8,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-125" >[125]</a> 9,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-126" >[126]</a> 10,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-127" >[127]</a> 11,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-128" >[128]</a> 12,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-129" >[129]</a> 13,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-130" >[130]</a> 14,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-131" >[131]</a> 15,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-132" >[132]</a> 16,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-133" >[133]</a> 17,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-134" >[134]</a> 18,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-135" >[135]</a> 19,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-136" >[136]</a> 20<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-137" >[137]</a>

Deficiencies in expression of DNA repair genes cause increased mutation rates. Mutations rates increase in mice defective for mismatch DNA repair genes <a href="http://en.wikipedia.org/wiki/PMS2" title="PMS2" >PMS2</a>, <a href="http://en.wikipedia.org/wiki/MLH1" title="MLH1" >MLH1</a>, <a href="http://en.wikipedia.org/wiki/MSH2" title="MSH2" >MSH2</a>, <a href="http://en.wikipedia.org/wiki/MSH3" title="MSH3" >MSH3</a> or <a href="http://en.wikipedia.org/wiki/MSH6" title="MSH6" >MSH6</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-138" >[138]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-139" >[139]</a> or for DNA repair gene <a href="http://en.wikipedia.org/wiki/BRCA2" title="BRCA2" >BRCA2</a>,<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-140" >[140]</a> while chromosomal rearrangements and aneuploidy are noted to increase in humans defective in DNA repair gene <a href="http://en.wikipedia.org/wiki/Bloom_syndrome_protein" title="Bloom syndrome protein" >BLM</a>.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-141" >[141]</a> Thus, deficiency in DNA repair causes<a href="http://en.wikipedia.org/wiki/Genome_instability" title="Genome instability" >genome instability</a> and this <a href="http://en.wikipedia.org/wiki/Genome_instability" title="Genome instability" >genome instability</a> is likely the main underlying cause of the genetic alterations leading to cancer. In fact, as indicated by Nowak et al.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-142" >[142]</a> through a mathematical calculation, the first event in many sporadic neoplasias is a heritable alteration that affects genetic instability, and we note that epigenetic defects in DNA repair are somatically heritable.

<h4 >Variant histones H2A in cancer[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=22" title="Edit section: Variant histones H2A in cancer" >edit</a>]</h4>

The <a href="http://en.wikipedia.org/wiki/Histone" title="Histone" >histone</a> variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering <a href="http://en.wikipedia.org/wiki/Chromatin" title="Chromatin" >chromatin</a> structure. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. Another variant, H2A.Z, plays an important role in both gene activation and repression. A high level of H2A.Z expression is ubiquitously detected in many cancers and is significantly associated with cellular proliferation and genomic instability.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-CraigJMWongNC-115" >[115]</a> Histone variant macroH2A1 is important in the pathogenesis of many types of cancers, for instance in hepatocellular carcinoma.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-143" >[143]</a>

<h4 >Cancer treatment[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=23" title="Edit section: Cancer treatment" >edit</a>]</h4>

Current research has shown that epigenetic pharmaceuticals could be a putative replacement or adjuvant therapy for currently accepted treatment methods such as <a href="http://en.wikipedia.org/wiki/Radiation_therapy" title="Radiation therapy" >radiation</a> and <a href="http://en.wikipedia.org/wiki/Chemotherapy" title="Chemotherapy" >chemotherapy</a>, or could enhance the effects of these current treatments.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid20664922-144" >[144]</a> It has been shown that the epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones directly affects the formation and progression of cancer.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-IglesiasLinares2010-145" >[145]</a> Epigenetics also has the factor of reversibility, a characteristic that other cancer treatments do not offer.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Li2005-112" >[112]</a>

Drug development has focused mainly on <a href="http://en.wikipedia.org/wiki/Histone_acetyltransferase" title="Histone acetyltransferase" >histone acetyltransferase</a> (HAT) and <a href="http://en.wikipedia.org/wiki/Histone_deacetylase" title="Histone deacetylase" >histone deacetylase</a> (HDAC), and has included the introduction to the market of the new pharmaceutical <a href="http://en.wikipedia.org/wiki/Vorinostat" title="Vorinostat" >vorinostat</a>, an HDAC inhibitor.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid18773966-146" >[146]</a> HDAC has been shown to play an integral role in the progression of oral squamous cancer.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-IglesiasLinares2010-145" >[145]</a>

Current front-runner candidates for new drug targets are <a href="http://en.wikipedia.org/wiki/Histone_methyltransferase" title="Histone methyltransferase" >histone lysine methyltransferases</a> (KMT) and protein arginine methyltransferases (PRMT).<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid20219369-147" >[147]</a>

<h3 >Twin studies[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=24" title="Edit section: Twin studies" >edit</a>]</h3>

Recent studies involving both dizygotic and monozygotic twins have produced some evidence of epigenetic influence in humans.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-148" >[148]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid19151718-149" >[149]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid16009939-150" >[150]</a>

Direct comparisons between identical twins constitute the ideal experimental model for testing environmental epigenetics, because DNA sequence differences that would be abundant in a singleton-based study do not interfere with the analysis. Research has shown that a difference in the environment can produce long-term epigenetic effects, and different developmental monozygotic twin subtypes may be different with respect to their susceptibility to be discordant from an epigenetic point of view.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-151" >[151]</a>

One of the first high-throughput studies of epigenetic differences between monozygotic twins focused in comparing global and locus-specific changes in DNA methylation and histone modifications in a sample of 40 monozygotic twin pairs.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-152" >[152]</a> In this case, only healthy twin pairs were studied, but a wide range of ages was represented, between 3 and 74 years. One of the major conclusions from this study was that there is an age-dependent accumulation of epigenetic differences between the two siblings of twin pairs. This accumulation suggests the existence of epigenetic “drift”.

A more recent study, where 114 monozygotic twins and 80 dizygotic twins were analyzed for the DNA methylation status of around 6000 unique genomic regions, concluded that epigenetic similarity at the time of blastocyst splitting may also contribute to phenotypic similarities in monozygotic co-twins. This supports the notion that microenvironment at early stages of embryonic development can be quite important for the establishment of epigenetic marks.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-153" >[153]</a>

<h2 >Epigenetics in microorganisms[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=25" title="Edit section: Epigenetics in microorganisms" >edit</a>]</h2>

Escherichia coli bacteria</div>

</div>

Bacteria make widespread use of postreplicative DNA methylation for the epigenetic control of DNA-protein interactions. Bacteria make use of DNA <a href="http://en.wikipedia.org/wiki/Adenine" title="Adenine" >adenine</a> methylation (rather than DNA <a href="http://en.wikipedia.org/wiki/Cytosine" title="Cytosine" >cytosine</a> methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as <a href="http://en.wikipedia.org/wiki/Escherichia_coli" title="Escherichia coli" >Escherichia coli</a>, <a href="http://en.wikipedia.org/wiki/Salmonella" title="Salmonella" >Salmonella</a>, <a href="http://en.wikipedia.org/wiki/Vibrio" title="Vibrio" >Vibrio</a>, <a href="http://en.wikipedia.org/wiki/Yersinia" title="Yersinia" >Yersinia</a>,<a href="http://en.wikipedia.org/wiki/Haemophilus" title="Haemophilus" >Haemophilus</a>, and <a href="http://en.wikipedia.org/wiki/Brucella" title="Brucella" >Brucella</a>. In <a href="http://en.wikipedia.org/wiki/Alphaproteobacteria" title="Alphaproteobacteria" >Alphaproteobacteria</a>, methylation of adenine regulates the cell cycle and couples gene transcription to DNA replication. In <a href="http://en.wikipedia.org/wiki/Gammaproteobacteria" title="Gammaproteobacteria" >Gammaproteobacteria</a>, adenine methylation provides signals for DNA replication, chromosome segregation, mismatch repair, packaging of bacteriophage, transposase activity and regulation of gene expression.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-Casadesus-154" >[154]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-JorgTost-155" >[155]</a>

The filamentous fungus Neurospora crassa is a prominent model system for understanding the control and function of cytosine methylation. In this organisms, DNA methylation is associated with relics of a genome defense system called RIP (repeat-induced point mutation) and silences gene expression by inhibiting transcription elongation.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-pmid19092133-156" >[156]</a>

The <a href="http://en.wikipedia.org/wiki/Yeast" title="Yeast" >yeast</a> <a href="http://en.wikipedia.org/wiki/Prion" title="Prion" >prion</a> PSI is generated by a conformational change of a translation termination factor, which is then inherited by daughter cells. This can provide a survival advantage under adverse conditions. This is an example of epigenetic regulation enabling unicellular organisms to respond rapidly to environmental stress. Prions can be viewed as epigenetic agents capable of inducing a phenotypic change without modification of the genome.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-JorgTost-155" >[155]</a>

Direct detection of epigenetic marks in microorganisms is possible with <a href="http://en.wikipedia.org/wiki/Single_molecule_real_time_sequencing" title="Single molecule real time sequencing" >single molecule real time sequencing</a>, in which polymerase sensitivity allows for measuring methylation and other modifications as a DNA molecule is being sequenced.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-157" >[157]</a> Several projects have demonstrated the ability to collect genome-wide epigenetic data in bacteria.<a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-158" >[158]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-159" >[159]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-160" >[160]</a><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_note-161" >[161]</a>

<ul >

<li ><a href="http://en.wikipedia.org/wiki/B_chromosome" title="B chromosome" >B chromosome</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Baldwin_effect" title="Baldwin effect" >Baldwin effect</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Behavioral_epigenetics" title="Behavioral epigenetics" >Behavioral epigenetics</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Centromere" title="Centromere" >Centromere</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Computational_epigenetics" title="Computational epigenetics" >Computational epigenetics</a></li>

<li ><a href="http://en.wikipedia.org/wiki/DNA_demethylation" title="DNA demethylation" >DNA demethylation</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Dutch_famine_of_1944#Legacy" title="Dutch famine of 1944" >Dutch famine of 1944 (Legacy)</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Biological_clock_(aging)" title="Biological clock (aging)" >Epigenetic clock</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Ecotype" title="Ecotype" >Ecotype</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Emergenesis" title="Emergenesis" >Emergenesis</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Epigenomics" title="Epigenomics" >Epigenomics</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Evolutionary_capacitance" title="Evolutionary capacitance" >Evolutionary capacitance</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Evolutionary_developmental_psychology" title="Evolutionary developmental psychology" >Evolutionary developmental psychology</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Extranuclear_inheritance" title="Extranuclear inheritance" >Extranuclear inheritance</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Histone_code" title="Histone code" >Histone code</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Hologenome_theory_of_evolution" title="Hologenome theory of evolution" >Hologenome theory of evolution</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Human_genome" title="Human genome" >Human genome</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Molecular_biology" title="Molecular biology" >Molecular biology</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Molecular_epidemiology" title="Molecular epidemiology" >Molecular epidemiology</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Molecular_pathological_epidemiology" title="Molecular pathological epidemiology" >Molecular pathological epidemiology</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Molecular_pathology" title="Molecular pathology" >Molecular pathology</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Nutriepigenomics" title="Nutriepigenomics" >Nutriepigenomics</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Position-effect_variegation" title="Position-effect variegation" >Position-effect variegation</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Preformationism" title="Preformationism" >Preformationism</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Somatic_epitype" title="Somatic epitype" >Somatic epitype</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Synthetic_genetic_array" title="Synthetic genetic array" >Synthetic genetic array</a></li>

<li ><a href="http://en.wikipedia.org/wiki/Weismann_barrier" title="Weismann barrier" >Weismann barrier</a></li>

</ul>

</div>

<h2 >Notes and references[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=27" title="Edit section: Notes and references" >edit</a>]</h2>

<li id="cite_note-1" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-1" >Jump up^{</a> Spector}, Tim (2012). Identically Different: Why You Can Change Your Genes. London: <a href="http://en.wikipedia.org/wiki/Weidenfeld_%26_Nicolson" title="Weidenfeld & Nicolson" >Weidenfeld & Nicolson</a>. p. 8. "Just over ten years ago researchers found that the diets of pregnant mothers could alter the behaviour of genes in their children and that these changes could last a lifetime and then be passed on in turn to their children. The genes were literally being switched on or off by a new mechanism we call epigenetics – meaning in Greek 'around the gene'. Contrary to traditional genetic dogma, these changes could be transferred to the next generation. In this case the mothers just happened to be rats, but recent similar findings in humans have created a revolution in our thinking."</li>

<li id="cite_note-pmid17522671-2" >^ <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid17522671_2-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid17522671_2-1" >b</a> Bird A (May 2007). "Perceptions of epigenetics". <a href="http://en.wikipedia.org/wiki/Nature_(journal)" title="Nature (journal)" >Nature</a> 447 (7143): 396–8.<a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2007Natur.447..396B" >2007Natur.447..396B</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fnature05913" >10.1038/nature05913</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17522671" >17522671</a>.</li>

<li id="cite_note-3" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-3" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://web.archive.org/web/20080501094940/http://www.prospect-magazine.co.uk/article_details.php?id=10140" >"Special report: 'What genes remember' by Philip Hunter | Prospect Magazine May 2008 issue 146"</a>. Web.archive.org. 1 May 2008. Retrieved 26 July 2012.</li>

<li id="cite_note-nature2008-4" >^ <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-nature2008_4-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-nature2008_4-1" >b</a> Ledford H. (2008). "Disputed definitions". Nature 455 (7216): 1023–8. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2F4551023a" >10.1038/4551023a</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18948925" >18948925</a>.</li>

<li id="cite_note-pmid17522676-5" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid17522676_5-0" >Jump up^{</a>&nbsp};Reik W (May 2007). "Stability and flexibility of epigenetic gene regulation in mammalian development".Nature 447 (7143): 425–32. <a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2007Natur.447..425R" >2007Natur.447..425R</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fnature05918" >10.1038/nature05918</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17522676" >17522676</a>.</li>

<li id="cite_note-6" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-6" >Jump up^{</a>&nbsp};Guifang Jia; Ye Fu; Xu Zhao; Qing Dai; Guanqun Zheng; Ying Yang; Chengqi Yi; Lindahl, Tomas; Tao Pan; Yun-Gui Yang; Chuan He (16 October 2011). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218240" >"N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO"</a>. <a href="http://en.wikipedia.org/wiki/Nature_Chemical_Biology" title="Nature Chemical Biology" >Nature Chemical Biology</a> 7 (12): 885–887. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fnchembio.687" >10.1038/nchembio.687</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218240" >3218240</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/22002720" >22002720</a>.</li>

<li id="cite_note-7" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-7" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.physorg.com/news/2011-10-links-common-rna-modification-obesity.html" >"New research links common RNA modification to obesity"</a>. Physorg.com. Retrieved 26 July 2012.</li>

<li id="cite_note-waddington-8" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-waddington_8-0" >Jump up^{</a>&nbsp};Waddington CH (1942). "The epigenotype". Endeavour 1: 18–20.</li>

<li id="cite_note-OED1-9" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-OED1_9-0" >Jump up^{</a>&nbsp};According to the <a href="http://en.wikipedia.org/wiki/Oxford_English_Dictionary" title="Oxford English Dictionary" >Oxford English Dictionary</a>:

The word is used by W. Harvey, Exercitationes 1651, p. 148, and in the English Anatomical Exercitations 1653, p. 272. It is explained to mean ‘partium super-exorientium additamentum’, ‘the additament of parts budding one out of another’.

</blockquote>

It is also worth quoting this adumbration of the definition given there (viz., "The formation of an organic germ as a new product"):

theory of epigenesis: the theory that the germ is brought into existence (by successive accretions), and not merely developed, in the process of reproduction. [...] The opposite theory was formerly known as the ‘theory of evolution’; to avoid the ambiguity of this name, it is now spoken of chiefly as the ‘theory of preformation’, sometimes as that of ‘encasement’ or ‘emboîtement’.

</blockquote>

</li>

<li id="cite_note-10" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-10" >Jump up^{</a> Waddington}, Conrad H. 1953. The Epigenetics of birds. Cambridge University Press</li>

<li id="cite_note-11" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-11" >Jump up^{</a> }<a rel="nofollow" class="external autonumber" href="http://www.ncbi.nlm.nih.gov/pubmed/14760651" >[1]</a>[url=<a rel="nofollow" class="external free" href="http://dx.doi.org/10.1002/jez.b.20002" >http://dx.doi.org/10.1002/jez.b.20002</a>] Hall BK. 2004. In search of evolutionary developmental mechanisms: the 30-year gap between 1944 and 1974. J Exp Zool B Mol Dev Evol. 15 January 2004;302(1):5-18.</li>

<li id="cite_note-12" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-12" >Jump up^{</a> }<a rel="nofollow" class="external autonumber" href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0003626" >[2]</a>[url=<a rel="nofollow" class="external free" href="http://dx.doi.org/10.1371/journal.pone.0003626" >http://dx.doi.org/10.1371/journal.pone.0003626</a>] Álvarez-Buylla ER, Chaos Á, Aldana M, Benítez M, Cortes-Poza Y, et al. 2008. Floral Morphogenesis: Stochastic Explorations of a Gene Network Epigenetic Landscape. PLoS ONE 3(11): e36265.</li>

<li id="cite_note-13" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-13" >Jump up^{</a> Gottlieb,G.}, (1991). Epigenetic systems view of human development. Developmental Psychology, 27(1), 33-34.</li>

<li id="cite_note-14" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-14" >Jump up^{</a>&nbsp};Gilbert Gottlieb. <a rel="nofollow" class="external text" href="http://chd.ucsd.edu/_files/winter2009/Gottlieb.probabilistic.pdf" >Probabilistic epigenesis</a>, Developmental Science 10:1 (2007), 1-11</li>

<li id="cite_note-Boeree1997-15" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Boeree1997_15-0" >Jump up^{</a> Boeree}, C. George, (1997/2006), <a rel="nofollow" class="external text" href="http://www.social-psychology.de/do/pt_erikson.pdf" >Personality Theories, Erik Erikson</a></li>

<li id="cite_note-16" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-16" >Jump up^{</a> Erikson}, Erik (1968). Identity: Youth and Crisis. Chapter 3: W.W. Norton and Company, Inc. p. 92.</li>

<li id="cite_note-17" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-17" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.bio-medicine.org/biology-definition/Epigenetics" >"Epigenetics"</a>. Bio-Medicine.org. Retrieved 21 May 2011.</li>

<li id="cite_note-pmid2265224-18" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid2265224_18-0" >Jump up^{</a>&nbsp};Holliday R (Jan. 30, 1990). "DNA Methylation and Epigenetic Inheritance". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 326 (1235): 329–338.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1098%2Frstb.1990.0015" >10.1098/rstb.1990.0015</a>.</li>

<li id="cite_note-isbn0-87969-490-4-19" >^ <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-isbn0-87969-490-4_19-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-isbn0-87969-490-4_19-1" >b</a> Riggs AD, Russo VEA, Martienssen RA (1996). Epigenetic mechanisms of gene regulation. Plainview, N.Y.: Cold Spring Harbor Laboratory Press. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/0-87969-490-4" title="Special:BookSources/0-87969-490-4" >0-87969-490-4</a>.[<a href="http://en.wikipedia.org/wiki/Wikipedia:Citing_sources" title="Wikipedia:Citing sources" >page needed</a>]</li>

<li id="cite_note-20" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-20" >Jump up^{</a>&nbsp};NIH Roadmap Epigenomics Project <a rel="nofollow" class="external text" href="http://www.roadmapepigenomics.org/overview" >Overview</a></li>

<li id="cite_note-pmid19339683-21" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid19339683_21-0" >Jump up^{</a>&nbsp};Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009). <a rel="nofollow" class="external text" href="http://genesdev.cshlp.org/content/23/7/781.full" >"An operational definition of epigenetics"</a>.Genes Dev. 23 (7): 781–3. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1101%2Fgad.1787609" >10.1101/gad.1787609</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19339683" >19339683</a>.</li>

<li id="cite_note-pmid17320501-22" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid17320501_22-0" >Jump up^{</a>&nbsp};Chandler VL (February 2007). "Paramutation: from maize to mice". Cell 128 (4): 641–5.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.cell.2007.02.007" >10.1016/j.cell.2007.02.007</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17320501" >17320501</a>.</li>

<li id="cite_note-23" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-23" >Jump up^{</a>&nbsp};Kovalchuk O, Baulch JE (January 2008). "Epigenetic changes and nontargeted radiation effects—is there a link?". Environ. Mol. Mutagen. 49 (1): 16–25. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1002%2Fem.20361" >10.1002/em.20361</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18172877" >18172877</a>.</li>

<li id="cite_note-24" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-24" >Jump up^{</a>&nbsp};Ilnytskyy Y, Kovalchuk O (September 2011). "Non-targeted radiation effects-an epigenetic connection".Mutat. Res. 714 (1–2): 113–25. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.mrfmmm.2011.06.014" >10.1016/j.mrfmmm.2011.06.014</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/21784089" >21784089</a>.</li>

<li id="cite_note-25" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-25" >Jump up^{</a>&nbsp};Friedl AA, Mazurek B, Seiler DM (2012). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445916" >"Radiation-induced alterations in histone modification patterns and their potential impact on short-term radiation effects"</a>. Front Oncol 2: 117.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.3389%2Ffonc.2012.00117" >10.3389/fonc.2012.00117</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445916" >3445916</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23050241" >23050241</a>.</li>

<li id="cite_note-26" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-26" >Jump up^{</a>&nbsp};Cuozzo C, Porcellini A, Angrisano T, et al. (July 2007). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1913100" >"DNA damage, homology-directed repair, and DNA methylation"</a>. PLoS Genet. 3 (7): e110. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pgen.0030110" >10.1371/journal.pgen.0030110</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1913100" >1913100</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17616978" >17616978</a>.</li>

<li id="cite_note-27" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-27" >Jump up^{</a> O}'Hagan HM, Mohammad HP, Baylin SB (2008). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491723" >"Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island"</a>. In Lee, Jeannie T.PLoS Genet. 4 (8): e1000155. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pgen.1000155" >10.1371/journal.pgen.1000155</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491723" >2491723</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18704159" >18704159</a>.</li>

<li id="cite_note-28" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-28" >Jump up^{</a>&nbsp};Malanga M, Althaus FR (2005). The role of poly(ADP-ribose) in the DNA damage signaling network.Biochem Cell Biol 83(3) 354-364. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/15959561?dopt=Abstract" >PMID 15959561</a></li>

<li id="cite_note-29" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-29" >Jump up^{</a>&nbsp};Gottschalk AJ, Timinszky G, Kong SE, et al. (August 2009). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722505" >"Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler"</a>. Proc. Natl. Acad. Sci. U.S.A. 106 (33): 13770–4.<a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2009PNAS..10613770G" >2009PNAS..10613770G</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1073%2Fpnas.0906920106" >10.1073/pnas.0906920106</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722505" >2722505</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19666485" >19666485</a>.</li>

<li id="cite_note-30" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-30" >Jump up^{</a>&nbsp};Lin JC, Jeong S, Liang G, et al. (November 2007). "Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island". Cancer Cell 12 (5): 432–44. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.ccr.2007.10.014" >10.1016/j.ccr.2007.10.014</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17996647" >17996647</a>.</li>

<li id="cite_note-31" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-31" >Jump up^{</a>&nbsp};Tabish AM, Poels K, Hoet P, Godderis L (2012). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324488" >"Epigenetic factors in cancer risk: effect of chemical carcinogens on global DNA methylation pattern in human TK6 cells"</a>. In Chiariotti, Lorenzo. PLoS ONE 7(4): e34674. <a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2012PLoSO...734674T" >2012PLoSO...734674T</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pone.0034674" >10.1371/journal.pone.0034674</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324488" >3324488</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/22509344" >22509344</a>.</li>

<li id="cite_note-32" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-32" >Jump up^{</a>&nbsp};Burdge GC, Hoile SP, Uller T, et al. (2011). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227644" >"Progressive, transgenerational changes in offspring phenotype and epigenotype following nutritional transition"</a>. In Imhof, Axel. PLoS ONE 6 (11): e28282.<a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2011PLoSO...628282B" >2011PLoSO...628282B</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pone.0028282" >10.1371/journal.pone.0028282</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227644" >3227644</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/22140567" >22140567</a>.</li>

<li id="cite_note-33" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-33" >Jump up^{</a>&nbsp};Fang M, Chen D, Yang CS (January 2007). "Dietary polyphenols may affect DNA methylation". J. Nutr. 137(1 Suppl): 223S–228S. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17182830" >17182830</a>.</li>

<li id="cite_note-34" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-34" >Jump up^{</a>&nbsp};Olaharski AJ, Rine J, Marshall BL, et al. (December 2005). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1315280" >"The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases"</a>. PLoS Genet. 1 (6): e77.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pgen.0010077" >10.1371/journal.pgen.0010077</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1315280" >1315280</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16362078" >16362078</a>.</li>

<li id="cite_note-35" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-35" >Jump up^{</a>&nbsp};Kikuno N, Shiina H, Urakami S, et al. (August 2008). "Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells". Int. J. Cancer 123 (3): 552–60.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1002%2Fijc.23590" >10.1002/ijc.23590</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18431742" >18431742</a>.</li>

<li id="cite_note-36" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-36" >Jump up^{</a>&nbsp};Davis JN, Kucuk O, Djuric Z, Sarkar FH (June 2001). "Soy isoflavone supplementation in healthy men prevents NF-kappa B activation by TNF-alpha in blood lymphocytes". Free Radic. Biol. Med. 30 (11): 1293–302. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2FS0891-5849%2801%2900535-4" >10.1016/S0891-5849(01)00535-4</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11368927" >11368927</a>.</li>

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<li id="cite_note-robertson99-45" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-robertson99_45-0" >Jump up^{</a>&nbsp};Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (June 1999). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC148793" >"The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors"</a>. Nucleic Acids Res. 27 (11): 2291–8. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1093%2Fnar%2F27.11.2291" >10.1093/nar/27.11.2291</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC148793" >148793</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/10325416" >10325416</a>.</li>

<li id="cite_note-leonhardt92-46" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-leonhardt92_46-0" >Jump up^{</a>&nbsp};Leonhardt H, Page AW, Weier HU, Bestor TH (November 1992). "A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei". Cell 71 (5): 865–73. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2F0092-8674%2892%2990561-P" >10.1016/0092-8674(92)90561-P</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/1423634" >1423634</a>.</li>

<li id="cite_note-chuang97-47" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-chuang97_47-0" >Jump up^{</a>&nbsp};Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF (September 1997). "Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1". Science 277 (5334): 1996–2000.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1126%2Fscience.277.5334.1996" >10.1126/science.277.5334.1996</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/9302295" >9302295</a>.</li>

<li id="cite_note-robertson00-48" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-robertson00_48-0" >Jump up^{</a>&nbsp};Robertson KD, Wolffe AP (October 2000). "DNA methylation in health and disease". Nature Reviews Genetics 1 (1): 11–9. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2F35049533" >10.1038/35049533</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11262868" >11262868</a>.</li>

<li id="cite_note-li93-49" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-li93_49-0" >Jump up^{</a>&nbsp};Li E, Beard C, Jaenisch R (November 1993). "Role for DNA methylation in genomic imprinting". Nature 366(6453): 362–5. <a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/1993Natur.366..362L" >1993Natur.366..362L</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2F366362a0" >10.1038/366362a0</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/8247133" >8247133</a>.</li>

<li id="cite_note-50" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-50" >Jump up^{</a>&nbsp};Viens A, Mechold U, Brouillard F, Gilbert C, Leclerc P, Ogryzko V (July 2006). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1592707" >"Analysis of human histone H2AZ deposition in vivo argues against its direct role in epigenetic templating mechanisms"</a>. Mol. Cell. Biol. 26 (14): 5325–35. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1128%2FMCB.00584-06" >10.1128/MCB.00584-06</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1592707" >1592707</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16809769" >16809769</a>.</li>

<li id="cite_note-51" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-51" >Jump up^{</a>&nbsp};Ogryzko VV. Erwin Schroedinger, Francis Crick and epigenetic stability. Biol Direct. 2008 Apr 17;3:15.<a rel="nofollow" class="external autonumber" href="http://www.biology-direct.com/content/3/1/15" >[3]</a> <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1186%2F1745-6150-3-15" >10.1186/1745-6150-3-15</a></li>

<li id="cite_note-pmid19234061-52" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid19234061_52-0" >Jump up^{</a>&nbsp};Nottke A, Colaiácovo MP, Shi Y (March 2009). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692332" >"Developmental roles of the histone lysine demethylases"</a>.Development 136 (6): 879–89. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1242%2Fdev.020966" >10.1242/dev.020966</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692332" >2692332</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19234061" >19234061</a>.</li>

<li id="cite_note-Rosenfeld_2009-53" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Rosenfeld_2009_53-0" >Jump up^{</a>&nbsp};Rosenfeld JA, Wang Z, Schones DE, Zhao K, DeSalle R, Zhang MQ (2009). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539" >"Determination of enriched histone modifications in non-genic portions of the human genome"</a>. BMC Genomics 10: 143.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1186%2F1471-2164-10-143" >10.1186/1471-2164-10-143</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667539" >2667539</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19335899" >19335899</a>.</li>

<li id="cite_note-54" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-54" >Jump up^{</a> Sneppen}, Kim; Mille A Micheelsen; Ian B Dold (April 15, 2008). <a rel="nofollow" class="external text" href="http://msb.embopress.org/content/4/1/182.export" >"Ultrasensitive gene regulation by positive feedback loops in nucleosome modification"</a>. Molecular systems biology 4 (1): 182.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fmsb.2008.21" >10.1038/msb.2008.21</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18414483" >18414483</a>. Retrieved 5 May 2014.</li>

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<li id="cite_note-Wang-60" >^ <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Wang_60-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Wang_60-1" >b</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Wang_60-2" >c</a> Wang Z, Yao H, Lin S, Zhu X, Shen Z, Lu G, Poon WS, Xie D, Lin MC, Kung HF (2012). Transcriptional and epigenetic regulation of human microRNAs" Cancer Lett 331(1) 1-10. doi: 10.1016/j.canlet.2012.12.006.<a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/3246373?dopt=Abstract" >PMID 3246373</a></li>

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<li id="cite_note-68" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-68" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://srnamap.mbc.nctu.edu.tw/" >Genomics maps for small non-coding RNA's and their targets in microbial genomes</a></li>

<li id="cite_note-69" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-69" >Jump up^{</a>&nbsp};Yool A, Edmunds WJ (1998). "Epigenetic inheritance and prions". Journal of Evolutionary Biology 11 (2): 241–242. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2Fs000360050085" >10.1007/s000360050085</a>.</li>

<li id="cite_note-70" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-70" >Jump up^{</a>&nbsp};Cox BS (1965). "[PSI], a cytoplasmic suppressor of super-suppression in yeast". Heredity 20 (4): 505–521.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fhdy.1965.65" >10.1038/hdy.1965.65</a>.</li>

<li id="cite_note-pmid5573734-71" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid5573734_71-0" >Jump up^{</a>&nbsp};Lacroute F (May 1971). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC285125" >"Non-Mendelian mutation allowing ureidosuccinic acid uptake in yeast"</a>. J. Bacteriol. 106 (2): 519–22. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC285125" >285125</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/5573734" >5573734</a>.</li>

<li id="cite_note-pmid225301-72" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid225301_72-0" >Jump up^{</a>&nbsp};Liebman SW, Sherman F (September 1979). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC218059" >"Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast"</a>. J. Bacteriol. 139 (3): 1068–71. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC218059" >218059</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/225301" >225301</a>.</li>

<li id="cite_note-pmid11028992-73" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid11028992_73-0" >Jump up^{</a>&nbsp};True HL, Lindquist SL (September 2000). "A yeast prion provides a mechanism for genetic variation and phenotypic diversity". Nature 407 (6803): 477–83. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2F35035005" >10.1038/35035005</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11028992" >11028992</a>.</li>

<li id="cite_note-pmid15931169-74" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid15931169_74-0" >Jump up^{</a>&nbsp};Shorter J, Lindquist S (June 2005). "Prions as adaptive conduits of memory and inheritance". Nature Reviews Genetics 6 (6): 435–50. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fnrg1616" >10.1038/nrg1616</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15931169" >15931169</a>.</li>

<li id="cite_note-75" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-75" >Jump up^{</a>&nbsp};Giacomelli M, Hancock AS, Masel J, (2007). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808353" >"The conversion of 3′ UTRs into coding regions"</a>. Molecular Biology & Evolution 24 (2): 457–464. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1093%2Fmolbev%2Fmsl172" >10.1093/molbev/msl172</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808353" >1808353</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17099057" >17099057</a>.</li>

<li id="cite_note-76" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-76" >Jump up^{</a>&nbsp};Lancaster AK, Bardill JP, True HL, Masel J (2010). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828720" >"The Spontaneous Appearance Rate of the Yeast Prion PSI+ and Its Implications for the Evolution of the Evolvability Properties of the PSI+ System"</a>. Genetics 184(2): 393–400. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1534%2Fgenetics.109.110213" >10.1534/genetics.109.110213</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828720" >2828720</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19917766" >19917766</a>.</li>

<li id="cite_note-pmid1804215-77" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid1804215_77-0" >Jump up^{</a>&nbsp};Sapp J (1991). "Concepts of organization. The leverage of ciliate protozoa". Dev. Biol. (NY) 7: 229–58.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/1804215" >1804215</a>.</li>

<li id="cite_note-isbn0-19-515619-6-78" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-isbn0-19-515619-6_78-0" >Jump up^{</a>&nbsp};Sapp J (2003). Genesis: the evolution of biology. Oxford [Oxfordshire]: Oxford University Press. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/0-19-515619-6" title="Special:BookSources/0-19-515619-6" >0-19-515619-6</a>.</li>

<li id="cite_note-isbn0-262-65063-0-79" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-isbn0-262-65063-0_79-0" >Jump up^{</a>&nbsp};Gray RD, Oyama S, Griffiths PE (2003). Cycles of Contingency: Developmental Systems and Evolution (Life and Mind: Philosophical Issues in Biology and Psychology). Cambridge, Mass: The MIT Press.<a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/0-262-65063-0" title="Special:BookSources/0-262-65063-0" >0-262-65063-0</a>.</li>

<li id="cite_note-pmid17194589-80" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid17194589_80-0" >Jump up^{</a>&nbsp};Costa S, Shaw P (March 2007). <a rel="nofollow" class="external text" href="http://cromatina.icb.ufmg.br/biomol/seminarios/outros/grupo_open.pdf" >"'Open minded' cells: how cells can change fate"</a> (PDF). Trends Cell Biol. 17 (3): 101–6. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.tcb.2006.12.005" >10.1016/j.tcb.2006.12.005</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17194589" >17194589</a>. "This might suggest that plant cells do not use or require a cellular memory mechanism and just respond to positional information. However, it has been shown that plants do use cellular memory mechanisms mediated by PcG proteins in several processes, ... (p.104)"</li>

<li id="cite_note-Griesemer_2005-81" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Griesemer_2005_81-0" >Jump up^{</a>&nbsp};Griesemer J, Haber MH, Yamashita G, Gannett L (March 2005). "Critical Notice: Cycles of Contingency – Developmental Systems and Evolution". Biology & Philosophy 20 (2–3): 517–544. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2Fs10539-004-0836-4" >10.1007/s10539-004-0836-4</a>.</li>

<li id="cite_note-pmid21447282-82" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid21447282_82-0" >Jump up^{</a>&nbsp};Chahwan R, Wontakal SN, Roa S (March 2011). "The multidimensional nature of epigenetic information and its role in disease". Discov Med 11 (58): 233–43. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/21447282" >21447282</a>.</li>

<li id="cite_note-83" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-83" >Jump up^{</a> }<a href="http://en.wikipedia.org/wiki/Mendelian_Inheritance_in_Man" title="Mendelian Inheritance in Man" class="mw-redirect" >Online 'Mendelian Inheritance in Man'</a> (OMIM) <a rel="nofollow" class="external text" href="http://omim.org/entry/105830" >105830</a></li>

<li id="cite_note-isbn0-262-10107-6-84" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-isbn0-262-10107-6_84-0" >Jump up^{</a>&nbsp};Lamb MJ, Jablonka E (2005). Evolution in four dimensions: genetic, epigenetic, behavioral, and symbolic variation in the history of life. Cambridge, Mass: MIT Press. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/0-262-10107-6" title="Special:BookSources/0-262-10107-6" >0-262-10107-6</a>.</li>

<li id="cite_note-85" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-85" >Jump up^{</a>&nbsp};See also <a href="http://en.wikipedia.org/wiki/Denis_Noble" title="Denis Noble" >Denis Noble</a> The Music of Life see esp pp. 93–8 and p. 48 where he cites Jablonka & Lamb and<a href="http://en.wikipedia.org/wiki/Massimo_Pigliucci" title="Massimo Pigliucci" >Massimo Pigliucci</a>'s review of Jablonka and Lamb in <a href="http://en.wikipedia.org/wiki/Nature_(journal)" title="Nature (journal)" >Nature</a> 435, 565–566 (2 June 2005)</li>

<li id="cite_note-86" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-86" >Jump up^{</a>&nbsp};Maynard Smith, John (1990). "Models of a Dual Inheritance System". Journal of Theoretical Biology 143(1): 41–53. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2FS0022-5193%2805%2980287-5" >10.1016/S0022-5193(05)80287-5</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/2359317" >2359317</a>.</li>

<li id="cite_note-87" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-87" >Jump up^{</a> Lynch}, M. (2007). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876435" >"The frailty of adaptive hypotheses for the origins of organismal complexity"</a>. PNAS 104(suppl. 1): 8597–8604. <a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2007PNAS..104.8597L" >2007PNAS..104.8597L</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1073%2Fpnas.0702207104" >10.1073/pnas.0702207104</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876435" >1876435</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17494740" >17494740</a>.</li>

<li id="cite_note-rando_and_verstrepen-88" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-rando_and_verstrepen_88-0" >Jump up^{</a>&nbsp};Rando OJ, Verstrepen KJ (February 2007). "Timescales of genetic and epigenetic inheritance". Cell 128(4): 655–68. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.cell.2007.01.023" >10.1016/j.cell.2007.01.023</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17320504" >17320504</a>.</li>

<li id="cite_note-89" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-89" >Jump up^{</a> Lancaster}, Alex K.; Masel, Joanna (1 September 2009). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770902" >"The evolution of reversible switches in the presence of irreversible mimics"</a>. Evolution 63 (9): 2350–2362. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1558-5646.2009.00729.x" >10.1111/j.1558-5646.2009.00729.x</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770902" >2770902</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19486147" >19486147</a>.</li>

<li id="cite_note-90" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-90" >Jump up^{</a>&nbsp};Griswold CK, Masel J (2009). <a rel="nofollow" class="external text" href="http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000517" >"Complex Adaptations Can Drive the Evolution of the Capacitor PSI+, Even with Realistic Rates of Yeast Sex"</a>. In Úbeda, Francisco. PLoS Genetics 5 (6): e1000517.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pgen.1000517" >10.1371/journal.pgen.1000517</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2686163" >2686163</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19521499" >19521499</a>.</li>

<li id="cite_note-pmid12163699-91" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid12163699_91-0" >Jump up^{</a>&nbsp};Cooney CA, Dave AA, Wolff GL (August 2002). "Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring". J. Nutr. 132 (8 Suppl): 2393S–2400S. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/12163699" >12163699</a>.</li>

<li id="cite_note-waterland-92" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-waterland_92-0" >Jump up^{</a>&nbsp};Waterland RA, Jirtle RL (August 2003). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC165709" >"Transposable elements: targets for early nutritional effects on epigenetic gene regulation"</a>. Mol. Cell. Biol. 23 (15): 5293–300. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1128%2FMCB.23.15.5293-5300.2003" >10.1128/MCB.23.15.5293-5300.2003</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC165709" >165709</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/12861015" >12861015</a>.</li>

<li id="cite_note-93" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-93" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.scientificamerican.com/article.cfm?id=fearful-memories-passed-down&print=true" >Fearful Memories Passed Down to Mouse Descendants: Genetic imprint from traumatic experiences carries through at least two generations</a>, By Ewen Callaway and Nature magazine | Sunday, 1 December 2013.</li>

<li id="cite_note-94" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-94" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://medicalxpress.com/news/2013-12-mice-sons-grandsons-dangers-sperm.html#ajTabs" >Mice can 'warn' sons, grandsons of dangers via sperm</a>, by Mariette Le Roux, 12/1/13.</li>

<li id="cite_note-95" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-95" >Jump up^{</a>&nbsp};Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M (2005)" Proc Natl Acad Sci U S A 102(30) 10604-10609. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/16009939?dopt=Abstract" >PMID 16009939</a></li>

<li id="cite_note-Jablonka09-96" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Jablonka09_96-0" >Jump up^{</a>&nbsp};Jablonka E, Raz G (June 2009). "Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution". Q Rev Biol 84 (2): 131–76. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1086%2F598822" >10.1086/598822</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19606595" >19606595</a>.</li>

<li id="cite_note-97" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-97" >Jump up^{</a> Davies}, Hazel (2008). Do Butterflies Bite?: Fascinating Answers to Questions about Butterflies and Moths (Animals Q&A). Rutgers University Press.</li>

<li id="cite_note-pmid20800313-98" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid20800313_98-0" >Jump up^{</a>&nbsp};Chahwan R, Wontakal SN, Roa S (October 2010). "Crosstalk between genetic and epigenetic information through cytosine deamination". Trends Genet. 26 (10): 443–8. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.tig.2010.07.005" >10.1016/j.tig.2010.07.005</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20800313" >20800313</a>.</li>

<li id="cite_note-pmid17121465-99" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid17121465_99-0" >Jump up^{</a>&nbsp};Wood AJ, Oakey RJ (November 2006). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1657038" >"Genomic imprinting in mammals: emerging themes and established theories"</a>. PLoS Genet. 2 (11): e147. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pgen.0020147" >10.1371/journal.pgen.0020147</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1657038" >1657038</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17121465" >17121465</a>.</li>

<li id="cite_note-pmid2564739-100" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid2564739_100-0" >Jump up^{</a>&nbsp};Knoll JH, Nicholls RD, Magenis RE, Graham JM, Lalande M, Latt SA (February 1989). "Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion".Am. J. Med. Genet. 32 (2): 285–90. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1002%2Fajmg.1320320235" >10.1002/ajmg.1320320235</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/2564739" >2564739</a>.</li>

<li id="cite_note-paternal-grandson-101" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-paternal-grandson_101-0" >Jump up^{</a>&nbsp};A person's paternal grandson is the son of a son of that person; a maternal grandson is the son of a daughter.</li>

<li id="cite_note-pmid16391557-102" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid16391557_102-0" >Jump up^{</a>&nbsp};Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjöström M, Golding J (February 2006). "Sex-specific, male-line transgenerational responses in humans". Eur. J. Hum. Genet. 14 (2): 159–66.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fsj.ejhg.5201538" >10.1038/sj.ejhg.5201538</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16391557" >16391557</a>. <a href="http://en.wikipedia.org/wiki/Robert_Winston" title="Robert Winston" >Robert Winston</a> refers to this study in a <a rel="nofollow" class="external text" href="http://www.dundee.ac.uk/externalrelations/events/lectures.html" >lecture</a>; see also discussion at <a href="http://en.wikipedia.org/wiki/Leeds_University" title="Leeds University" class="mw-redirect" >Leeds University</a>, here <a rel="nofollow" class="external autonumber" href="https://web.archive.org/web/20061003060251/http://www.fbs.leeds.ac.uk/staff/pm/epigenetics.htm#exciting2" >[4]</a></li>

<li id="cite_note-103" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-103" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.pbs.org/wgbh/nova/transcripts/3413_genes.html" >"NOVA | Transcripts | Ghost in Your Genes"</a>. PBS. 16 October 2007. Retrieved 26 July 2012.</li>

<li id="cite_note-bishop97-104" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-bishop97_104-0" >Jump up^{</a>&nbsp};Bishop JB, Witt KL, Sloane RA (December 1997). "Genetic toxicities of human teratogens". Mutat. Res.396 (1–2): 9–43. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2FS0027-5107%2897%2900173-5" >10.1016/S0027-5107(97)00173-5</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/9434858" >9434858</a>.</li>

<li id="cite_note-gurvich04-105" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-gurvich04_105-0" >Jump up^{</a>&nbsp};Gurvich N, Berman MG, Wittner BS, Gentleman RC, Klein PS, Green JB (July 2005). "Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo". FASEB J. 19 (9): 1166–8.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1096%2Ffj.04-3425fje" >10.1096/fj.04-3425fje</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15901671" >15901671</a>.</li>

<li id="cite_note-smithells98-106" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-smithells98_106-0" >Jump up^{</a>&nbsp};Smithells D (November 1998). "Does thalidomide cause second generation birth defects?". Drug Saf 19(5): 339–41. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.2165%2F00002018-199819050-00001" >10.2165/00002018-199819050-00001</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/9825947" >9825947</a>.</li>

<li id="cite_note-friedler96-107" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-friedler96_107-0" >Jump up^{</a>&nbsp};Friedler G (December 1996). "Paternal exposures: impact on reproductive and developmental outcome. An overview". Pharmacol. Biochem. Behav. 55 (4): 691–700. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2FS0091-3057%2896%2900286-9" >10.1016/S0091-3057(96)00286-9</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/8981601" >8981601</a>.</li>

<li id="cite_note-108" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-108" >Jump up^{</a> }<a rel="nofollow" class="external text" href="http://www.webcitation.org/5QeAQ5n5o" >WebCite query result</a></li>

<li id="cite_note-cicero91-109" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-cicero91_109-0" >Jump up^{</a>&nbsp};Cicero TJ, Adams ML, Giordano A, Miller BT, O'Connor L, Nock B (March 1991). "Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring". J. Pharmacol. Exp. Ther. 256 (3): 1086–93. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/2005573" >2005573</a>.</li>

<li id="cite_note-newbold06-110" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-newbold06_110-0" >Jump up^{</a>&nbsp};Newbold RR, Padilla-Banks E, Jefferson WN (June 2006). "Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations". Endocrinology 147 (6 Suppl): S11–7.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1210%2Fen.2005-1164" >10.1210/en.2005-1164</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16690809" >16690809</a>.</li>

<li id="cite_note-pmid20236314-111" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid20236314_111-0" >Jump up^{</a>&nbsp};Mandal SS (April 2010). "Mixed lineage leukemia: versatile player in epigenetics and human disease".FEBS J. 277 (8): 1789. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1111%2Fj.1742-4658.2010.07605.x" >10.1111/j.1742-4658.2010.07605.x</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20236314" >20236314</a>.</li>

<li id="cite_note-Li2005-112" >^ <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Li2005_112-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Li2005_112-1" >b</a> Li LC, Carroll PR, Dahiya R (January 2005). "Epigenetic changes in prostate cancer: implication for diagnosis and treatment". J. Natl. Cancer Inst. 97 (2): 103–15. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1093%2Fjnci%2Fdji010" >10.1093/jnci/dji010</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15657340" >15657340</a>.</li>

<li id="cite_note-pmid18559852-113" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid18559852_113-0" >Jump up^{</a>&nbsp};Ornish D, Magbanua MJ, Weidner G, Weinberg V, Kemp C, Green C, Mattie MD, Marlin R, Simko J, Shinohara K, Haqq CM, Carroll PR (June 2008). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430265" >"Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention"</a>. Proc. Natl. Acad. Sci. U.S.A. 105 (24): 8369–74.<a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2008PNAS..105.8369O" >2008PNAS..105.8369O</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1073%2Fpnas.0803080105" >10.1073/pnas.0803080105</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430265" >2430265</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18559852" >18559852</a>.</li>

<li id="cite_note-114" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-114" >Jump up^{</a> Beil}, Laura (Winter 2008). <a rel="nofollow" class="external text" href="http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/949" >"Medicine's New Epicenter? Epigenetics: New field of epigenetics may hold the secret to flipping cancer's "off" switch."</a>. CURE (Cancer Updates, Research and Education).</li>

<li id="cite_note-CraigJMWongNC-115" >^ <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-CraigJMWongNC_115-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-CraigJMWongNC_115-1" >b</a> Wong NC, Craig JM (2011). Epigenetics: A Reference Manual. Norfolk, England: Caister Academic Press. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/1-904455-88-3" title="Special:BookSources/1-904455-88-3" >1-904455-88-3</a>.</li>

<li id="cite_note-116" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-116" >Jump up^{</a>&nbsp};Jasperson KW, Tuohy TM, Neklason DW, Burt RW (2010). Hereditary and familial colon cancer"Gastroenterology 138(6) 2044-2058. doi: 10.1053/j.gastro.2010.01.054. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/20420945?dopt=Abstract" >PMID 20420945</a></li>

<li id="cite_note-117" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-117" >Jump up^{</a>&nbsp};Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007). The genomic landscapes of human breast and colorectal cancers" Science 318(5853) 1108-1113. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/17932254?dopt=Abstract" >PMID 17932254</a></li>

<li id="cite_note-118" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-118" >Jump up^{</a>&nbsp};Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG (2000). Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92(7) 564-569. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/10749912?dopt=Abstract" >PMID 10749912</a></li>

<li id="cite_note-119" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-119" >Jump up^{</a>&nbsp};Agrelo R, Cheng WH, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga J, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M (2006). Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer" Proc Natl Acad Sci U S A 2006;103(23) 8822-8827. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/16723399?dopt=Abstract" >PMID 16723399</a> PMCID: PMC1466544</li>

<li id="cite_note-120" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-120" >Jump up^{</a>&nbsp};Baldwin RL, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S, Karlan BY (2000). BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study" Cancer Res 60(19) 5329-5333. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/11034065?dopt=Abstract" >PMID 11034065</a></li>

<li id="cite_note-121" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-121" >Jump up^{</a>&nbsp};Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J, Houlihan PS, Krouse RS, Prasad AR, Einspahr JG, Buckmeier J, Alberts DS, Hamilton SR, Issa JP (2005). MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst 97(18) 1330-1338. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/16174854?dopt=Abstract" >PMID 16174854</a></li>

<li id="cite_note-122" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-122" >Jump up^{</a>&nbsp};Psofaki V, Kalogera C, Tzambouras N, Stephanou D, Tsianos E, Seferiadis K, Kolios G (2010). Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas. World J Gastroenterol 16(28) 3553-3560. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/20653064?dopt=Abstract" >PMID 20653064</a> PMCID: PMC2909555</li>

<li id="cite_note-123" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-123" >Jump up^{</a>&nbsp};Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH (2011). Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence. Langenbecks Arch Surg 396(7) 1017-1026. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/21706233?dopt=Abstract" >PMID 21706233</a></li>

<li id="cite_note-124" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-124" >Jump up^{</a>&nbsp};Amatu A, Sartore-Bianchi A, Moutinho C, Belotti A, Bencardino K, Chirico G, Cassingena A, Rusconi F, Esposito A, Nichelatti M, Esteller M, Siena S (2013). Promoter CpG Island Hypermethylation of the DNA Repair Enzyme MGMT Predicts Clinical Response to Dacarbazine in a Phase II Study for Metastatic Colorectal Cancer. Clin Cancer Res [Epub ahead of print] <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/23422094?dopt=Abstract" >PMID 23422094</a></li>

<li id="cite_note-125" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-125" >Jump up^{</a>&nbsp};Mokarram P, Zamani M, Kavousipour S, Naghibalhossaini F, Irajie C, Moradi Sarabi M, Hosseini SV (2012). Different patterns of DNA methylation of the two distinct O6-methylguanine-DNA methyltransferase (O(6)-MGMT) promoter regions in colorectal cancer. Mol Biol Rep December 28. [Epub ahead of print] <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/23271133?dopt=Abstract" >PMID 23271133</a></li>

<li id="cite_note-126" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-126" >Jump up^{</a>&nbsp};Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer" Gastroenterology 2005;128(5) 1160-1171.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1053%2Fj.gastro.2005.01.056" >10.1053/j.gastro.2005.01.056</a> <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/15887099?dopt=Abstract" >PMID 15887099</a></li>

<li id="cite_note-127" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-127" >Jump up^{</a>&nbsp};Facista A, Nguyen H, Lewis C, Prasad AR, Ramsey L, Zaitlin B, Nfonsam V, Krouse RS, Bernstein H, Payne CM, Stern S, Oatman N, Banerjee B, Bernstein C (2012). Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer. Genome Integr 3(1) 3. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/22494821?dopt=Abstract" >PMID 22494821</a></li>

<li id="cite_note-128" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-128" >Jump up^{</a>&nbsp};Rigakos G, Razis E (2012). BRCAness: finding the Achilles heel in ovarian cancer" Oncologist 17(7) 956-962. doi: 10.1634/theoncologist.2012-0028. Review. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/22673632?dopt=Abstract" >PMID 22673632</a></li>

<li id="cite_note-129" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-129" >Jump up^{</a>&nbsp};Stefansson OA, Villanueva A, Vidal A, Martí L, Esteller M (2012). BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer. Epigenetics 7(11) 1225-1229. doi: 10.4161/epi.22561. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/23069641?dopt=Abstract" >PMID 23069641</a></li>

<li id="cite_note-130" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-130" >Jump up^{</a>&nbsp};Chaisaingmongkol J, Popanda O, Warta R, Dyckhoff G, Herpel E, Geiselhart L, Claus R, Lasitschka F, Campos B, Oakes CC, Bermejo JL, Herold-Mende C, Plass C, Schmezer P (2012). Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma" Oncogene 31(49) 5108-16. doi: 10.1038/onc.2011.660. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/22286769?dopt=Abstract" >PMID 22286769</a></li>

<li id="cite_note-131" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-131" >Jump up^{</a>&nbsp};Fan CY (2004). Epigenetic alterations in head and neck cancer: prevalence, clinical significance, and implications. Curr Oncol Rep 6(2) 152-161. Review. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/14751093?dopt=Abstract" >PMID 14751093</a></li>

<li id="cite_note-132" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-132" >Jump up^{</a>&nbsp};Koutsimpelas D, Pongsapich W, Heinrich U, Mann S, Mann WJ, Brieger J (2012). Promoter methylation of MGMT, MLH1 and RASSF1A tumor suppressor genes in head and neck squamous cell carcinoma: pharmacological genome demethylation reduces proliferation of head and neck squamous carcinoma cells. Oncol Rep 27(4) 1135-41. doi: 10.3892/or.2012.1624. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/22246327?dopt=Abstract" >PMID 22246327</a></li>

<li id="cite_note-133" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-133" >Jump up^{</a>&nbsp};Sun W, Zaboli D, Liu Y, Arnaoutakis D, Khan T, Wang H, Koch W, Khan Z, Califano JA (2012). Comparison of promoter hypermethylation pattern in salivary rinses collected with and without an exfoliating brush from patients with HNSCC" PLoS One 7(3) e33642. doi: 10.1371/journal.pone.0033642. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/22438973?dopt=Abstract" >PMID 22438973</a></li>

<li id="cite_note-134" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-134" >Jump up^{</a>&nbsp};Puri SK, Si L, Fan CY, Hanna E (2005). Aberrant promoter hypermethylation of multiple genes in head and neck squamous cell carcinoma. Am J Otolaryngol 26(1) 12-17. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/15635575?dopt=Abstract" >PMID 15635575</a></li>

<li id="cite_note-135" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-135" >Jump up^{</a>&nbsp};Ai L, Vo QN, Zuo C, Li L, Ling W, Suen JY, Hanna E, Brown KD, Fan CY (2004). Ataxia-telangiectasia-mutated (ATM) gene in head and neck squamous cell carcinoma: promoter hypermethylation with clinical correlation in 100 cases. Cancer Epidemiol Biomarkers Prev (1) 150-6. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/14744748?dopt=Abstract" >PMID 14744748</a></li>

<li id="cite_note-136" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-136" >Jump up^{</a>&nbsp};Zuo C, Zhang H, Spencer HJ, Vural E, Suen JY, Schichman SA, Smoller BR, Kokoska MS, Fan CY (2009). Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 141(4) 484-490. doi: 10.1016/j.otohns.2009.07.007.<a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/19786217?dopt=Abstract" >PMID 19786217</a></li>

<li id="cite_note-137" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-137" >Jump up^{</a>&nbsp};Tawfik HM, El-Maqsoud NM, Hak BH, El-Sherbiny YM (2011). Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene. Am J Otolaryngol 32(6) 528-536. doi: 10.1016/j.amjoto.2010.11.005. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/21353335?dopt=Abstract" >PMID 21353335</a></li>

<li id="cite_note-138" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-138" >Jump up^{</a>&nbsp};Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM. (1997). Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2" Proc Natl Acad Sci U S A 94(7) 3122-3127. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/9096356?dopt=Abstract" >PMID 9096356</a></li>

<li id="cite_note-139" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-139" >Jump up^{</a>&nbsp};Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM. (2006). Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6"Carcinogenesis 2006 Dec;27(12) 2402-2408. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/16728433?dopt=Abstract" >PMID 16728433</a></li>

<li id="cite_note-140" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-140" >Jump up^{</a>&nbsp};Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A. (2002). Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation" EMBO Rep 3(3) 255-260. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/11850397?dopt=Abstract" >PMID 11850397</a> PMCID: PMC1084010</li>

<li id="cite_note-141" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-141" >Jump up^{</a>&nbsp};German J. (1969). Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients" Am J Hum Genet 1969 Mar;21(2) 196-227. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/5770175?dopt=Abstract" >PMID 5770175</a> PMCID: PMC1706430</li>

<li id="cite_note-142" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-142" >Jump up^{</a>&nbsp};Nowak MA, Komarova NL, Sengupta A, Jallepalli PV, Shih IeM, Vogelstein B, Lengauer C (2002). The role of chromosomal instability in tumor initiation" Proc Natl Acad Sci U S A 99(25) 16226-16231. <a class="external mw-magiclink-pmid" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/12446840?dopt=Abstract" >PMID 12446840</a></li>

<li id="cite_note-143" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-143" >Jump up^{</a>&nbsp};Rappa F, Greco A, Podrini C, et al. (2013). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553099" >"Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma"</a>. In Folli, Franco. PLoS ONE 8 (1): e54458.<a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2013PLoSO...854458R" >2013PLoSO...854458R</a>. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pone.0054458" >10.1371/journal.pone.0054458</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553099" >3553099</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23372727" >23372727</a>.</li>

<li id="cite_note-pmid20664922-144" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid20664922_144-0" >Jump up^{</a>&nbsp};Wang LG, Chiao JW (September 2010). "Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review)". Int. J. Oncol. 37 (3): 533–9.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.3892%2Fijo_00000702" >10.3892/ijo_00000702</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20664922" >20664922</a>.</li>

<li id="cite_note-IglesiasLinares2010-145" >^ <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-IglesiasLinares2010_145-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-IglesiasLinares2010_145-1" >b</a> Iglesias-Linares A, Yañez-Vico RM, González-Moles MA (May 2010). "Potential role of HDAC inhibitors in cancer therapy: insights into oral squamous cell carcinoma". Oral Oncol. 46 (5): 323–9.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.oraloncology.2010.01.009" >10.1016/j.oraloncology.2010.01.009</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20207580" >20207580</a>.</li>

<li id="cite_note-pmid18773966-146" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid18773966_146-0" >Jump up^{</a>&nbsp};Spannhoff A, Sippl W, Jung M (January 2009). "Cancer treatment of the future: inhibitors of histone methyltransferases". Int. J. Biochem. Cell Biol. 41 (1): 4–11. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.biocel.2008.07.024" >10.1016/j.biocel.2008.07.024</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18773966" >18773966</a>.</li>

<li id="cite_note-pmid20219369-147" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid20219369_147-0" >Jump up^{</a>&nbsp};Dowden J, Hong W, Parry RV, Pike RA, Ward SG (April 2010). "Toward the development of potent and selective bisubstrate inhibitors of protein arginine methyltransferases". Bioorg. Med. Chem. Lett. 20 (7): 2103–5. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.bmcl.2010.02.069" >10.1016/j.bmcl.2010.02.069</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20219369" >20219369</a>.</li>

<li id="cite_note-148" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-148" >Jump up^{</a> O'Connor}, Anahad (11 March 2008). <a rel="nofollow" class="external text" href="http://www.nytimes.com/2008/03/11/health/11real.html" >"The Claim: Identical Twins Have Identical DNA"</a>. New York Times. Retrieved 2 May 2010.</li>

<li id="cite_note-pmid19151718-149" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid19151718_149-0" >Jump up^{</a>&nbsp};Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GH, Wong AH, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman II, Martin NG, Petronis A (February 2009). "DNA methylation profiles in monozygotic and dizygotic twins". Nat. Genet. 41 (2): 240–5. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fng.286" >10.1038/ng.286</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19151718" >19151718</a>.</li>

<li id="cite_note-pmid16009939-150" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid16009939_150-0" >Jump up^{</a>&nbsp};Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M (July 2005). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1174919" >"Epigenetic differences arise during the lifetime of monozygotic twins"</a>. Proc. Natl. Acad. Sci. U.S.A. 102 (30): 10604–9. <a href="http://en.wikipedia.org/wiki/Bibcode" title="Bibcode" >Bibcode</a>:<a rel="nofollow" class="external text" href="http://adsabs.harvard.edu/abs/2005PNAS..10210604F" >2005PNAS..10210604F</a>.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1073%2Fpnas.0500398102" >10.1073/pnas.0500398102</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1174919" >1174919</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16009939" >16009939</a>.</li>

<li id="cite_note-151" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-151" >Jump up^{</a> Ballestar}, E. (2009). Epigenetics Lessons from Twins: Prospects for Autoimmune Disease. Clinical Reviews in allergy & immunology, 39(1), 30-41. Retrieved 6 December 2013, from<a rel="nofollow" class="external free" href="http://download.springer.com/static/pdf/554/art%253A10.1007%252Fs12016-009-8168-4.pdf?auth66=1386532566_ad74522bafd84f602ad13988b1c4b3c7&ext=.pdf" >http://download.springer.com/static/pdf/554/art%253A10.1007%252Fs12016-009-8168-4.pdf?auth66=1386532566_ad74522bafd84f602ad13988b1c4b3c7&ext=.pdf</a></li>

<li id="cite_note-152" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-152" >Jump up^{</a>&nbsp};Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102:10604–10609</li>

<li id="cite_note-153" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-153" >Jump up^{</a>&nbsp};Kaminsky ZA, Tang T, Wang SC et al (2009) DNA methylation profiles in monozygotic and dizygotic twins.Nat Genet 41:240–245</li>

<li id="cite_note-Casadesus-154" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-Casadesus_154-0" >Jump up^{</a>&nbsp};Casadesús J, Low D (September 2006). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1594586" >"Epigenetic gene regulation in the bacterial world"</a>. Microbiol. Mol. Biol. Rev. 70 (3): 830–56. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1128%2FMMBR.00016-06" >10.1128/MMBR.00016-06</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1594586" >1594586</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16959970" >16959970</a>.</li>

<li id="cite_note-JorgTost-155" >^ <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-JorgTost_155-0" >Jump up to:a</a> <a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-JorgTost_155-1" >b</a> Jorg Tost (2008). Epigenetics. Norfolk, England: Caister Academic Press. <a href="http://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number" >ISBN</a> <a href="http://en.wikipedia.org/wiki/Special:BookSources/1-904455-23-9" title="Special:BookSources/1-904455-23-9" >1-904455-23-9</a>.</li>

<li id="cite_note-pmid19092133-156" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-pmid19092133_156-0" >Jump up^{</a>&nbsp};Lewis ZA, Honda S, Khlafallah TK, Jeffress JK, Freitag M, Mohn F, Schübeler D, Selker EU (March 2009).<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661801" >"Relics of repeat-induced point mutation direct heterochromatin formation in Neurospora crassa"</a>. Genome Res. 19 (3): 427–37. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1101%2Fgr.086231.108" >10.1101/gr.086231.108</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661801" >2661801</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19092133" >19092133</a>.</li>

<li id="cite_note-157" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-157" >Jump up^{</a> Schadt}, E. E.; Banerjee, O.; Fang, G.; Feng, Z.; Wong, W. H.; Zhang, X.; Kislyuk, A.; Clark, T. A.; Luong, K.; Keren-Paz, A.; Chess, A.; Kumar, V.; Chen-Plotkin, A.; Sondheimer, N.; Korlach, J.; Kasarskis, A. (2012).<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530673" >"Modeling kinetic rate variation in third generation DNA sequencing data to detect putative modifications to DNA bases"</a>. Genome Research 23 (1): 129–41. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1101%2Fgr.136739.111" >10.1101/gr.136739.111</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530673" >3530673</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23093720" >23093720</a>.</li>

<li id="cite_note-158" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-158" >Jump up^{</a> Davis}, Brigid M; Chao, Michael C; Waldor, Matthew K (2013). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646917" >"Entering the era of bacterial epigenomics with single molecule real time DNA sequencing"</a>. Current Opinion in Microbiology 16 (2): 192–8.<a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.mib.2013.01.011" >10.1016/j.mib.2013.01.011</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646917" >3646917</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23434113" >23434113</a>.</li>

<li id="cite_note-159" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-159" >Jump up^{</a> Lluch-Senar}, Maria; Luong, Khai; Lloréns-Rico, Verónica; Delgado, Javier; Fang, Gang; Spittle, Kristi; Clark, Tyson A.; Schadt, Eric; Turner, Stephen W.; Korlach, Jonas; Serrano, Luis (2013). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536716" >"Comprehensive Methylome Characterization of Mycoplasma genitalium and Mycoplasma pneumoniae at Single-Base Resolution"</a>. In Richardson, Paul M. PLoS Genetics 9 (1): e1003191. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1371%2Fjournal.pgen.1003191" >10.1371/journal.pgen.1003191</a>.<a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536716" >3536716</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23300489" >23300489</a>.</li>

<li id="cite_note-160" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-160" >Jump up^{</a> Murray}, I. A.; Clark, T. A.; Morgan, R. D.; Boitano, M.; Anton, B. P.; Luong, K.; Fomenkov, A.; Turner, S. W.; Korlach, J.; Roberts, R. J. (2012). <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526280" >"The methylomes of six bacteria"</a>. Nucleic Acids Research 40 (22): 11450–62. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1093%2Fnar%2Fgks891" >10.1093/nar/gks891</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central" >PMC</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526280" >3526280</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23034806" >23034806</a>.</li>

<li id="cite_note-161" ><a href="http://en.wikipedia.org/wiki/Epigenetics#cite_ref-161" >Jump up^{</a> Fang}, Gang; Munera, Diana; Friedman, David I; Mandlik, Anjali; Chao, Michael C; Banerjee, Onureena; Feng, Zhixing; Losic, Bojan; Mahajan, Milind C; Jabado, Omar J; Deikus, Gintaras; Clark, Tyson A; Luong, Khai; Murray, Iain A; Davis, Brigid M; Keren-Paz, Alona; Chess, Andrew; Roberts, Richard J; Korlach, Jonas; Turner, Steve W; Kumar, Vipin; Waldor, Matthew K; Schadt, Eric E (2012). "Genome-wide mapping of methylated adenine residues in pathogenic Escherichia coli using single-molecule real-time sequencing".Nature Biotechnology 30 (12): 1232–9. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2Fnbt.2432" >10.1038/nbt.2432</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/23138224" >23138224</a>.</li>

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<h2 >External links[<a href="http://en.wikipedia.org/w/index.php?title=Epigenetics&action=edit&section=28" title="Edit section: External links" >edit</a>]</h2>

<ul >

<li >Haque FN, Gottesman II, Wong AH (May 2009). "Not really identical: epigenetic differences in monozygotic twins and implications for twin studies in psychiatry". Am J Med Genet C Semin Med Genet151C (2): 136–41. <a href="http://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier" >doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1002%2Fajmg.c.30206" >10.1002/ajmg.c.30206</a>. <a href="http://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect" >PMID</a> <a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/19378334" >19378334</a>.</li>

<li ><a rel="nofollow" class="external text" href="http://www.epigenome.org/" >The Human Epigenome Project (HEP)</a></li>

<li ><a rel="nofollow" class="external text" href="http://www.epigenome-noe.net/index.php" >The Epigenome Network of Excellence (NoE)</a></li>

<li ><a rel="nofollow" class="external text" href="http://www.epigenomes.ca/" >Canadian Epigenetics, Environment and Health Research Consortium (CEEHRC)</a></li>

<li ><a rel="nofollow" class="external text" href="http://www.epigenome.eu/" >The Epigenome Network of Excellence (NoE)- public international site</a></li>

<li ><a rel="nofollow" class="external text" href="http://discovermagazine.com/2006/nov/cover" >DNA Is Not Destiny</a> – Discover Magazine cover story</li>

<li ><a rel="nofollow" class="external text" href="http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ghostgenes.shtml" >BBC – Horizon – 2005 – The Ghost In Your Genes</a></li>

<li ><a rel="nofollow" class="external text" href="http://www.hopkinsmedicine.org/press/2002/november/epigenetics.htm" >Epigenetics article</a> at Hopkins Medicine</li>

<li ><a rel="nofollow" class="external text" href="http://genome.wellcome.ac.uk/doc_WTX036556.html" >Towards a global map of epigenetic variation</a></li>

</ul>

Epigenetics

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