Examine individual changes

'{{Short description|Study of DNA modifications that do not change its sequence}} {{other uses|Epigenetic (disambiguation)}} {{Use dmy dates|date=December 2019}} {{Technical|date=September 2023}} [[File:Epigenetic mechanisms.png|thumb|right|449px|Epigenetic mechanisms]] In [[biology]], '''epigenetics''' is the study of [[Heritability|heritable traits]], or a stable change of cell function, that happen without changes to the [[DNA sequence]].<ref name="Epigenetics 2009 review">{{cite journal | vauthors = Dupont C, Armant DR, Brenner CA | title = Epigenetics: definition, mechanisms and clinical perspective | journal = Seminars in Reproductive Medicine | volume = 27 | issue = 5 | pages = 351–7 | date = September 2009 | pmid = 19711245 | pmc = 2791696 | doi = 10.1055/s-0029-1237423 | quote = In the original sense of this definition, epigenetics referred to all molecular pathways modulating the expression of a genotype into a particular phenotype. Over the following years, with the rapid growth of genetics, the meaning of the word has gradually narrowed. Epigenetics has been defined and today is generally accepted as 'the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence.' }}</ref> The [[Ancient Greek|Greek]] prefix ''[[wikt:epi-|epi-]]'' ({{wikt-lang|grc|ἐπι-}} "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in addition to" the traditional (DNA sequence based) [[gene]]tic mechanism of inheritance.<ref name = science>{{cite news | title=Beware the pseudo gene genies | vauthors = Rutherford A | url= https://www.theguardian.com/science/2015/jul/19/epigenetics-dna--darwin-adam-rutherford | work=[[The Guardian]] | date=19 July 2015 }}</ref> Epigenetics usually involves a change that is not erased by cell division, and affects the [[regulation of gene expression]].<ref>{{cite journal | vauthors = Deans C, Maggert KA | title = What do you mean, "epigenetic"? | journal = Genetics | volume = 199 | issue = 4 | pages = 887–896 | date = April 2015 | pmid = 25855649 | doi = 10.1534/genetics.114.173492 | pmc = 4391566 }}</ref> Such effects on [[cell (biology)|cellular]] and [[physiology|physiological]] [[phenotypic trait]]s may result from [[environment (biophysical)|environmental]] factors, or be part of normal development. They can lead to cancer.<ref>{{cite journal | vauthors = Sharma S, Kelly TK, Jones PA | title = Epigenetics in cancer | journal = Carcinogenesis | volume = 31 | issue = 1 | pages = 27–36 | date = January 2010 | pmid = 19752007 | pmc = 2802667 | doi = 10.1093/carcin/bgp220 }}</ref> The term also refers to the mechanism of changes: functionally relevant alterations to the [[genome]] that do not involve mutation of the [[nucleotide sequence]]. Examples of mechanisms that produce such changes are [[DNA methylation]] and [[histone modification]], each of which alters how genes are expressed without altering the underlying [[DNA]] sequence.<ref>{{cite journal | vauthors = Kanwal R, Gupta S | title = Epigenetic modifications in cancer | journal = Clinical Genetics | volume = 81 | issue = 4 | pages = 303–311 | date = April 2012 | pmid = 22082348 | pmc = 3590802 | doi = 10.1111/j.1399-0004.2011.01809.x }}</ref> Further, non-coding RNA sequences have shown to play a key role in the regulation of gene expression.<ref>{{cite journal | vauthors = Frías-Lasserre D, Villagra CA | title = The Importance of ncRNAs as Epigenetic Mechanisms in Phenotypic Variation and Organic Evolution | journal = Frontiers in Microbiology | volume = 8 | pages = 2483 | date = 2017 | pmid = 29312192 | pmc = 5744636 | doi = 10.3389/fmicb.2017.02483 | doi-access = free }}</ref> Gene expression can be controlled through the action of [[repressor protein]]s that attach to [[silencer (DNA)|silencer]] regions of the DNA. These epigenetic changes may last through [[cell division]]s 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 DNA sequence of the organism;<ref name="pmid17522671">{{cite journal | vauthors = Bird A | title = Perceptions of epigenetics | journal = Nature | volume = 447 | issue = 7143 | pages = 396–398 | date = May 2007 | pmid = 17522671 | doi = 10.1038/nature05913 | s2cid = 4357965 | doi-access = free | bibcode = 2007Natur.447..396B }}</ref> instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.<ref>{{cite web| vauthors = Hunter P |date=1 May 2008|title=What genes remember|url=https://www.prospectmagazine.co.uk/magazine/whatgenesremember|url-status=dead|archive-url=https://web.archive.org/web/20080501094940/http://www.prospect-magazine.co.uk/article_details.php?id=10140|archive-date=1 May 2008|access-date=26 July 2012 |magazine=Prospect Magazine|issue=146}}</ref> One example of an epigenetic change in [[eukaryotic]] biology is the process of [[cellular differentiation]]. During [[morphogenesis]], [[totipotent]] [[stem cells]] become the various [[pluripotent]] [[cell line]]s of the [[embryo]], which in turn become fully differentiated cells. In other words, as a single fertilized [[egg cell]] – the [[zygote]] – continues to [[mitosis|divide]], the resulting daughter cells change into all the different cell types in an organism, including [[neurons]], [[muscle cells]], [[epithelium]], [[endothelium]] of [[blood vessels]], etc., by activating some genes while inhibiting the expression of others.<ref name="pmid17522676">{{cite journal | vauthors = Reik W | title = Stability and flexibility of epigenetic gene regulation in mammalian development | journal = Nature | volume = 447 | issue = 7143 | pages = 425–32 | date = May 2007 | pmid = 17522676 | doi = 10.1038/nature05918 | bibcode = 2007Natur.447..425R | s2cid = 11794102 }}</ref> ==Definitions== The term ''epigenesis'' has a generic meaning of "extra growth" that has been used in English since the 17th century.<ref>[[Oxford English Dictionary]]: "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’."</ref> In scientific publications, the term ''epigenetics'' started to appear in the 1930s (see Fig. on the right). However, its contemporary meaning emerged only in the 1990s.<ref name="Moore_2015">{{cite book |last1=Moore |first1=David S. |title=The Developing Genome: An Introduction to Behavioral Epigenetics |date=2015 |publisher=Oxford University Press |isbn=978-0-19-992235-2 }}{{pn|date=March 2024}}</ref> [[File:EpigenByYear 1.png|thumb|Number of patent families and non-patent documents with the term "epigenetic*" by publication year]] A definition of the concept of ''epigenetic trait'' as a "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" was formulated at a [[Cold Spring Harbor Laboratory|Cold Spring Harbor]] meeting in 2008,<ref name="pmid19339683"/> although alternate definitions that include non-heritable traits are still being used widely.<ref name="NIH">{{cite web |title=Overview |url=http://www.roadmapepigenomics.org/overview |work=NIH Roadmap Epigenomics Project |access-date=7 December 2013 |archive-date=21 November 2019 |archive-url=https://web.archive.org/web/20191121014029/http://www.roadmapepigenomics.org/overview |url-status=dead }}</ref> ===Waddington's canalisation, 1940s=== The hypothesis of epigenetic changes affecting the expression of [[chromosome]]s was put forth by the Russian biologist [[Nikolai Koltsov]].<ref>Morange M. ''La tentative de Nikolai Koltzoff (Koltsov) de lier génétique, embryologie et chimie physique'', J. Biosciences. 2011. V. 36. P. 211-214</ref> From the generic meaning, and the associated adjective ''epigenetic'', British embryologist [[C. H. Waddington]] coined the term ''epigenetics'' in 1942 as pertaining to ''[[epigenesis (biology)|epigenesis]]'', in parallel to [[Valentin Haecker]]'s 'phenogenetics' ({{lang|de|Phänogenetik}}).<ref name=waddington>{{cite journal| vauthors = Waddington CH | title=The epigenotype| journal=Endeavour | volume=1 | pages=18–20 | year=1942 }} "For the purpose of a study of inheritance, the relation between phenotypes and genotypes [...] is, from a wider biological point of view, of crucial importance, since it is the kernel of the whole problem of development." </ref> ''Epigenesis'' in the context of the biology of that period referred to the [[cellular differentiation|differentiation]] of cells from their initial [[totipotent]] state during [[embryonic development]].<ref>See ''[[preformationism]]'' for historical background. ''[[Oxford English Dictionary]]'': "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'."</ref> When Waddington coined the term, the physical nature of [[gene]]s and their role in heredity was not known. He used it instead as a conceptual model of how genetic components might interact with their surroundings to produce a [[phenotype]]; he used the phrase "[[epigenetic landscape]]" as a metaphor for [[morphogenesis|biological development]]. Waddington held that cell fates were established during development in a process he called [[canalisation (genetics)|canalisation]] much as a marble rolls down to the point of [[local optimum|lowest local elevation]].<ref name="Waddington2014">{{cite book | vauthors = Waddington CH |title=The Epigenetics of Birds |date=2014 |publisher=Cambridge University Press |isbn=978-1-107-44047-0 }}{{page needed|date=January 2020}}</ref> Waddington suggested visualising increasing irreversibility of cell type differentiation as ridges rising between the valleys where the marbles (analogous to cells) are travelling.<ref>{{cite journal | vauthors = Hall BK | title = In search of evolutionary developmental mechanisms: the 30-year gap between 1944 and 1974 | journal = Journal of Experimental Zoology Part B: Molecular and Developmental Evolution | volume = 302 | issue = 1 | pages = 5–18 | date = January 2004 | pmid = 14760651 | doi = 10.1002/jez.b.20002 | bibcode = 2004JEZ...302....5H | doi-access = free }}</ref> In recent times, Waddington's notion of the epigenetic landscape has been rigorously formalized in the context of the [[system dynamics|systems dynamics]] state approach to the study of cell-fate.<ref>{{cite journal | vauthors = Alvarez-Buylla ER, Chaos A, Aldana M, Benítez M, Cortes-Poza Y, Espinosa-Soto C, Hartasánchez DA, Lotto RB, Malkin D, Escalera Santos GJ, Padilla-Longoria P | display-authors = 6 | title = Floral morphogenesis: stochastic explorations of a gene network epigenetic landscape | journal = PLOS ONE | volume = 3 | issue = 11 | pages = e3626 | date = 3 November 2008 | pmid = 18978941 | pmc = 2572848 | doi = 10.1371/journal.pone.0003626 | bibcode = 2008PLoSO...3.3626A | doi-access = free }}</ref><ref name="sciencedirect.com">{{cite journal | vauthors = Rabajante JF, Babierra AL | title = Branching and oscillations in the epigenetic landscape of cell-fate determination | journal = Progress in Biophysics and Molecular Biology | volume = 117 | issue = 2–3 | pages = 240–249 | date = March 2015 | pmid = 25641423 | doi = 10.1016/j.pbiomolbio.2015.01.006 | s2cid = 2579314 }}</ref> Cell-fate determination is predicted to exhibit certain dynamics, such as attractor-convergence (the attractor can be an equilibrium point, limit cycle or [[strange attractor]]) or oscillatory.<ref name="sciencedirect.com"/> ===Contemporary=== [[Robin Holliday]] defined in 1990 epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms."<ref name="pmid2265224">{{cite journal | vauthors = Holliday R | title = DNA methylation and epigenetic inheritance | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 326 | issue = 1235 | pages = 329–38 | date = January 1990 | pmid = 1968668 | doi = 10.1098/rstb.1990.0015 | bibcode = 1990RSPTB.326..329H | doi-access = free }}</ref> More recent usage of the word in biology follows stricter definitions. As defined by [[Arthur Riggs (geneticist)|Arthur Riggs]] and colleagues, it is "the study of [[mitosis|mitotically]] and/or [[meiosis|meiotically]] heritable changes in gene function that cannot be explained by changes in DNA sequence."<ref name="isbn0-87969-490-4">{{cite book |vauthors=Riggs AD, Martienssen RA, Russo VE | title=Epigenetic mechanisms of gene regulation | publisher=Cold Spring Harbor Laboratory Press | location=Plainview, NY | year=1996 | pages=1–4| isbn=978-0-87969-490-6 }}{{page needed|date=August 2013}}</ref> The term has also been used, however, to describe processes which have not been demonstrated to be heritable, such as some forms of histone modification. Consequently, there are attempts to redefine "epigenetics" in broader terms that would avoid the constraints of requiring [[heritability]]. For example, [[Adrian Peter Bird|Adrian Bird]] defined epigenetics as "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states."<ref name="pmid17522671" /> This definition would be inclusive of transient modifications associated with [[DNA repair]] or [[cell-cycle]] phases as well as stable changes maintained across multiple cell generations, but exclude others such as templating of membrane architecture and [[prions]] unless they impinge on chromosome function. Such redefinitions however are not universally accepted and are still subject to debate.<ref name="nature2008">{{cite journal | vauthors = Ledford H | title = Language: Disputed definitions | journal = Nature | volume = 455 | issue = 7216 | pages = 1023–8 | date = October 2008 | pmid = 18948925 | doi = 10.1038/4551023a | doi-access = free }}</ref> The [[National Institutes of Health|NIH]] "Roadmap Epigenomics Project", which ran from 2008 to 2017, uses the following definition: "For purposes of this program, epigenetics refers to both heritable changes in gene activity and [[gene expression|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."<ref>{{cite journal | vauthors = Gibney ER, Nolan CM | title = Epigenetics and gene expression | journal = Heredity | volume = 105 | issue = 1 | pages = 4–13 | date = July 2010 | pmid = 20461105 | doi = 10.1038/hdy.2010.54 | s2cid = 31611763 | doi-access = free }}</ref> In 2008, a consensus definition of the epigenetic trait, a "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence," was made at a [[Cold Spring Harbor Laboratory|Cold Spring Harbor]] meeting.<ref name="pmid19339683">{{cite journal | vauthors = Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A | title = An operational definition of epigenetics | journal = Genes & Development | volume = 23 | issue = 7 | pages = 781–3 | date = April 2009 | pmid = 19339683 | pmc = 3959995 | doi = 10.1101/gad.1787609 }}</ref> The similarity of the word to "genetics" has generated many parallel usages. The "[[epigenome]]" is a parallel to the word "[[genome]]", referring to the overall epigenetic state of a cell, and [[epigenomics]] refers to global analyses of epigenetic changes across the entire genome.<ref name="NIH"/> The phrase "[[genetic code]]" has also been adapted – the "[[epigenetic code]]" has been used to describe the set of epigenetic features that create different phenotypes in different cells from the same underlying DNA sequence. 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 [[histone code hypothesis|histone code]] or [[DNA methylation]] patterns.{{citation needed|date=April 2019}} ==Mechanisms== [[Covalent]] modification of either DNA (e.g. cytosine methylation and hydroxymethylation) or of histone proteins (e.g. lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation) play central roles in many types of epigenetic inheritance. Therefore, 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.<ref name="pmid17407749">{{cite journal | vauthors = Ptashne M | title = On the use of the word 'epigenetic' | journal = Current Biology | volume = 17 | issue = 7 | pages = R233-6 | date = April 2007 | pmid = 17407749 | doi = 10.1016/j.cub.2007.02.030 | s2cid = 17490277 | doi-access = free | bibcode = 2007CBio...17.R233P }}</ref> In 2019, a further lysine modification appeared in the scientific literature linking epigenetics modification to cell metabolism, i.e. Lactylation<ref>{{cite journal | vauthors = Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Becker L, Zhao Y | display-authors = 6 | title = Metabolic regulation of gene expression by histone lactylation | journal = Nature | volume = 574 | issue = 7779 | pages = 575–580 | date = October 2019 | pmid = 31645732 | pmc = 6818755 | doi = 10.1038/s41586-019-1678-1 | bibcode = 2019Natur.574..575Z }}</ref> [[File:Nucleosome 1KX5 2.png|thumb|DNA associates with histone proteins to form chromatin.]] Because the [[phenotype]] of a cell or individual is affected by which of its genes are transcribed, heritable [[Transcription (genetics)|transcription states]] can give rise to epigenetic effects. There are several layers of regulation of [[gene expression]]. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the [[histone]] 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: # The first way is [[post translational modification]] 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 them, these modified histones would ensure that a lineage-specific transcription program is maintained after cell division. # The second way is the addition of methyl groups to the DNA, mostly at [[CpG site]]s, to convert [[cytosine]] to [[5-methylcytosine]]. 5-Methylcytosine performs much like a regular cytosine, pairing with a guanine in double-stranded DNA. However, when methylated cytosines are present in [[CpG site]]s in the [[Promoter (genetics)|promoter]] and [[Enhancer (genetics)|enhancer]] regions of genes, the genes are often repressed.<ref name="pmid30619465">{{cite journal | vauthors = Kumar S, Chinnusamy V, Mohapatra T | title = Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond | journal = Frontiers in Genetics | volume = 9 | pages = 640 | date = 2018 | pmid = 30619465 | pmc = 6305559 | doi = 10.3389/fgene.2018.00640 | doi-access = free }}</ref><ref name="pmid31399642">{{cite journal | vauthors = Greenberg MV, Bourc'his D | title = The diverse roles of DNA methylation in mammalian development and disease | journal = Nature Reviews. Molecular Cell Biology | volume = 20 | issue = 10 | pages = 590–607 | date = October 2019 | pmid = 31399642 | doi = 10.1038/s41580-019-0159-6 | s2cid = 199512037 }}</ref> When methylated cytosines are present in [[CpG site]]s in the gene body (in the [[coding region]] excluding the transcription start site) expression of the gene is often enhanced. Transcription of a gene usually depends on a [[transcription factor]] binding to a (10 base or less) [[recognition sequence]] at the enhancer that interacts with the promoter region of that gene ([[Gene expression#Enhancers, transcription factors, mediator complex and DNA loops in mammalian transcription]]).<ref name="pmid22868264">{{cite journal |vauthors=Spitz F, Furlong EE |title=Transcription factors: from enhancer binding to developmental control |journal=Nat Rev Genet |volume=13 |issue=9 |pages=613–26 |date=September 2012 |pmid=22868264 |doi=10.1038/nrg3207 |s2cid=205485256 |url=}}</ref> About 22% of transcription factors are inhibited from binding when the recognition sequence has a methylated cytosine. In addition, presence of methylated cytosines at a promoter region can attract [[methyl-CpG-binding domain]] (MBD) proteins. All MBDs interact with [[nucleosome]] remodeling and [[histone deacetylase]] complexes, which leads to gene silencing. In addition, another covalent modification involving methylated cytosine is its [[DNA demethylation|demethylation]] by [[TET enzymes]]. Hundreds of such demethylations occur, for instance, during [[DNA demethylation#Learnking and memory|learning and memory]] forming events in [[neuron]]s.<ref name="pmid28620075">{{cite journal |vauthors=Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD |title=Experience-dependent epigenomic reorganization in the hippocampus |journal=Learn Mem |volume=24 |issue=7 |pages=278–288 |date=July 2017 |pmid=28620075 |pmc=5473107 |doi=10.1101/lm.045112.117 |url=}}</ref><ref name="Bernstein">{{cite journal |vauthors=Bernstein C |title=DNA Methylation and Establishing Memory |journal=Epigenet Insights |volume=15 |issue= |pages=25168657211072499 |date=2022 |pmid=35098021 |pmc=8793415 |doi=10.1177/25168657211072499 |url=}}</ref> There is frequently a reciprocal relationship between DNA methylation and histone lysine methylation.<ref name=Rose>{{cite journal |vauthors=Rose NR, Klose RJ |title=Understanding the relationship between DNA methylation and histone lysine methylation |journal=Biochim Biophys Acta |volume=1839 |issue=12 |pages=1362–72 |date=December 2014 |pmid=24560929 |pmc=4316174 |doi=10.1016/j.bbagrm.2014.02.007 |url=}}</ref> For instance, the [[Methyl-CpG-binding domain|methyl binding domain protein MBD1]], attracted to and associating with [[5-Methylcytosine|methylated cytosine]] in a DNA [[CpG site]], can also associate with H3K9 [[DNA methyltransferase|methyltransferase]] activity to methylate histone 3 at lysine 9. On the other hand, DNA maintenance methylation by [[DNMT1]] appears to partly rely on recognition of histone methylation on the nucleosome present at the DNA site to carry out cytosine methylation on newly synthesized DNA.<ref name=Rose /> There is further crosstalk between DNA methylation carried out by [[DNMT3A]] and [[DNMT3B]] and histone methylation so that there is a correlation between the genome-wide distribution of DNA methylation and histone methylation.<ref name=Li2021>{{cite journal |vauthors=Li Y, Chen X, Lu C |title=The interplay between DNA and histone methylation: molecular mechanisms and disease implications |journal=EMBO Rep |volume=22 |issue=5 |pages=e51803 |date=May 2021 |pmid=33844406 |pmc=8097341 |doi=10.15252/embr.202051803 |url=}}</ref> 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 [[DNA methyltransferase|DNMT1]]) 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. However, it is now known that DNMT1 physically interacts with the protein [[UHRF1]]. UHRF1 has been recently recognized as essential for DNMT1-mediated maintenance of DNA methylation. UHRF1 is the protein that specifically recognizes hemi-methylated DNA, therefore bringing DNMT1 to its substrate to maintain DNA methylation.<ref name=Li2021 /> [[File:Histone tails set for transcriptional activation.jpg|thumb|'''Some acetylations and some methylations of lysines (symbol K) are activation signals for transcription when present on a [[nucleosome]], as shown in the top figure.''' '''Some methylations on lysines or arginine (R) are repression signals for transcription when present on a [[nucleosome]], as shown in the bottom figure.''' [[Nucleosome]]s consist of four pairs of [[histone]] proteins in a tightly assembled core region plus up to 30% of each histone remaining in a loosely organized tail<ref name="pmid33133421">{{cite journal |vauthors=Bendandi A, Patelli AS, Diaspro A, Rocchia W |title=The role of histone tails in nucleosome stability: An electrostatic perspective |journal=Comput Struct Biotechnol J |volume=18 |issue= |pages=2799–2809 |date=2020 |pmid=33133421 |pmc=7575852 |doi=10.1016/j.csbj.2020.09.034 |url=}}</ref> (only one tail of each pair is shown). DNA is wrapped around the histone core proteins in [[chromatin]]. The lysines (K) are designated with a number showing their position as, for instance (K4), indicating lysine as the 4th amino acid from the amino (N) end of the tail in the histone protein. [[Methylation]]s [Me], and [[acetylation]]s [Ac] are common [[post-translational modification]]s on the lysines of the histone tails.]] [[File:Histone tails set for transcriptional repression.jpg|thumb]] Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include [[acetylation]], [[methylation]], [[ubiquitylation]], [[phosphorylation]], [[sumoylation]], ribosylation and citrullination. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 [[lysine]]s of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally related to transcriptional competence<ref>{{cite journal | vauthors = Stewart MD, Li J, Wong J | title = Relationship between histone H3 lysine 9 methylation, transcription repression, and heterochromatin protein 1 recruitment | journal = Molecular and Cellular Biology | volume = 25 | issue = 7 | pages = 2525–2538 | date = April 2005 | pmid = 15767660 | pmc = 1061631 | doi = 10.1128/MCB.25.7.2525-2538.2005 }}</ref> (see Figure). 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 [[SWI/SNF]] and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of the epigenetic function. In other words, changes to the histone tails have a direct effect on the DNA itself.<ref>{{cite book |doi=10.1201/b16905-14 |chapter=Genetic disorders and gene therapy |title=Biotechnology in Medical Sciences |date=2014 |pages=264–289 |isbn=978-0-429-17411-7 |first1=Firdos Alam |last1=Khan }}</ref> 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 [[SWI/SNF]] 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 [[histone methylation]] as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive [[heterochromatin]]) (see bottom Figure). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein [[Heterochromatin Protein 1|HP1]] 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 (see top Figure). 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.<ref name="pmid9487389">{{cite journal | vauthors = Jenuwein T, Laible G, Dorn R, Reuter G | title = SET domain proteins modulate chromatin domains in eu- and heterochromatin | journal = Cellular and Molecular Life Sciences | volume = 54 | issue = 1 | pages = 80–93 | date = January 1998 | pmid = 9487389 | doi = 10.1007/s000180050127 | s2cid = 7769686 }}</ref> 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 [[histone code]], 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 orchestrate chromatin-based silencing is the [[SIR protein]] based silencing of the yeast hidden mating-type loci HML and HMR. ===DNA methylation=== {{further|Methylation}} [[DNA methylation]] frequently occurs in repeated sequences, and helps to suppress the expression and mobility of '[[transposable elements]]':<ref name="slotkin2007">{{cite journal | vauthors = Slotkin RK, Martienssen R | title = Transposable elements and the epigenetic regulation of the genome | journal = Nature Reviews. Genetics | volume = 8 | issue = 4 | pages = 272–85 | date = April 2007 | pmid = 17363976 | doi = 10.1038/nrg2072 | s2cid = 9719784 }}</ref> Because [[5-methylcytosine]] can be spontaneously deaminated (replacing nitrogen by oxygen) to [[thymidine]], CpG sites are frequently mutated and become rare in the genome, except at [[CpG islands]] where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent [[DNA methyltransferase]]s, DNMT1, DNMT3A, and DNMT3B, the loss of any of which is lethal in mice.<ref name="li92">{{cite journal | vauthors = Li E, Bestor TH, Jaenisch R | title = Targeted mutation of the DNA methyltransferase gene results in embryonic lethality | journal = Cell | volume = 69 | issue = 6 | pages = 915–26 | date = June 1992 | pmid = 1606615 | doi = 10.1016/0092-8674(92)90611-F | s2cid = 19879601 }}</ref> In invertebrate of social honey bees, main enzymes are DNMT1 and DNMT3.<ref>{{cite journal |last1=Li-Byarlay |first1=Hongmei |title=The Function of DNA Methylation Marks in Social Insects |journal=Frontiers in Ecology and Evolution |date=19 May 2016 |volume=4 |doi=10.3389/fevo.2016.00057 |doi-access=free }}</ref> DNMT1 is the most abundant methyltransferase in somatic cells,<ref name="robertson99">{{cite journal | vauthors = Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA | title = The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors | journal = Nucleic Acids Research | volume = 27 | issue = 11 | pages = 2291–8 | date = June 1999 | pmid = 10325416 | pmc = 148793 | doi = 10.1093/nar/27.11.2291 }}</ref> localizes to replication foci,<ref name="leonhardt92">{{cite journal | vauthors = Leonhardt H, Page AW, Weier HU, Bestor TH | title = A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei | journal = Cell | volume = 71 | issue = 5 | pages = 865–73 | date = November 1992 | pmid = 1423634 | doi = 10.1016/0092-8674(92)90561-P | s2cid = 5995820 | url = https://epub.ub.uni-muenchen.de/5003/1/003.pdf }}</ref> has a 10–40-fold preference for hemimethylated DNA and interacts with the [[proliferating cell nuclear antigen]] (PCNA).<ref name="chuang97">{{cite journal | vauthors = Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF | title = Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1 | journal = Science | volume = 277 | issue = 5334 | pages = 1996–2000 | date = September 1997 | pmid = 9302295 | doi = 10.1126/science.277.5334.1996 }}</ref> By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after [[DNA replication]], and therefore is often referred to as the 'maintenance' methyltransferase.<ref name="robertson00">{{cite journal | vauthors = Robertson KD, Wolffe AP | title = DNA methylation in health and disease | journal = Nature Reviews. Genetics | volume = 1 | issue = 1 | pages = 11–9 | date = October 2000 | pmid = 11262868 | doi = 10.1038/35049533 | s2cid = 1915808 }}</ref> DNMT1 is essential for proper embryonic development, imprinting and X-inactivation.<ref name="li92" /><ref name="li93">{{cite journal | vauthors = Li E, Beard C, Jaenisch R | title = Role for DNA methylation in genomic imprinting | journal = Nature | volume = 366 | issue = 6453 | pages = 362–5 | date = November 1993 | pmid = 8247133 | doi = 10.1038/366362a0 | bibcode = 1993Natur.366..362L | s2cid = 4311091 }}</ref> 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.<ref>{{cite journal | vauthors = Viens A, Mechold U, Brouillard F, Gilbert C, Leclerc P, Ogryzko V | title = Analysis of human histone H2AZ deposition in vivo argues against its direct role in epigenetic templating mechanisms | journal = Molecular and Cellular Biology | volume = 26 | issue = 14 | pages = 5325–35 | date = July 2006 | pmid = 16809769 | pmc = 1592707 | doi = 10.1128/MCB.00584-06 }}</ref> 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 ([[Structural inheritance|structural]]) heritable states.<ref name="pmid18419815">{{cite journal | vauthors = Ogryzko VV | title = Erwin Schroedinger, Francis Crick and epigenetic stability | journal = Biology Direct | volume = 3 | pages = 15 | date = April 2008 | pmid = 18419815 | pmc = 2413215 | doi = 10.1186/1745-6150-3-15 | doi-access = free }}</ref> In invertebrates of [[honey bee]]s, DNA methylation has been studied since the honey bee genome <ref>The Honeybee Genome Sequencing Consortium [https://www.nature.com/articles/nature05260 The Honeybee Genome Sequencing Consortium]</ref> was sequenced in 2006. DNA methylation is associated with alternative splicing and gene regulation based on functional genomic research published in 2013.<ref name="ReferenceC"/> In addition, DNA methylation is associated with the changes of expression in immune genes when honey bees were under lethal viral infection in a timely manner.<ref name="Li-Byarlay et al 2020"/> Several review papers have been published on the topics of DNA methylation in social insects.<ref>{{cite book |doi=10.1016/bs.aiip.2015.06.002 |title=Physiological and Molecular Mechanisms of Nutrition in Honey Bees |series=Advances in Insect Physiology |date=2015 |last1=Wang |first1=Ying |last2=Li-Byarlay |first2=Hongmei |volume=49 |pages=25–58 |isbn=978-0-12-802586-4 }}</ref> ===RNA methylation=== {{further|Methylation}} RNA methylation of N6-methyladenosine (m6A) as the most abundant eukaryotic RNA modification has recently been recognized as an important gene regulatory mechanism.<ref>Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer. 2020;20(6):303–22.</ref> In invertebrates such as social insects of honey bees, RNA methylation is studied to be a possible epigenetic mechanism underlying aggression via reciprocal crosses.<ref>{{cite journal |last1=Bresnahan |first1=Sean T. |last2=Lee |first2=Ellen |last3=Clark |first3=Lindsay |last4=Ma |first4=Rong |last5=Rangel |first5=Juliana |last6=Grozinger |first6=Christina M. |last7=Li-Byarlay |first7=Hongmei |title=Examining parent-of-origin effects on transcription and RNA methylation in mediating aggressive behavior in honey bees (Apis mellifera) |journal=BMC Genomics |date=12 June 2023 |volume=24 |issue=1 |page=315 |doi=10.1186/s12864-023-09411-4 |doi-access=free |pmid=37308882 |pmc=10258952 }}</ref> ===Histone modifications=== 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.<ref name="pmid19234061">{{cite journal | vauthors = Nottke A, Colaiácovo MP, Shi Y | title = Developmental roles of the histone lysine demethylases | journal = Development | volume = 136 | issue = 6 | pages = 879–89 | date = March 2009 | pmid = 19234061 | pmc = 2692332 | doi = 10.1242/dev.020966 }}</ref> 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 [[covalent modification]]s of histones.<ref name="Rosenfeld_2009">{{cite journal | vauthors = Rosenfeld JA, Wang Z, Schones DE, Zhao K, DeSalle R, Zhang MQ | title = Determination of enriched histone modifications in non-genic portions of the human genome | journal = BMC Genomics | volume = 10 | pages = 143 | date = March 2009 | pmid = 19335899 | pmc = 2667539 | doi = 10.1186/1471-2164-10-143 | doi-access = free }}</ref> The stability and heritability of states of larger chromosomal regions are suggested to involve positive feedback where modified [[nucleosome]]s recruit enzymes that similarly modify nearby nucleosomes.<ref>{{cite journal | vauthors = Sneppen K, Micheelsen MA, Dodd IB | title = Ultrasensitive gene regulation by positive feedback loops in nucleosome modification | journal = Molecular Systems Biology | volume = 4 | issue = 1 | pages = 182 | date = 15 April 2008 | pmid = 18414483 | pmc = 2387233 | doi = 10.1038/msb.2008.21 }}</ref> A simplified stochastic model for this type of epigenetics is found here.<ref>{{cite web |url=http://cmol.nbi.dk/models/epigen/Epigen.html |title=Epigenetic cell memory |publisher=Cmol.nbi.dk |access-date=26 July 2012 |archive-url=https://web.archive.org/web/20110930093915/http://cmol.nbi.dk/models/epigen/Epigen.html |archive-date=30 September 2011 |url-status=dead }}</ref><ref name="pmid17512413">{{cite journal | vauthors = Dodd IB, Micheelsen MA, Sneppen K, Thon G | title = Theoretical analysis of epigenetic cell memory by nucleosome modification | journal = Cell | volume = 129 | issue = 4 | pages = 813–22 | date = May 2007 | pmid = 17512413 | doi = 10.1016/j.cell.2007.02.053 | s2cid = 16091877 | doi-access = free }}</ref> It has been suggested that chromatin-based transcriptional regulation could be mediated by the effect of small RNAs. [[Small interfering RNA]]s can modulate transcriptional gene expression via epigenetic modulation of targeted [[Promoter (biology)|promoters]].<ref name="Morris">{{cite book | vauthors = Morris KL | title=RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity | chapter=Epigenetic Regulation of Gene Expression | publisher=Caister Academic Press | location=Norfolk, England | year=2008 | isbn=978-1-904455-25-7 }}{{page needed|date=August 2013}}</ref> ===RNA transcripts=== Sometimes a gene, after being turned on, transcribes a product that (directly or indirectly) maintains the activity of that gene. For example, [[Hnf4]] and [[MyoD]] enhance the transcription of many liver-specific and muscle-specific genes, respectively, including their own, through the [[transcription factor]] activity of the [[proteins]] 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.<ref name="pmid19154003">{{cite journal | vauthors = Mattick JS, Amaral PP, Dinger ME, Mercer TR, Mehler MF | title = RNA regulation of epigenetic processes | journal = BioEssays | volume = 31 | issue = 1 | pages = 51–9 | date = January 2009 | pmid = 19154003 | doi = 10.1002/bies.080099 | s2cid = 19293469 | doi-access = free }}</ref> Other epigenetic changes are mediated by the production of [[alternative splicing|different splice forms]] of [[RNA]], or by formation of double-stranded RNA ([[RNAi]]). 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 [[signal transduction]], although in some systems where [[syncytia]] or [[gap junction]]s are important, RNA may spread directly to other cells or nuclei by [[diffusion]]. A large amount of RNA and protein is contributed to the [[zygote]] by the mother during [[oogenesis]] or via [[nurse cell]]s, resulting in [[maternal effect]] 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.<ref name="choi06">{{cite web| vauthors = Choi CQ |title=RNA can be hereditary molecule |website=The Scientist |url=http://www.the-scientist.com/news/display/23494/ |date=25 May 2006 |url-status=dead |archive-date=8 February 2007 |archive-url=https://web.archive.org/web/20070208182915/http://www.the-scientist.com/news/display/23494/ }}</ref> ===MicroRNAs=== [[MicroRNA]]s (miRNAs) are members of [[non-coding RNA]]s that range in size from 17 to 25 nucleotides. miRNAs regulate a large variety of biological functions in plants and animals.<ref name=Wang>{{cite journal | vauthors = Wang Z, Yao H, Lin S, Zhu X, Shen Z, Lu G, Poon WS, Xie D, Lin MC, Kung HF | display-authors = 6 | title = Transcriptional and epigenetic regulation of human microRNAs | journal = Cancer Letters | volume = 331 | issue = 1 | pages = 1–10 | date = April 2013 | pmid = 23246373 | doi = 10.1016/j.canlet.2012.12.006 }}</ref> So far, in 2013, about 2000 miRNAs have been discovered in humans and these can be found online in a miRNA database.<ref>{{cite web| url = http://www.mirbase.org/cgi-bin/browse.pl| title = Browse miRBase by species<!-- Bot generated title -->}}</ref> Each miRNA expressed in a cell may target about 100 to 200 messenger RNAs(mRNAs) that it downregulates.<ref>{{cite journal | vauthors = Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM | display-authors = 6 | title = Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs | journal = Nature | volume = 433 | issue = 7027 | pages = 769–73 | date = February 2005 | pmid = 15685193 | doi = 10.1038/nature03315 | bibcode = 2005Natur.433..769L | s2cid = 4430576 }}</ref> 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.<ref>{{cite journal | vauthors = Lee D, Shin C | title = MicroRNA-target interactions: new insights from genome-wide approaches | journal = Annals of the New York Academy of Sciences | volume = 1271 | issue = 1 | pages = 118–28 | date = October 2012 | pmid = 23050973 | pmc = 3499661 | doi = 10.1111/j.1749-6632.2012.06745.x | bibcode = 2012NYASA1271..118L }}</ref> It appears that about 60% of human protein coding genes are regulated by miRNAs.<ref>{{cite journal | vauthors = Friedman RC, Farh KK, Burge CB, Bartel DP | title = Most mammalian mRNAs are conserved targets of microRNAs | journal = Genome Research | volume = 19 | issue = 1 | pages = 92–105 | date = January 2009 | pmid = 18955434 | pmc = 2612969 | doi = 10.1101/gr.082701.108 }}</ref> Many miRNAs are epigenetically regulated. About 50% of miRNA genes are associated with [[CpG island]]s,<ref name=Wang /> that may be repressed by epigenetic methylation. Transcription from methylated CpG islands is strongly and heritably repressed.<ref>{{cite journal | vauthors = Goll MG, Bestor TH | title = Eukaryotic cytosine methyltransferases | journal = Annual Review of Biochemistry | volume = 74 | pages = 481–514 | year = 2005 | pmid = 15952895 | doi = 10.1146/annurev.biochem.74.010904.153721 | s2cid = 32123961 }}</ref> Other miRNAs are epigenetically regulated by either histone modifications or by combined DNA methylation and histone modification.<ref name=Wang /> ===mRNA=== In 2011, it was demonstrated that the [[methylation]] of [[messenger RNA|mRNA]] plays a critical role in human [[energy balance (biology)|energy homeostasis]]. The obesity-associated [[FTO gene]] is shown to be able to [[demethylate]] [[N6-methyladenosine]] in RNA.<ref>{{cite journal | vauthors = Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C | display-authors = 6 | title = N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO | journal = Nature Chemical Biology | volume = 7 | issue = 12 | pages = 885–7 | date = October 2011 | pmid = 22002720 | pmc = 3218240 | doi = 10.1038/nchembio.687 }}</ref><ref>{{cite web|url=http://www.physorg.com/news/2011-10-links-common-rna-modification-obesity.html |title=New research links common RNA modification to obesity |publisher=Physorg.com |access-date=26 July 2012}}</ref> ===sRNAs=== [[Bacterial small RNA|sRNAs]] are small (50–250 nucleotides), highly structured, non-coding RNA fragments found in bacteria. They control gene expression including [[virulence]] genes in pathogens and are viewed as new targets in the fight against drug-resistant bacteria.<ref>{{cite journal | vauthors = Howden BP, Beaume M, Harrison PF, Hernandez D, Schrenzel J, Seemann T, Francois P, Stinear TP | display-authors = 6 | title = Analysis of the small RNA transcriptional response in multidrug-resistant Staphylococcus aureus after antimicrobial exposure | journal = Antimicrobial Agents and Chemotherapy | volume = 57 | issue = 8 | pages = 3864–74 | date = August 2013 | pmid = 23733475 | pmc = 3719707 | doi = 10.1128/AAC.00263-13 }}</ref> 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 [[Hfq binding sRNA|binding properties]], are used to build comprehensive databases.<ref>{{cite web | url = http://ccb.bmi.ac.cn/srnatarbase/ | title = sRNATarBase 2.0 A comprehensive database of bacterial SRNA targets verified by experiments | archive-url = https://web.archive.org/web/20130926215123/http://ccb.bmi.ac.cn/srnatarbase/ | archive-date=26 September 2013 }}</ref> sRNA-[[gene map]]s based on their targets in microbial genomes are also constructed.<ref>{{cite web| url = http://srnamap.mbc.nctu.edu.tw/| title = Genomics maps for small non-coding RNA's and their targets in microbial genomes| access-date = 13 August 2013| archive-date = 8 June 2017| archive-url = https://web.archive.org/web/20170608145627/http://srnamap.mbc.nctu.edu.tw/| url-status = dead}}</ref> ===Long non-coding RNAs=== Numerous investigations have demonstrated the pivotal involvement of long non-coding RNAs (lncRNAs) in the regulation of gene expression and chromosomal modifications, thereby exerting significant control over cellular differentiation. These long non-coding RNAs also contribute to genomic imprinting and the inactivation of the X chromosome.<ref>Ruffo, Paola, et al. "Long-noncoding RNAs as epigenetic regulators in neurodegenerative diseases." Neural Regeneration Research 18.6 (2023): 1243.</ref> In invertebrates such as social insects of honey bees, long non-coding RNAs are detected as a possible epigenetic mechanism via allele-specific genes underlying aggression via reciprocal crosses.<ref>{{cite journal |last1=Bresnahan |first1=Sean T. |last2=Lee |first2=Ellen |last3=Clark |first3=Lindsay |last4=Ma |first4=Rong |last5=Rangel |first5=Juliana |last6=Grozinger |first6=Christina M. |last7=Li-Byarlay |first7=Hongmei |title=Examining parent-of-origin effects on transcription and RNA methylation in mediating aggressive behavior in honey bees (Apis mellifera) |journal=BMC Genomics |date=12 June 2023 |volume=24 |issue=1 |page=315 |doi=10.1186/s12864-023-09411-4 |doi-access=free |pmid=37308882 |pmc=10258952 }}</ref> ===Prions=== {{further|Fungal prions}} [[Prion]]s are [[Infection|infectious]] forms of [[protein]]s. 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 [[Transmissible spongiform encephalopathy|infectious disease]], 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.<ref>{{cite journal | title=Epigenetic inheritance and prions|vauthors=Yool A, Edmunds WJ | journal=Journal of Evolutionary Biology | year=1998 | pages=241–42 | volume=11 | doi=10.1007/s000360050085 | issue=2}}</ref> [[Fungal prion]]s are considered by some to be epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. [[PSI (prion)|PSI+]] and URE3, discovered in [[Saccharomyces cerevisiae|yeast]] in 1965 and 1971, are the two best studied of this type of prion.<ref>{{cite journal|title=[PSI], a cytoplasmic suppressor of super-suppression in yeast | vauthors = Cox BS| journal=Heredity | volume=20 | pages=505–21 | year=1965 | doi=10.1038/hdy.1965.65 | issue=4| doi-access=free }}</ref><ref name="pmid5573734">{{cite journal | vauthors = Lacroute F | title = Non-Mendelian mutation allowing ureidosuccinic acid uptake in yeast | journal = Journal of Bacteriology | volume = 106 | issue = 2 | pages = 519–22 | date = May 1971 | pmid = 5573734 | pmc = 285125 | doi = 10.1128/JB.106.2.519-522.1971}}</ref> 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 [[codon]]s, an effect that results in suppression of [[nonsense mutation]]s in other genes.<ref name="pmid225301">{{cite journal | vauthors = Liebman SW, Sherman F | title = Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast | journal = Journal of Bacteriology | volume = 139 | issue = 3 | pages = 1068–71 | date = September 1979 | pmid = 225301 | pmc = 218059 | doi = 10.1128/JB.139.3.1068-1071.1979}}</ref> The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to [[Evolutionary capacitance|switch into a PSI+ state]] and express dormant genetic features normally terminated by stop codon mutations.<ref name="pmid11028992">{{cite journal | vauthors = True HL, Lindquist SL | title = A yeast prion provides a mechanism for genetic variation and phenotypic diversity | journal = Nature | volume = 407 | issue = 6803 | pages = 477–83 | date = September 2000 | pmid = 11028992 | doi = 10.1038/35035005 | bibcode = 2000Natur.407..477T | s2cid = 4411231 }}</ref><ref name="pmid15931169">{{cite journal | vauthors = Shorter J, Lindquist S | title = Prions as adaptive conduits of memory and inheritance | journal = Nature Reviews. Genetics | volume = 6 | issue = 6 | pages = 435–50 | date = June 2005 | pmid = 15931169 | doi = 10.1038/nrg1616 | s2cid = 5575951 }}</ref><ref>{{cite journal | vauthors = Giacomelli MG, Hancock AS, Masel J | title = The conversion of 3' UTRs into coding regions | journal = Molecular Biology and Evolution | volume = 24 | issue = 2 | pages = 457–64 | date = February 2007 | pmid = 17099057 | pmc = 1808353 | doi = 10.1093/molbev/msl172 | author3-link = Joanna Masel }}</ref><ref>{{cite journal | vauthors = Lancaster AK, Bardill JP, True HL, Masel J | title = The spontaneous appearance rate of the yeast prion [PSI+] and its implications for the evolution of the evolvability properties of the [PSI+] system | journal = Genetics | volume = 184 | issue = 2 | pages = 393–400 | date = February 2010 | pmid = 19917766 | pmc = 2828720 | doi = 10.1534/genetics.109.110213 }}</ref> Prion-based epigenetics has also been observed in ''[[Saccharomyces cerevisiae]]''.<ref>{{cite journal | vauthors = Garcia DM, Campbell EA, Jakobson CM, Tsuchiya M, Shaw EA, DiNardo AL, Kaeberlein M, Jarosz DF | display-authors = 6 | title = A prion accelerates proliferation at the expense of lifespan | journal = eLife | volume = 10 | pages = e60917 | date = September 2021 | pmid = 34545808 | pmc = 8455135 | doi = 10.7554/eLife.60917 | doi-access = free }}</ref> ==Molecular basis== Epigenetic changes modify the activation of certain genes, but not the genetic code sequence of DNA.<ref name="Topart">{{cite journal |vauthors=Topart C, Werner E, Arimondo PB |title=Wandering along the epigenetic timeline |journal=Clin Epigenetics |volume=12 |issue=1 |pages=97 |date=July 2020 |pmid=32616071 |pmc=7330981 |doi=10.1186/s13148-020-00893-7 |doi-access=free |url=}}</ref> The microstructure (not code) of DNA itself or the associated [[chromatin]] proteins may be modified, causing activation or silencing. This mechanism enables differentiated cells in a multicellular organism to 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; however, these epigenetic changes can be transmitted to the organism's offspring through a process called [[transgenerational epigenetic inheritance]]. Moreover, if gene inactivation occurs in a sperm or egg cell that results in fertilization, this epigenetic modification may also be transferred to the next generation.<ref name="pmid17320501">{{cite journal | vauthors = Chandler VL | title = Paramutation: from maize to mice | journal = Cell | volume = 128 | issue = 4 | pages = 641–5 | date = February 2007 | pmid = 17320501 | doi = 10.1016/j.cell.2007.02.007 | s2cid = 6928707 | doi-access = free }}</ref> Specific epigenetic processes include [[paramutation]], [[bookmarking]], [[Imprinting (genetics)|imprinting]], [[gene silencing]], [[X-inactivation|X chromosome inactivation]], [[position effect]], [[DNA methylation reprogramming]], [[transvection (genetics)|transvection]], [[maternal effect]]s, the progress of [[carcinogenesis]], many effects of [[teratogen]]s, regulation of [[histone]] modifications and [[heterochromatin]], and technical limitations affecting [[parthenogenesis]] and [[cloning]].<ref>{{cite book | vauthors = Zaidi SK, Lian JB, van Wijnen A, Stein JL, Stein GS | title = RUNX Proteins in Development and Cancer | chapter = Mitotic Gene Bookmarking: An Epigenetic Mechanism for Coordination of Lineage Commitment, Cell Identity and Cell Growth | series = Advances in Experimental Medicine and Biology | volume = 962 | pages = 95–102 | year = 2017 | pmid = 28299653 | pmc = 7233416 | doi = 10.1007/978-981-10-3233-2_7 | isbn = 978-981-10-3231-8 }}</ref><ref>{{cite journal | vauthors = Suter CM, Martin DI | title = Paramutation: the tip of an epigenetic iceberg? | journal = Trends in Genetics | volume = 26 | issue = 1 | pages = 9–14 | date = January 2010 | pmid = 19945764 | pmc = 3137459 | doi = 10.1016/j.tig.2009.11.003 }}</ref><ref>{{cite journal | vauthors = Ferguson-Smith AC | title = Genomic imprinting: the emergence of an epigenetic paradigm | journal = Nature Reviews. Genetics | volume = 12 | issue = 8 | pages = 565–575 | date = July 2011 | pmid = 21765458 | doi = 10.1038/nrg3032 | s2cid = 23630392 }}</ref> === DNA damage === DNA damage can also cause epigenetic changes.<ref>{{cite journal | vauthors = Kovalchuk O, Baulch JE | title = Epigenetic changes and nontargeted radiation effects--is there a link? | journal = Environmental and Molecular Mutagenesis | volume = 49 | issue = 1 | pages = 16–25 | date = January 2008 | pmid = 18172877 | doi = 10.1002/em.20361 | bibcode = 2008EnvMM..49...16K | s2cid = 38705208 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ilnytskyy Y, Kovalchuk O | title = Non-targeted radiation effects-an epigenetic connection | journal = Mutation Research | volume = 714 | issue = 1–2 | pages = 113–25 | date = September 2011 | pmid = 21784089 | doi = 10.1016/j.mrfmmm.2011.06.014 }}</ref><ref>{{cite journal | vauthors = Friedl AA, Mazurek B, Seiler DM | title = Radiation-induced alterations in histone modification patterns and their potential impact on short-term radiation effects | journal = Frontiers in Oncology | volume = 2 | pages = 117 | year = 2012 | pmid = 23050241 | pmc = 3445916 | doi = 10.3389/fonc.2012.00117 | doi-access = free }}</ref> DNA damage is very frequent, occurring on average about 60,000 times a day per cell of the human body (see [[DNA damage (naturally occurring)]]). These damages are largely repaired, however, epigenetic changes can still remain at the site of DNA repair.<ref>{{cite journal | vauthors = Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV | display-authors = 6 | title = DNA damage, homology-directed repair, and DNA methylation | journal = PLOS Genetics | volume = 3 | issue = 7 | pages = e110 | date = July 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }}</ref> 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).<ref>{{cite journal | vauthors = O'Hagan HM, Mohammad HP, Baylin SB | title = Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island | journal = PLOS Genetics | volume = 4 | issue = 8 | pages = e1000155 | date = August 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | veditors = Lee JT | doi-access = free }}</ref> In addition, the enzyme [[Poly ADP ribose polymerase|Parp1 (poly(ADP)-ribose polymerase)]] and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of the repair process.<ref>{{cite journal | vauthors = Malanga M, Althaus FR | title = The role of poly(ADP-ribose) in the DNA damage signaling network | journal = Biochemistry and Cell Biology | volume = 83 | issue = 3 | pages = 354–64 | date = June 2005 | pmid = 15959561 | doi = 10.1139/o05-038 | url = https://www.zora.uzh.ch/id/eprint/5838/1/RPViewDoc.pdf }}</ref> This accumulation, in turn, directs recruitment and activation of the chromatin remodeling protein, ALC1, that can cause [[nucleosome]] remodeling.<ref>{{cite journal | vauthors = Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, Swanson SK, Washburn MP, Florens L, Ladurner AG, Conaway JW, Conaway RC | display-authors = 6 | title = Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 33 | pages = 13770–4 | date = August 2009 | pmid = 19666485 | pmc = 2722505 | doi = 10.1073/pnas.0906920106 | bibcode = 2009PNAS..10613770G | doi-access = free }}</ref> Nucleosome remodeling has been found to cause, for instance, epigenetic silencing of DNA repair gene MLH1.<ref name="isbn0-87969-490-4"/><ref>{{cite journal | vauthors = Lin JC, Jeong S, Liang G, Takai D, Fatemi M, Tsai YC, Egger G, Gal-Yam EN, Jones PA | display-authors = 6 | title = Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island | journal = Cancer Cell | volume = 12 | issue = 5 | pages = 432–44 | date = November 2007 | pmid = 17996647 | pmc = 4657456 | doi = 10.1016/j.ccr.2007.10.014 }}</ref> DNA damaging chemicals, such as [[benzene]], [[hydroquinone]], [[styrene]], [[carbon tetrachloride]] and [[trichloroethylene]], cause considerable hypomethylation of DNA, some through the activation of oxidative stress pathways.<ref>{{cite journal | vauthors = Tabish AM, Poels K, Hoet P, Godderis L | title = Epigenetic factors in cancer risk: effect of chemical carcinogens on global DNA methylation pattern in human TK6 cells | journal = PLOS ONE | volume = 7 | issue = 4 | pages = e34674 | year = 2012 | pmid = 22509344 | pmc = 3324488 | doi = 10.1371/journal.pone.0034674 | veditors = Chiariotti L | bibcode = 2012PLoSO...734674T | doi-access = free }}</ref> Foods are known to alter the epigenetics of rats on different diets.<ref>{{cite journal | vauthors = Burdge GC, Hoile SP, Uller T, Thomas NA, Gluckman PD, Hanson MA, [[Karen A. Lillycrop|Lillycrop KA]] | title = Progressive, transgenerational changes in offspring phenotype and epigenotype following nutritional transition | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e28282 | year = 2011 | pmid = 22140567 | pmc = 3227644 | doi = 10.1371/journal.pone.0028282 | veditors = Imhof A | bibcode = 2011PLoSO...628282B | doi-access = free }}</ref> Some food components epigenetically increase the levels of DNA repair enzymes such as [[O-6-methylguanine-DNA methyltransferase|MGMT]] and [[MLH1]]<ref>{{cite journal | vauthors = Fang M, Chen D, Yang CS | title = Dietary polyphenols may affect DNA methylation | journal = The Journal of Nutrition | volume = 137 | issue = 1 Suppl | pages = 223S–228S | date = January 2007 | pmid = 17182830 | doi = 10.1093/jn/137.1.223S | doi-access = free }}</ref> and [[p53]].<ref>{{cite journal | vauthors = Olaharski AJ, Rine J, Marshall BL, Babiarz J, Zhang L, Verdin E, Smith MT | title = The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases | journal = PLOS Genetics | volume = 1 | issue = 6 | pages = e77 | date = December 2005 | pmid = 16362078 | pmc = 1315280 | doi = 10.1371/journal.pgen.0010077 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Majid S, Igawa M, Dahiya R | display-authors = 6 | title = Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells | journal = International Journal of Cancer | volume = 123 | issue = 3 | pages = 552–60 | date = August 2008 | pmid = 18431742 | doi = 10.1002/ijc.23590 | s2cid = 4704450 }}</ref> Other food components can reduce DNA damage, such as soy [[isoflavones]]. In one study, markers for oxidative stress, such as modified nucleotides that can result from DNA damage, were decreased by a 3-week diet supplemented with soy.<ref>{{cite journal | vauthors = Djuric Z, Chen G, Doerge DR, Heilbrun LK, Kucuk O | title = Effect of soy isoflavone supplementation on markers of oxidative stress in men and women | journal = Cancer Letters | volume = 172 | issue = 1 | pages = 1–6 | date = October 2001 | pmid = 11595123 | doi = 10.1016/S0304-3835(01)00627-9 }}</ref> A decrease in oxidative DNA damage was also observed 2 h after consumption of [[anthocyanin]]-rich [[bilberry]] (''[[Vaccinium myrtillus|Vaccinium myrtillius]]'' L.) [[pomace]] extract.<ref>{{cite journal | vauthors = Kropat C, Mueller D, Boettler U, Zimmermann K, Heiss EH, Dirsch VM, Rogoll D, Melcher R, Richling E, Marko D | display-authors = 6 | title = Modulation of Nrf2-dependent gene transcription by bilberry anthocyanins in vivo | journal = Molecular Nutrition & Food Research | volume = 57 | issue = 3 | pages = 545–50 | date = March 2013 | pmid = 23349102 | doi = 10.1002/mnfr.201200504 }}</ref> ===DNA repair=== Damage to DNA is very common and is constantly being repaired. Epigenetic alterations can accompany DNA repair of oxidative damage or double-strand breaks. In human cells, oxidative DNA damage occurs about 10,000 times a day and DNA double-strand breaks occur about 10 to 50 times a cell cycle in somatic replicating cells (see [[DNA damage (naturally occurring)]]). The selective advantage of DNA repair is to allow the cell to survive in the face of DNA damage. The selective advantage of epigenetic alterations that occur with DNA repair is not clear.{{citation needed|date=March 2023}} ====Repair of oxidative DNA damage can alter epigenetic markers==== In the steady state (with endogenous damages occurring and being repaired), there are about 2,400 oxidatively damaged guanines that form [[8-oxo-2'-deoxyguanosine]] (8-OHdG) in the average mammalian cell DNA.<ref name="pmid21163908">{{cite journal |vauthors=Swenberg JA, Lu K, Moeller BC, Gao L, Upton PB, Nakamura J, Starr TB |title=Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment |journal=Toxicol Sci |volume=120 |issue= Suppl 1|pages=S130–45 |date=March 2011 |pmid=21163908 |pmc=3043087 |doi=10.1093/toxsci/kfq371 |url=}}</ref> 8-OHdG constitutes about 5% of the oxidative damages commonly present in DNA.<ref name=Hamilton>{{cite journal |vauthors=Hamilton ML, Guo Z, Fuller CD, Van Remmen H, Ward WF, Austad SN, Troyer DA, Thompson I, Richardson A |title=A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA |journal=Nucleic Acids Res |volume=29 |issue=10 |pages=2117–26 |date=May 2001 |pmid=11353081 |pmc=55450 |doi=10.1093/nar/29.10.2117 |url=}}</ref> The oxidized guanines do not occur randomly among all guanines in DNA. There is a sequence preference for the guanine at a [[DNA methylation|methylated]] [[CpG site]] (a cytosine followed by guanine along its [[Directionality (molecular biology)|5' → 3' direction]] and where the cytosine is methylated (5-mCpG)).<ref name="pmid24571128">{{cite journal |vauthors=Ming X, Matter B, Song M, Veliath E, Shanley R, Jones R, Tretyakova N |title=Mapping structurally defined guanine oxidation products along DNA duplexes: influence of local sequence context and endogenous cytosine methylation |journal=J Am Chem Soc |volume=136 |issue=11 |pages=4223–35 |date=March 2014 |pmid=24571128 |pmc=3985951 |doi=10.1021/ja411636j |url=}}</ref> A 5-mCpG site has the lowest ionization potential for guanine oxidation.{{citation needed|date=March 2023}} [[File:Initiation of DNA demethylation at a CpG site.svg|thumb|200 px|Initiation of [[DNA demethylation]] at a [[CpG site]]. In adult somatic cells DNA methylation typically occurs in the context of CpG dinucleotides ([[CpG sites]]), forming [[5-methylcytosine]]-pG, or 5mCpG. Reactive oxygen species (ROS) may attack guanine at the dinucleotide site, forming [[8-oxo-2'-deoxyguanosine|8-hydroxy-2'-deoxyguanosine]] (8-OHdG), and resulting in a 5mCp-8-OHdG dinucleotide site. The [[base excision repair]] enzyme [[oxoguanine glycosylase|OGG1]] targets 8-OHdG and binds to the lesion without immediate excision. OGG1, present at a 5mCp-8-OHdG site recruits [[Tet methylcytosine dioxygenase 1|TET1]] and TET1 oxidizes the 5mC adjacent to the 8-OHdG. This initiates demethylation of 5mC.<ref name=Zhou>{{cite journal |vauthors=Zhou X, Zhuang Z, Wang W, He L, Wu H, Cao Y, Pan F, Zhao J, Hu Z, Sekhar C, Guo Z |title=OGG1 is essential in oxidative stress-induced DNA demethylation |journal=Cell Signal |volume=28 |issue=9 |pages=1163–1171 |date=September 2016 |pmid=27251462 |doi=10.1016/j.cellsig.2016.05.021 |url=}}</ref>]] Oxidized guanine has mispairing potential and is mutagenic.<ref name="pmid31993111">{{cite journal |vauthors=Poetsch AR |title=The genomics of oxidative DNA damage, repair, and resulting mutagenesis |journal=Comput Struct Biotechnol J |volume=18 |issue= |pages=207–219 |date=2020 |pmid=31993111 |pmc=6974700 |doi=10.1016/j.csbj.2019.12.013 |url=}}</ref> [[Oxoguanine glycosylase]] (OGG1) is the primary enzyme responsible for the excision of the oxidized guanine during DNA repair. OGG1 finds and binds to an 8-OHdG within a few seconds.<ref name="pmid33171795">{{cite journal |vauthors=D'Augustin O, Huet S, Campalans A, Radicella JP |title=Lost in the Crowd: How Does Human 8-Oxoguanine DNA Glycosylase 1 (OGG1) Find 8-Oxoguanine in the Genome? |journal=Int J Mol Sci |volume=21 |issue=21 |date=November 2020 |page=8360 |pmid=33171795 |pmc=7664663 |doi=10.3390/ijms21218360 |url=|doi-access=free }}</ref> However, OGG1 does not immediately excise 8-OHdG. In HeLa cells half maximum removal of 8-OHdG occurs in 30 minutes,<ref name="pmid15365186">{{cite journal |vauthors=Lan L, Nakajima S, Oohata Y, Takao M, Okano S, Masutani M, Wilson SH, Yasui A |title=In situ analysis of repair processes for oxidative DNA damage in mammalian cells |journal=Proc Natl Acad Sci U S A |volume=101 |issue=38 |pages=13738–43 |date=September 2004 |pmid=15365186 |pmc=518826 |doi=10.1073/pnas.0406048101 |bibcode=2004PNAS..10113738L |url=|doi-access=free }}</ref> and in irradiated mice, the 8-OHdGs induced in the mouse liver are removed with a half-life of 11 minutes.<ref name=Hamilton /> When OGG1 is present at an oxidized guanine within a methylated [[CpG site]] it recruits [[TET enzymes|TET1]] to the 8-OHdG lesion (see Figure). This allows TET1 to demethylate an adjacent methylated cytosine. Demethylation of cytosine is an epigenetic alteration.{{citation needed|date=March 2023}} As an example, when human mammary epithelial cells were treated with H₂O₂ for six hours, 8-OHdG increased about 3.5-fold in DNA and this caused about 80% demethylation of the 5-methylcytosines in the genome.<ref name=Zhou /> Demethylation of CpGs in a gene promoter by [[TET enzymes|TET enzyme]] activity increases transcription of the gene into messenger RNA.<ref name="pmid24108092">{{cite journal |vauthors=Maeder ML, Angstman JF, Richardson ME, Linder SJ, Cascio VM, Tsai SQ, Ho QH, Sander JD, Reyon D, Bernstein BE, Costello JF, Wilkinson MF, Joung JK |title=Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins |journal=Nat. Biotechnol. |volume=31 |issue=12 |pages=1137–42 |date=December 2013 |pmid=24108092 |pmc=3858462 |doi=10.1038/nbt.2726 }}</ref> In cells treated with H₂O₂, one particular gene was examined, [[Beta-secretase 1|''BACE1'']].<ref name=Zhou /> The methylation level of the ''BACE1'' [[CpG site#CpG islands|CpG island]] was reduced (an epigenetic alteration) and this allowed about 6.5 fold increase of expression of ''BACE1'' messenger RNA.{{citation needed|date=March 2023}} While six-hour incubation with H₂O₂ causes considerable demethylation of 5-mCpG sites, shorter times of H₂O₂ incubation appear to promote other epigenetic alterations. Treatment of cells with H₂O₂ for 30 minutes causes the mismatch repair protein heterodimer MSH2-MSH6 to recruit DNA methyltransferase 1 ([[DNMT1]]) to sites of some kinds of oxidative DNA damage.<ref name="pmid26186941">{{cite journal |vauthors=Ding N, Bonham EM, Hannon BE, Amick TR, Baylin SB, O'Hagan HM |title=Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage |journal=J Mol Cell Biol |volume=8 |issue=3 |pages=244–54 |date=June 2016 |pmid=26186941 |pmc=4937888 |doi=10.1093/jmcb/mjv050 |url=}}</ref> This could cause increased methylation of cytosines (epigenetic alterations) at these locations. Jiang et al.<ref name=Jiang>{{cite journal |vauthors=Jiang Z, Lai Y, Beaver JM, Tsegay PS, Zhao ML, Horton JK, Zamora M, Rein HL, Miralles F, Shaver M, Hutcheson JD, Agoulnik I, Wilson SH, Liu Y |title=Oxidative DNA Damage Modulates DNA Methylation Pattern in Human Breast Cancer 1 (BRCA1) Gene via the Crosstalk between DNA Polymerase β and a de novo DNA Methyltransferase |journal=Cells |volume=9 |issue=1 |date=January 2020 |page=225 |pmid=31963223 |pmc=7016758 |doi=10.3390/cells9010225 |url=|doi-access=free }}</ref> treated [[HEK 293 cells]] with agents causing oxidative DNA damage, ([[potassium bromate]] (KBrO3) or [[potassium chromate]] (K2CrO4)). [[Base excision repair]] (BER) of oxidative damage occurred with the DNA repair enzyme [[DNA polymerase|polymerase beta]] localizing to oxidized guanines. Polymerase beta is the main human polymerase in short-patch BER of oxidative DNA damage. Jiang et al.<ref name=Jiang /> also found that polymerase beta recruited the [[DNA methyltransferase]] protein DNMT3b to BER repair sites. They then evaluated the methylation pattern at the single nucleotide level in a small region of DNA including the [[promoter (genetics)|promoter]] region and the early transcription region of the [[BRCA1]] gene. Oxidative DNA damage from bromate modulated the DNA methylation pattern (caused epigenetic alterations) at CpG sites within the region of DNA studied. In untreated cells, CpGs located at −189, −134, −29, −19, +16, and +19 of the BRCA1 gene had methylated cytosines (where numbering is from the [[messenger RNA]] transcription start site, and negative numbers indicate nucleotides in the upstream [[Promoter (genetics)|promoter]] region). Bromate treatment-induced oxidation resulted in the loss of cytosine methylation at −189, −134, +16 and +19 while also leading to the formation of new methylation at the CpGs located at −80, −55, −21 and +8 after DNA repair was allowed. ====Homologous recombinational repair alters epigenetic markers==== At least four articles report the recruitment of [[DNA methyltransferase|DNA methyltransferase 1 (DNMT1)]] to sites of DNA double-strand breaks.<ref name="pmid15956212">{{cite journal |vauthors=Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H |title=Recruitment of DNA methyltransferase I to DNA repair sites |journal=Proc Natl Acad Sci U S A |volume=102 |issue=25 |pages=8905–9 |date=June 2005 |pmid=15956212 |pmc=1157029 |doi=10.1073/pnas.0501034102 |bibcode=2005PNAS..102.8905M |url=|doi-access=free }}</ref><ref name=Cuozzo>{{cite journal |vauthors=Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV |title=DNA damage, homology-directed repair, and DNA methylation |journal=PLOS Genet |volume=3 |issue=7 |pages=e110 |date=July 2007 |pmid=17616978 |pmc=1913100 |doi=10.1371/journal.pgen.0030110 |url= |doi-access=free }}</ref><ref name="pmid18704159">{{cite journal |vauthors=O'Hagan HM, Mohammad HP, Baylin SB |title=Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island |journal=PLOS Genet |volume=4 |issue=8 |pages=e1000155 |date=August 2008 |pmid=18704159 |pmc=2491723 |doi=10.1371/journal.pgen.1000155 |url= |doi-access=free }}</ref><ref name="pmid20940144">{{cite journal |vauthors=Ha K, Lee GE, Palii SS, Brown KD, Takeda Y, Liu K, Bhalla KN, Robertson KD |title=Rapid and transient recruitment of DNMT1 to DNA double-strand breaks is mediated by its interaction with multiple components of the DNA damage response machinery |journal=Hum Mol Genet |volume=20 |issue=1 |pages=126–40 |date=January 2011 |pmid=20940144 |pmc=3000680 |doi=10.1093/hmg/ddq451 |url=}}</ref> During [[homologous recombination|homologous recombinational repair (HR)]] of the double-strand break, the involvement of DNMT1 causes the two repaired strands of DNA to have different levels of methylated cytosines. One strand becomes frequently methylated at about 21 [[CpG site]]s downstream of the repaired double-strand break. The other DNA strand loses methylation at about six CpG sites that were previously methylated downstream of the double-strand break, as well as losing methylation at about five CpG sites that were previously methylated upstream of the double-strand break. When the chromosome is replicated, this gives rise to one daughter chromosome that is heavily methylated downstream of the previous break site and one that is unmethylated in the region both upstream and downstream of the previous break site. With respect to the gene that was broken by the double-strand break, half of the progeny cells express that gene at a high level and in the other half of the progeny cells expression of that gene is repressed. When clones of these cells were maintained for three years, the new methylation patterns were maintained over that time period.<ref name="pmid27629060">{{cite journal |vauthors=Russo G, Landi R, Pezone A, Morano A, Zuchegna C, Romano A, Muller MT, Gottesman ME, Porcellini A, Avvedimento EV |title=DNA damage and Repair Modify DNA methylation and Chromatin Domain of the Targeted Locus: Mechanism of allele methylation polymorphism |journal=Sci Rep |volume=6 |issue= |pages=33222 |date=September 2016 |pmid=27629060 |pmc=5024116 |doi=10.1038/srep33222 |bibcode=2016NatSR...633222R |url=}}</ref> In mice with a CRISPR-mediated homology-directed recombination insertion in their genome there were a large number of increased methylations of CpG sites within the double-strand break-associated insertion.<ref name="pmid33267773">{{cite journal |vauthors=Farris MH, Texter PA, Mora AA, Wiles MV, Mac Garrigle EF, Klaus SA, Rosfjord K |title=Detection of CRISPR-mediated genome modifications through altered methylation patterns of CpG islands |journal=BMC Genomics |volume=21 |issue=1 |pages=856 |date=December 2020 |pmid=33267773 |pmc=7709351 |doi=10.1186/s12864-020-07233-2 |url= |doi-access=free }}</ref> ====Non-homologous end joining can cause some epigenetic marker alterations==== [[Non-homologous end joining]] (NHEJ) repair of a double-strand break can cause a small number of demethylations of pre-existing cytosine DNA methylations downstream of the repaired double-strand break.<ref name=Cuozzo /> Further work by Allen et al.<ref name="pmid28423717">{{cite journal |vauthors=Allen B, Pezone A, Porcellini A, Muller MT, Masternak MM |title=Non-homologous end joining induced alterations in DNA methylation: A source of permanent epigenetic change |journal=Oncotarget |volume=8 |issue=25 |pages=40359–40372 |date=June 2017 |pmid=28423717 |pmc=5522286 |doi=10.18632/oncotarget.16122 |url=}}</ref> showed that NHEJ of a DNA double-strand break in a cell could give rise to some progeny cells having repressed expression of the gene harboring the initial double-strand break and some progeny having high expression of that gene due to epigenetic alterations associated with NHEJ repair. The frequency of epigenetic alterations causing repression of a gene after an NHEJ repair of a DNA double-strand break in that gene may be about 0.9%.<ref name="pmid18704159"/> === Techniques used to study epigenetics === Epigenetic research uses a wide range of [[molecular biology|molecular biological]] techniques to further understanding of epigenetic phenomena. These techniques include [[chromatin immunoprecipitation]] (together with its large-scale variants [[ChIP-on-chip]] and [[ChIP-Seq]]), [[fluorescent in situ hybridization]], methylation-sensitive [[restriction enzymes]], DNA adenine methyltransferase identification ([[DamID]]) and [[bisulfite sequencing]].<ref name="verma">{{cite journal | vauthors = Verma M, Rogers S, Divi RL, Schully SD, Nelson S, Joseph Su L, Ross SA, Pilch S, Winn DM, Khoury MJ | display-authors = 6 | title = Epigenetic research in cancer epidemiology: trends, opportunities, and challenges | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 23 | issue = 2 | pages = 223–33 | date = February 2014 | pmid = 24326628 | pmc = 3925982 | doi = 10.1158/1055-9965.EPI-13-0573 }}</ref> Furthermore, the use of [[bioinformatics]] methods has a role in [[computational epigenetics]].<ref name=verma/> ==== Chromatin Immunoprecipitation ==== Chromatin Immunoprecipitation (ChIP) has helped bridge the gap between DNA and epigenetic interactions.<ref name="Abcam">{{Cite web|title=Studying epigenetics using ChIP|url=https://www.abcam.com/epigenetics/studying-epigenetics-using-chip | work = Abcam }}</ref> With the use of ChIP, researchers are able to make findings in regards to gene regulation, transcription mechanisms, and chromatin structure.<ref name="Abcam" /> ==== Fluorescent ''in situ'' hybridization ==== Fluorescent ''in situ'' hybridization (FISH) is very important to understand epigenetic mechanisms.<ref name="Chaumeil_2008">{{cite book | vauthors = Chaumeil J, Augui S, Chow JC, Heard E | chapter = Combined Immunofluorescence, RNA Fluorescent in Situ Hybridization, and DNA Fluorescent in Situ Hybridization to Study Chromatin Changes, Transcriptional Activity, Nuclear Organization, and X-Chromosome Inactivation | title = The Nucleus | series = Methods in Molecular Biology | location = Clifton, N.J. | volume = 463 | pages = 297–308 | date = 2008 | pmid = 18951174 | doi = 10.1007/978-1-59745-406-3_18 | isbn = 978-1-58829-977-2 | chapter-url = }}</ref> FISH can be used to find the location of genes on chromosomes, as well as finding noncoding RNAs.<ref name="Chaumeil_2008" /><ref name="O'Connor_2008">{{Cite journal | vauthors = O'Connor C | title = Fluorescence in situ hybridization (FISH). | journal = Nature Education | date = 2008 | volume = 1 | issue = 1 | page = 171 |url= https://www.nature.com/scitable/topicpage/fluorescence-in-situ-hybridization-fish-327/ }}</ref> FISH is predominantly used for detecting chromosomal abnormalities in humans.<ref name="O'Connor_2008" /> ==== Methylation-sensitive restriction enzymes ==== Methylation sensitive restriction enzymes paired with PCR is a way to evaluate methylation in DNA - specifically the CpG sites.<ref name="Hashimoto_2007">{{cite journal | vauthors = Hashimoto K, Kokubun S, Itoi E, Roach HI | title = Improved quantification of DNA methylation using methylation-sensitive restriction enzymes and real-time PCR | journal = Epigenetics | volume = 2 | issue = 2 | pages = 86–91 | year = 2007 | pmid = 17965602 | doi = 10.4161/epi.2.2.4203 | s2cid = 26728480 | doi-access = free }}</ref> If DNA is methylated, the restriction enzymes will not cleave the strand.<ref name="Hashimoto_2007" /> Contrarily, if the DNA is not methylated, the enzymes will cleave the strand and it will be amplified by PCR.<ref name="Hashimoto_2007" /> ==== Bisulfite sequencing ==== Bisulfite sequencing is another way to evaluate DNA methylation. Cytosine will be changed to uracil from being treated with sodium bisulfite, whereas methylated cytosines will not be affected.<ref name="Hashimoto_2007" /><ref name="Li-Byarlay et al 2020">{{cite journal |last1=Li-Byarlay |first1=Hongmei |last2=Boncristiani |first2=Humberto |last3=Howell |first3=Gary |last4=Herman |first4=Jake |last5=Clark |first5=Lindsay |last6=Strand |first6=Micheline K. |last7=Tarpy |first7=David |last8=Rueppell |first8=Olav |title=Transcriptomic and Epigenomic Dynamics of Honey Bees in Response to Lethal Viral Infection |journal=Frontiers in Genetics |date=24 September 2020 |volume=11 |doi=10.3389/fgene.2020.566320 |doi-access=free |pmid=33101388 |pmc=7546774 }}</ref><ref name="ReferenceC">{{cite journal |last1=Li-Byarlay |first1=Hongmei |last2=Li |first2=Yang |last3=Stroud |first3=Hume |last4=Feng |first4=Suhua |last5=Newman |first5=Thomas C. |last6=Kaneda |first6=Megan |last7=Hou |first7=Kirk K. |last8=Worley |first8=Kim C. |last9=Elsik |first9=Christine G. |last10=Wickline |first10=Samuel A. |last11=Jacobsen |first11=Steven E. |last12=Ma |first12=Jian |last13=Robinson |first13=Gene E. |title=RNA interference knockdown of DNA methyl-transferase 3 affects gene alternative splicing in the honey bee |journal=Proceedings of the National Academy of Sciences |date=30 July 2013 |volume=110 |issue=31 |pages=12750–12755 |doi=10.1073/pnas.1310735110 |doi-access=free |pmid=23852726 |bibcode=2013PNAS..11012750L |pmc=3732956 }}</ref> ==== Nanopore sequencing ==== Certain sequencing methods, such as [[nanopore sequencing]], allow sequencing of native DNA. Native (=unamplified) DNA retains the epigenetic modifications which would otherwise be lost during the amplification step. Nanopore basecaller models can distinguish between the signals obtained for epigenetically modified bases and unaltered based and provide an epigenetic profile in addition to the sequencing result.<ref>{{Cite journal |last1=Simpson |first1=Jared T. |last2=Workman |first2=Rachael E. |last3=Zuzarte |first3=P. C. |last4=David |first4=Matei |last5=Dursi |first5=L. J. |last6=Timp |first6=Winston |title=Detecting DNA cytosine methylation using nanopore sequencing |url=https://www.nature.com/articles/nmeth.4184 |journal=Nature Methods |date=2017 |language=en |volume=14 |issue=4 |pages=407–410 |doi=10.1038/nmeth.4184 |pmid=28218898 |s2cid=16152628 |issn=1548-7105}}</ref> ===Structural inheritance=== {{further|Structural inheritance}} In [[ciliate]]s such as ''[[Tetrahymena]]'' and ''[[Paramecium]]'', 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.<ref name="pmid1804215">{{cite book |doi=10.1007/978-1-4615-6823-0_11 |pmid=1804215 |chapter=Concepts of Organization the Leverage of Ciliate Protozoa |title=A Conceptual History of Modern Embryology |series=Developmental Biology |volume=7 |pages=229–258 |year=1991 | vauthors = Sapp J |isbn=978-1-4615-6825-4 }}</ref><ref name="isbn0-19-515619-6">{{cite book | vauthors=Sapp J | title=Genesis: the evolution of biology | publisher=Oxford University Press | location=Oxford | year=2003 | isbn=978-0-19-515619-5 | url-access=registration | url=https://archive.org/details/genesisevolution00sapp }}</ref><ref name="isbn0-262-65063-0">{{cite book |vauthors=Gray RD, Oyama S, Griffiths PE | title=Cycles of Contingency: Developmental Systems and Evolution (Life and Mind: Philosophical Issues in Biology and Psychology) | publisher=The MIT Press | location=Cambridge, Massachusetts | year=2003 | isbn=978-0-262-65063-2 }}</ref> ===Nucleosome positioning=== Eukaryotic genomes have numerous [[nucleosomes]]. Nucleosome position is not random, and determine the accessibility of DNA to regulatory proteins. Promoters active in different tissues have been shown to have different nucleosome positioning features.<ref>{{Cite journal| vauthors = Serizay J, Dong Y, Jänes J, Chesney M, Cerrato C, Ahringer J |date=2020-02-20|title=Tissue-specific profiling reveals distinctive regulatory architectures for ubiquitous, germline and somatic genes |journal=bioRxiv |pages=2020.02.20.958579|doi=10.1101/2020.02.20.958579|s2cid=212943176|doi-access=free}}</ref> This determines differences in gene expression and cell differentiation. It has been shown that at least some nucleosomes are retained in sperm cells (where most but not all histones are replaced by [[protamines]]). Thus nucleosome positioning is to some degree inheritable. Recent studies have uncovered connections between nucleosome positioning and other epigenetic factors, such as DNA methylation and hydroxymethylation.<ref name=Teif_2014>{{cite journal | vauthors = Teif VB, Beshnova DA, Vainshtein Y, Marth C, Mallm JP, Höfer T, Rippe K | title = Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development | journal = Genome Research | volume = 24 | issue = 8 | pages = 1285–95 | date = August 2014 | pmid = 24812327 | pmc = 4120082 | doi = 10.1101/gr.164418.113 }}</ref> ===Histone variants=== Different [[histone variants]] are incorporated into specific regions of the genome non-randomly. Their differential biochemical characteristics can affect genome functions via their roles in gene regulation,<ref>{{cite journal | vauthors = Buschbeck M, Hake SB | title = Variants of core histones and their roles in cell fate decisions, development and cancer | journal = Nature Reviews. Molecular Cell Biology | volume = 18 | issue = 5 | pages = 299–314 | date = May 2017 | pmid = 28144029 | doi = 10.1038/nrm.2016.166 | url = https://www.nature.com/articles/nrm.2016.166 | s2cid = 3307731 }}</ref> and maintenance of chromosome structures.<ref>{{cite journal | vauthors = Jang CW, Shibata Y, Starmer J, Yee D, Magnuson T | title = Histone H3.3 maintains genome integrity during mammalian development | journal = Genes & Development | volume = 29 | issue = 13 | pages = 1377–92 | date = July 2015 | pmid = 26159997 | pmc = 4511213 | doi = 10.1101/gad.264150.115 }}</ref> ===Genomic architecture=== The three-dimensional configuration of the genome (the 3D genome) is complex, dynamic and crucial for regulating genomic function and nuclear processes such as DNA replication, transcription and DNA-damage repair.<ref>{{Cite web|title=The 3D genome|url=https://www.nature.com/collections/rsxlmsyslk/|access-date=2021-09-26|website=www.nature.com|date=2 September 2019 |language=en}}</ref> ==Functions and consequences== ===In the brain=== {{See also|#Addiction|#Depression}} ====Memory==== {{main|Epigenetics in learning and memory}} [[Encoding (memory)|Memory formation]] and maintenance are due to epigenetic alterations that cause the required dynamic changes in [[gene transcription]] that create and renew memory in neurons.<ref name="Bernstein"/> An event can set off a chain of reactions that result in altered methylations of a large set of genes in neurons, which give a representation of the event, a memory.<ref name=Bernstein /> [[File:Brain regions in memory formation updated.jpg|thumb|250px|including medial prefrontal cortex (mPFC)]] Areas of the brain important in the formation of memories include the hippocampus, medial prefrontal cortex (mPFC), anterior cingulate cortex and amygdala, as shown in the diagram of the human brain in this section.<ref name="pmid28386011">{{cite journal |vauthors=Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, Redondo RL, Tonegawa S |title=Engrams and circuits crucial for systems consolidation of a memory |journal=Science |volume=356 |issue=6333 |pages=73–78 |date=April 2017 |pmid=28386011 |pmc=5493329 |doi=10.1126/science.aam6808 |bibcode=2017Sci...356...73K |url=}}</ref> When a strong memory is created, as in a rat subjected to [[Fear conditioning|contextual fear conditioning]] (CFC), one of the earliest events to occur is that more than 100 DNA double-strand breaks are formed by [[topoisomerase|topoisomerase IIB]] in neurons of the hippocampus and the medial prefrontal cortex (mPFC).<ref name=Stott>{{cite journal |vauthors=Stott RT, Kritsky O, Tsai LH |title=Profiling DNA break sites and transcriptional changes in response to contextual fear learning |journal=PLOS ONE |volume=16 |issue=7 |pages=e0249691 |date=2021 |pmid=34197463 |pmc=8248687 |doi=10.1371/journal.pone.0249691 |bibcode=2021PLoSO..1649691S |url=|doi-access=free }}</ref> These double-strand breaks are at specific locations that allow activation of transcription of [[immediate early genes]] (IEGs) that are important in memory formation, allowing their expression in [[messenger RNA|mRNA]], with peak mRNA transcription at seven to ten minutes after CFC.<ref name=Stott /><ref name="pmid35776545">{{cite journal |vauthors=Lee BH, Shim JY, Moon HC, Kim DW, Kim J, Yook JS, Kim J, Park HY |title=Real-time visualization of mRNA synthesis during memory formation in live mice |journal=Proc Natl Acad Sci U S A |volume=119 |issue=27 |pages=e2117076119 |date=July 2022 |pmid=35776545 |pmc=9271212 |doi=10.1073/pnas.2117076119 |doi-access=free |bibcode=2022PNAS..11917076L |url=}}</ref> Two important IEGs in memory formation are ''[[EGR1]]''<ref name="pmid10357227">{{cite journal |vauthors=Tischmeyer W, Grimm R |title=Activation of immediate early genes and memory formation |journal=Cell Mol Life Sci |volume=55 |issue=4 |pages=564–74 |date=April 1999 |pmid=10357227 |doi=10.1007/s000180050315 |s2cid=6923522 |url=}}</ref> and [[DNA methyltransferase|the alternative promoter variant of ''DNMT3A'', ''DNMT3A2'']].<ref name="pmid22751036">{{cite journal |vauthors=Oliveira AM, Hemstedt TJ, Bading H |title=Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities |journal=Nat Neurosci |volume=15 |issue=8 |pages=1111–3 |date=July 2012 |pmid=22751036 |doi=10.1038/nn.3151 |s2cid=10590208 |url=}}</ref> EGR1 protein binds to DNA at its binding motifs, 5′-GCGTGGGCG-3′ or 5′-GCGGGGGCGG-3', and there are about 12,000 genome locations at which EGR1 protein can bind.<ref name=Sun>{{cite journal |vauthors=Sun Z, Xu X, He J, Murray A, Sun MA, Wei X, Wang X, McCoig E, Xie E, Jiang X, Li L, Zhu J, Chen J, Morozov A, Pickrell AM, Theus MH, Xie H |title=EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity |journal=Nat Commun |volume=10 |issue=1 |pages=3892 |date=August 2019 |pmid=31467272 |pmc=6715719 |doi=10.1038/s41467-019-11905-3 |bibcode=2019NatCo..10.3892S |url=}}</ref> EGR1 protein binds to DNA in gene [[Promoter (genetics)|promoter]] and [[Enhancer (genetics)|enhancer]] regions. EGR1 recruits the demethylating enzyme [[TET enzymes|TET1]] to an association, and brings TET1 to about 600 locations on the genome where TET1 can then demethylate and activate the associated genes.<ref name=Sun /> [[File:Cytosine and 5-methylcytosine.jpg|thumb|Cytosine and 5-methylcytosine]] The DNA methyltransferases DNMT3A1, DNMT3A2 and DNMT3B can all methylate cytosines (see image this section) at [[CpG site]]s in or near the promoters of genes. As shown by Manzo et al.,<ref name="pmid29074627">{{cite journal |vauthors=Manzo M, Wirz J, Ambrosi C, Villaseñor R, Roschitzki B, Baubec T |title=Isoform-specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands |journal=EMBO J |volume=36 |issue=23 |pages=3421–3434 |date=December 2017 |pmid=29074627 |pmc=5709737 |doi=10.15252/embj.201797038 |url=}}</ref> these three DNA methyltransferases differ in their genomic binding locations and DNA methylation activity at different regulatory sites. Manzo et al. located 3,970 genome regions exclusively enriched for DNMT3A1, 3,838 regions for DNMT3A2 and 3,432 regions for DNMT3B. When DNMT3A2 is newly induced as an IEG (when neurons are activated), many new cytosine methylations occur, presumably in the target regions of DNMT3A2. Oliviera et al.<ref name="pmid22751036"/> found that the neuronal activity-inducible IEG levels of Dnmt3a2 in the hippocampus determined the ability to form long-term memories. Rats form long-term associative memories after [[fear conditioning|contextual fear conditioning (CFC)]].<ref name="pmid25324744">{{cite journal |vauthors=Joels G, Lamprecht R |title=Fear memory formation can affect a different memory: fear conditioning affects the extinction, but not retrieval, of conditioned taste aversion (CTA) memory |journal=Front Behav Neurosci |volume=8 |issue= |pages=324 |date=2014 |pmid=25324744 |pmc=4179742 |doi=10.3389/fnbeh.2014.00324 |url=|doi-access=free }}</ref> Duke et al.<ref name="pmid28620075"/> found that 24 hours after CFC in rats, in hippocampus neurons, 2,097 genes (9.17% of the genes in the rat genome) had altered methylation. When newly methylated cytosines are present in [[CpG site]]s in the promoter regions of genes, the genes are often repressed, and when newly demethylated cytosines are present the genes may be activated.<ref name="pmid22781841">{{cite journal |vauthors=Moore LD, Le T, Fan G |title=DNA methylation and its basic function |journal=Neuropsychopharmacology |volume=38 |issue=1 |pages=23–38 |date=January 2013 |pmid=22781841 |pmc=3521964 |doi=10.1038/npp.2012.112 |url=}}</ref> After CFC, there were 1,048 genes with reduced mRNA expression and 564 genes with upregulated mRNA expression. Similarly, when mice undergo CFC, one hour later in the hippocampus region of the mouse brain there are 675 demethylated genes and 613 hypermethylated genes.<ref name=Halder>{{cite journal |vauthors=Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A, Centeno TP, van Bebber F, Capece V, Garcia Vizcaino JC, Schuetz AL, Burkhardt S, Benito E, Navarro Sala M, Javan SB, Haass C, Schmid B, Fischer A, Bonn S |title=DNA methylation changes in plasticity genes accompany the formation and maintenance of memory |journal=Nat Neurosci |volume=19 |issue=1 |pages=102–10 |date=January 2016 |pmid=26656643 |doi=10.1038/nn.4194 |s2cid=1173959 |url=}}</ref> However, memories do not remain in the hippocampus, but after four or five weeks the memories are stored in the anterior cingulate cortex.<ref name="pmid15131309">{{cite journal |vauthors=Frankland PW, Bontempi B, Talton LE, Kaczmarek L, Silva AJ |title=The involvement of the anterior cingulate cortex in remote contextual fear memory |journal=Science |volume=304 |issue=5672 |pages=881–3 |date=May 2004 |pmid=15131309 |doi=10.1126/science.1094804 |bibcode=2004Sci...304..881F |s2cid=15893863 |url=}}</ref> In the studies on mice after CFC, Halder et al.<ref name=Halder /> showed that four weeks after CFC there were at least 1,000 differentially methylated genes and more than 1,000 differentially expressed genes in the anterior cingulate cortex, while at the same time the altered methylations in the hippocampus were reversed. The epigenetic alteration of methylation after a new memory is established creates a different pool of nuclear mRNAs. As reviewed by Bernstein,<ref name=Bernstein /> the epigenetically determined new mix of nuclear [[messenger RNA|mRNAs]] are often packaged into neuronal granules, or [[messenger RNP]], consisting of mRNA, [[ribosome|small and large ribosomal subunits]], translation initiation factors and RNA-binding proteins that regulate mRNA function. These neuronal granules are transported from the neuron nucleus and are directed, according to 3′ untranslated regions of the mRNA in the granules (their "zip codes"), to neuronal [[dendrite]]s. Roughly 2,500 mRNAs may be localized to the dendrites of hippocampal pyramidal neurons and perhaps 450 transcripts are in excitatory presynaptic nerve terminals (dendritic spines). The altered assortments of transcripts (dependent on epigenetic alterations in the neuron nucleus) have different sensitivities in response to signals, which is the basis of altered synaptic plasticity. Altered synaptic plasticity is often considered the neurochemical foundation of learning and memory. ====Aging==== {{See also|DNA methylation#In aging|Hallmarks of aging#Epigenomic alterations}} Epigenetics play a major role in [[brain aging]] and age-related cognitive decline, with relevance to [[life extension]].<ref>{{cite journal | vauthors = Barter JD, Foster TC | title = Aging in the Brain: New Roles of Epigenetics in Cognitive Decline | journal = The Neuroscientist | volume = 24 | issue = 5 | pages = 516–525 | date = October 2018 | pmid = 29877135 | doi = 10.1177/1073858418780971 | s2cid = 46965080 }}</ref><ref>{{cite journal | vauthors = Harman MF, Martín MG | title = Epigenetic mechanisms related to cognitive decline during aging | journal = Journal of Neuroscience Research | volume = 98 | issue = 2 | pages = 234–246 | date = February 2020 | pmid = 31045277 | doi = 10.1002/jnr.24436 | s2cid = 143423862 }}</ref><ref>{{cite journal | vauthors = Braga DL, Mousovich-Neto F, Tonon-da-Silva G, Salgueiro WG, Mori MA | title = Epigenetic changes during ageing and their underlying mechanisms | journal = Biogerontology | volume = 21 | issue = 4 | pages = 423–443 | date = August 2020 | pmid = 32356238 | doi = 10.1007/s10522-020-09874-y | s2cid = 254292058 }}</ref><ref>{{cite journal | vauthors = Zhang W, Qu J, Liu GH, Belmonte JC | title = The ageing epigenome and its rejuvenation | journal = Nature Reviews. Molecular Cell Biology | volume = 21 | issue = 3 | pages = 137–150 | date = March 2020 | pmid = 32020082 | doi = 10.1038/s41580-019-0204-5 | s2cid = 211028527 }}</ref><ref>{{cite journal | vauthors = Simpson DJ, Olova NN, Chandra T | title = Cellular reprogramming and epigenetic rejuvenation | journal = Clinical Epigenetics | volume = 13 | issue = 1 | pages = 170 | date = September 2021 | pmid = 34488874 | pmc = 8419998 | doi = 10.1186/s13148-021-01158-7 | doi-access = free }}</ref> ====Other and general==== In adulthood, changes in the [[epigenome]] are important for various higher cognitive functions. Dysregulation of epigenetic mechanisms is implicated in [[neurodegenerative disorders]] and diseases. Epigenetic modifications in [[neuron]]s are dynamic and reversible.<ref>{{cite journal | vauthors = Hwang JY, Aromolaran KA, Zukin RS | title = The emerging field of epigenetics in neurodegeneration and neuroprotection | journal = Nature Reviews. Neuroscience | volume = 18 | issue = 6 | pages = 347–361 | date = May 2017 | pmid = 28515491 | pmc = 6380351 | doi = 10.1038/nrn.2017.46 }}</ref> Epigenetic regulation impacts neuronal action, affecting learning, memory, and other [[cognitive]] processes.<ref>{{cite journal | vauthors = Grigorenko EL, Kornilov SA, Naumova OY | title = Epigenetic regulation of cognition: A circumscribed review of the field | journal = Development and Psychopathology | volume = 28 | issue = 4pt2 | pages = 1285–1304 | date = November 2016 | pmid = 27691982 | doi = 10.1017/S0954579416000857 | s2cid = 21422752 }}</ref> Early events, including during [[embryonic development]], can influence development, cognition, and health outcomes through [[epigenetic mechanisms]].<ref>{{cite journal | vauthors = Bacon ER, Brinton RD | title = Epigenetics of the developing and aging brain: Mechanisms that regulate onset and outcomes of brain reorganization | journal = Neuroscience and Biobehavioral Reviews | volume = 125 | pages = 503–516 | date = June 2021 | pmid = 33657435 | pmc = 8989071 | doi = 10.1016/j.neubiorev.2021.02.040 }}</ref> Epigenetic mechanisms have been proposed as "a potential molecular mechanism for effects of endogenous [[hormone]]s on the organization of developing brain circuits".<ref>{{cite book | vauthors = Streifer M, Gore AC | title = Endocrine-Disrupting Chemicals | chapter = Epigenetics, estrogenic endocrine-disrupting chemicals (EDCs), and the brain | volume = 92 | pages = 73–99 | date = 2021 | pmid = 34452697 | doi = 10.1016/bs.apha.2021.03.006 | isbn = 9780128234662 | series = Advances in Pharmacology | s2cid = 237339845 }}</ref> [[Nutrients]] could interact with the epigenome to "protect or boost cognitive processes across the lifespan".<ref>{{cite journal | vauthors = Bekdash RA | title = Choline, the brain and neurodegeneration: insights from epigenetics | journal = Frontiers in Bioscience | volume = 23 | issue = 6 | pages = 1113–1143 | date = January 2018 | pmid = 28930592 | doi = 10.2741/4636 }}</ref><ref>{{cite journal | vauthors = Ekstrand B, Scheers N, Rasmussen MK, Young JF, Ross AB, Landberg R | title = Brain foods - the role of diet in brain performance and health | journal = Nutrition Reviews | volume = 79 | issue = 6 | pages = 693–708 | date = May 2021 | pmid = 32989449 | doi = 10.1093/nutrit/nuaa091 }}</ref> A review suggests [[neurobiological effects of physical exercise]] via [[Epigenetics of physical exercise|epigenetics]] seem "central to building an 'epigenetic memory' to influence long-term brain function and behavior" and may even be heritable.<ref>{{cite journal | vauthors = Fernandes J, Arida RM, Gomez-Pinilla F | title = Physical exercise as an epigenetic modulator of brain plasticity and cognition | journal = Neuroscience and Biobehavioral Reviews | volume = 80 | pages = 443–456 | date = September 2017 | pmid = 28666827 | pmc = 5705447 | doi = 10.1016/j.neubiorev.2017.06.012 }}</ref> With the axo-ciliary [[synapse]], there is communication between [[Serotonin|serotonergic]] [[axon]]s and antenna-like [[primary cilia]] of [[Hippocampus anatomy#Basic hippocampal circuit|CA1]] [[Pyramidal cell|pyramidal]] [[neuron]]s that alters the neuron's [[epigenetic]] state in the [[Cell nucleus|nucleus]] via the signalling distinct from that at the [[plasma membrane]] (and longer-term).<ref>{{cite news | vauthors = Tamim B |title=New discovery: Synapse hiding in the mice brain may advance our understanding of neuronal communication |url=https://interestingengineering.com/science/new-discovery-synapse-hiding-in-mice-brain |access-date=19 October 2022 |work=interestingengineering.com |date=4 September 2022}}</ref><ref>{{cite journal | vauthors = Sheu SH, Upadhyayula S, Dupuy V, Pang S, Deng F, Wan J, Walpita D, Pasolli HA, Houser J, Sanchez-Martinez S, Brauchi SE, Banala S, Freeman M, Xu CS, Kirchhausen T, Hess HF, Lavis L, Li Y, Chaumont-Dubel S, Clapham DE | display-authors = 6 | title = A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility | language = English | journal = Cell | volume = 185 | issue = 18 | pages = 3390–3407.e18 | date = September 2022 | pmid = 36055200 | pmc = 9789380 | doi = 10.1016/j.cell.2022.07.026 | s2cid = 251958800 }} * University press release: {{cite news |title=Scientists discover new kind of synapse in neurons' tiny hairs |url=https://phys.org/news/2022-09-scientists-kind-synapse-neurons-tiny.html |access-date=19 October 2022 |work=Howard Hughes Medical Institute via phys.org |language=en}}</ref> Epigenetics also play a major role in the [[Evolution of the brain#Genetic factors of recent evolution|brain evolution in and to humans]].<ref>{{cite journal | vauthors = Keverne EB | title = Epigenetics and brain evolution | journal = Epigenomics | volume = 3 | issue = 2 | pages = 183–191 | date = April 2011 | pmid = 22122280 | doi = 10.2217/epi.11.10 }}</ref> ===Development=== Developmental 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.<ref name=Griesemer_2005>{{cite journal | vauthors=Griesemer J, Haber MH, Yamashita G, Gannett L | title=Critical Notice: Cycles of Contingency – Developmental Systems and Evolution | journal=Biology & Philosophy |date=March 2005 | volume=20 | issue =2–3 | pages=517–44 | doi=10.1007/s10539-004-0836-4| s2cid=2995306 }}</ref> Somatic epigenetic inheritance, particularly through DNA and histone covalent modifications and [[nucleosome]] repositioning, is very important in the development of multicellular eukaryotic organisms.<ref name="Teif_2014"/> 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 signaling. Thus, as individuals develop, [[morphogen]]s activate or silence genes in an epigenetically heritable fashion, giving cells a memory. In mammals, most cells terminally differentiate, with only [[stem cells]] retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In [[mammal]]s, some stem cells continue producing newly differentiated cells throughout life, such as in [[Epigenetic Regulation of Neurogenesis|neurogenesis]], 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. Epigenetic modifications regulate the transition from neural stem cells to glial progenitor cells (for example, differentiation into oligodendrocytes is regulated by the deacetylation and methylation of histones.<ref>Chapter: "Nervous System Development" in "Epigenetics," by Benedikt Hallgrimsson and Brian Hall</ref> Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilize many of the same epigenetic mechanisms as animals, such as [[chromatin remodeling]], it has been hypothesized 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.<ref name="pmid17194589">{{cite journal | vauthors = Costa S, Shaw P | title = 'Open minded' cells: how cells can change fate | journal = Trends in Cell Biology | volume = 17 | issue = 3 | pages = 101–6 | date = March 2007 | pmid = 17194589 | doi = 10.1016/j.tcb.2006.12.005 | url = http://cromatina.icb.ufmg.br/biomol/seminarios/outros/grupo_open.pdf | url-status = dead | quote = 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) | archive-url = https://web.archive.org/web/20131215042638/http://cromatina.icb.ufmg.br/biomol/seminarios/outros/grupo_open.pdf | df = dmy-all | archive-date = 15 December 2013 }}</ref> Epigenetic changes can occur in response to environmental exposure – for example, maternal dietary supplementation with [[genistein]] (250&nbsp;mg/kg) have epigenetic changes affecting expression of the [[agouti gene]], which affects their fur color, weight, and propensity to develop cancer.<ref name="pmid12163699">{{cite journal | vauthors = Cooney CA, Dave AA, Wolff GL | title = Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring | journal = The Journal of Nutrition | volume = 132 | issue = 8 Suppl | pages = 2393S–2400S | date = August 2002 | pmid = 12163699 | doi = 10.1093/jn/132.8.2393S | doi-access = free }}</ref><ref name="waterland">{{cite journal | vauthors = Waterland RA, Jirtle RL | title = Transposable elements: targets for early nutritional effects on epigenetic gene regulation | journal = Molecular and Cellular Biology | volume = 23 | issue = 15 | pages = 5293–300 | date = August 2003 | pmid = 12861015 | pmc = 165709 | doi = 10.1128/MCB.23.15.5293-5300.2003 }}</ref><ref>{{cite journal | vauthors = Dolinoy DC | title = The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome | journal = Nutrition Reviews | volume = 66 | issue = Suppl 1 | pages = S7-11 | date = August 2008 | pmid = 18673496 | pmc = 2822875 | doi = 10.1111/j.1753-4887.2008.00056.x }}</ref> Ongoing research is focused on exploring the impact of other known [[teratogen]]s, such as [[diabetic embryopathy]], on [[methylation]] signatures.<ref>{{cite journal | vauthors = Schulze KV, Bhatt A, Azamian MS, Sundgren NC, Zapata GE, Hernandez P, Fox K, Kaiser JR, Belmont JW, Hanchard NA | display-authors = 6 | title = Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy | journal = Genetics in Medicine | volume = 21 | issue = 11 | pages = 2453–2461 | date = November 2019 | pmid = 30992551 | doi = 10.1038/s41436-019-0516-z | s2cid = 116880337 | doi-access = free }}</ref> Controversial results from one study suggested that traumatic experiences might produce an epigenetic signal that is capable of being passed to future generations. Mice were trained, using foot shocks, to fear a cherry blossom odor. The investigators reported that the mouse offspring had an increased aversion to this specific odor.<ref>{{cite web | url = https://www.scientificamerican.com/article/fearful-memories-passed-down/ | title = Fearful Memories Passed Down to Mouse Descendants: Genetic imprint from traumatic experiences carries through at least two generations | vauthors = Callaway E | work = Nature Magazine | date = 1 December 2013 | via = Scientific American }}</ref><ref>{{cite web | url = http://medicalxpress.com/news/2013-12-mice-sons-grandsons-dangers-sperm.html#ajTabs | title = Mice can 'warn' sons, grandsons of dangers via sperm | vauthors = Le Roux M | date = 13 December 2013 }}</ref> They suggested epigenetic changes that increase gene expression, rather than in DNA itself, in a gene, M71, that governs the functioning of an odor receptor in the nose that responds specifically to this cherry blossom smell. There were physical changes that correlated with olfactory (smell) function in the brains of the trained mice and their descendants. Several criticisms were reported, including the study's low statistical power as evidence of some irregularity such as bias in reporting results.<ref name="Francis_2014">{{cite journal | vauthors = Francis G | title = Too much success for recent groundbreaking epigenetic experiments | journal = Genetics | volume = 198 | issue = 2 | pages = 449–451 | date = October 2014 | pmid = 25316784 | pmc = 4196602 | doi = 10.1534/genetics.114.163998 }}</ref> Due to limits of sample size, there is a probability that an effect will not be demonstrated to within statistical significance even if it exists. The criticism suggested that the probability that all the experiments reported would show positive results if an identical protocol was followed, assuming the claimed effects exist, is merely 0.4%. The authors also did not indicate which mice were siblings, and treated all of the mice as statistically independent.<ref>{{cite journal | vauthors = Dias BG, Ressler KJ | title = Parental olfactory experience influences behavior and neural structure in subsequent generations | journal = Nature Neuroscience | volume = 17 | issue = 1 | pages = 89–96 | date = January 2014 | pmid = 24292232 | pmc = 3923835 | doi = 10.1038/nn.3594 }} (see comment by Gonzalo Otazu)</ref> The original researchers pointed out negative results in the paper's appendix that the criticism omitted in its calculations, and undertook to track which mice were siblings in the future.<ref>{{Cite web | url=http://www.the-scientist.com/?articles.view/articleNo/41239/title/Epigenetics-Paper-Raises-Questions/ | title=Epigenetics Paper Raises Questions}}</ref> ===Transgenerational=== {{main|Transgenerational epigenetic inheritance}} <!--Note that the first sentence of this section clashes with the first sentence of the article defining 'epigenetics', by which epigenetics is necessarily heritable. This may arise from confusing the molecular marks sometimes associated with epigenetic variation (e.g. DNA methylation) with epigenetic phenotypic variation itself.--> Epigenetic mechanisms were a necessary part of the evolutionary origin of [[cell differentiation]].<ref name="isbn0-19-854968-7">{{cite book | author = Hoekstra RF | title = Evolution: an introduction | publisher = Oxford University Press | location = Oxford | year = 2000 | page = 285 | isbn = 978-0-19-854968-0 }}</ref>{{request quotation|date=November 2020}} Although epigenetics in multicellular organisms is generally thought to be a mechanism involved in differentiation, with epigenetic patterns "reset" when organisms reproduce, there have been some observations of transgenerational epigenetic inheritance (e.g., the phenomenon of [[paramutation]] observed in [[maize]]). Although most of these multigenerational epigenetic traits are gradually lost over several generations, the possibility remains that multigenerational epigenetics could be another aspect to [[evolution]] and adaptation. As mentioned above, some define epigenetics as heritable. A sequestered germ line or [[Weismann barrier]] is specific to animals, and epigenetic inheritance is more common in plants and microbes. [[Eva Jablonka]], [[Marion J. Lamb]] and Étienne Danchin have argued that these effects may require enhancements to the standard conceptual framework of the [[modern synthesis (20th century)|modern synthesis]] and have called for an [[extended evolutionary synthesis]].<ref name="isbn0-262-10107-6">{{cite book |vauthors= Lamb MJ, Jablonka E | title= Evolution in four dimensions: genetic, epigenetic, behavioral, and symbolic variation in the history of life | publisher= MIT Press | location= Cambridge, Massachusetts | year= 2005 | isbn= 978-0-262-10107-3 }}</ref><ref>See also [[Denis Noble]]: ''The Music of Life'', esp pp. 93–98 and p. 48, where he cites Jablonka & Lamb and [[Massimo Pigliucci]]'s review of Jablonka and Lamb in [[Nature (journal)|''Nature'']] '''435''', 565–566 (2 June 2005)</ref><ref>{{cite journal | vauthors = Danchin É, Charmantier A, Champagne FA, Mesoudi A, Pujol B, Blanchet S | title = Beyond DNA: integrating inclusive inheritance into an extended theory of evolution | journal = Nature Reviews. Genetics | volume = 12 | issue = 7 | pages = 475–86 | date = June 2011 | pmid = 21681209 | doi = 10.1038/nrg3028 | s2cid = 8837202 }}</ref> Other evolutionary biologists, such as [[John Maynard Smith]], have incorporated epigenetic inheritance into [[population genetics|population-genetics]] models<ref>{{cite journal | vauthors = Maynard Smith J | title = Models of a dual inheritance system | journal = Journal of Theoretical Biology | volume = 143 | issue = 1 | pages = 41–53 | date = March 1990 | pmid = 2359317 | doi = 10.1016/S0022-5193(05)80287-5 | bibcode = 1990JThBi.143...41M }}</ref> or are openly skeptical of the extended evolutionary synthesis ([[Michael Lynch (geneticist)|Michael Lynch]]).<ref>{{cite journal | vauthors = Lynch M | title = The frailty of adaptive hypotheses for the origins of organismal complexity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = Suppl 1 | pages = 8597–604 | date = May 2007 | pmid = 17494740 | pmc = 1876435 | doi = 10.1073/pnas.0702207104 | bibcode = 2007PNAS..104.8597L | doi-access = free }}</ref> Thomas Dickins and Qazi Rahman state that epigenetic mechanisms such as DNA methylation and histone modification are genetically inherited under the control of [[natural selection]] and therefore fit under the earlier [[Modern synthesis (20th century)|"modern synthesis"]].<ref>{{cite journal | vauthors = Dickins TE, Rahman Q | title = The extended evolutionary synthesis and the role of soft inheritance in evolution | journal = Proceedings. Biological Sciences | volume = 279 | issue = 1740 | pages = 2913–21 | date = August 2012 | pmid = 22593110 | pmc = 3385474 | doi = 10.1098/rspb.2012.0273 }}</ref> Two important ways in which epigenetic inheritance can differ from traditional genetic inheritance, with important consequences for evolution, are: * rates of epimutation can be much faster than rates of mutation<ref name=rando_and_verstrepen>{{cite journal | vauthors = Rando OJ, Verstrepen KJ | title = Timescales of genetic and epigenetic inheritance | journal = Cell | volume = 128 | issue = 4 | pages = 655–68 | date = February 2007 | pmid = 17320504 | doi = 10.1016/j.cell.2007.01.023 | s2cid = 17964015 | doi-access = free }}</ref> * the epimutations are more easily reversible<ref>{{cite journal | vauthors = Lancaster AK, Masel J | title = The evolution of reversible switches in the presence of irreversible mimics | journal = Evolution; International Journal of Organic Evolution | volume = 63 | issue = 9 | pages = 2350–62 | date = September 2009 | pmid = 19486147 | pmc = 2770902 | doi = 10.1111/j.1558-5646.2009.00729.x }}</ref> In plants, heritable DNA methylation mutations are 100,000 times more likely to occur compared to DNA mutations.<ref name=van_der_Graaf_et_al>{{cite journal | vauthors = van der Graaf A, Wardenaar R, Neumann DA, Taudt A, Shaw RG, Jansen RC, Schmitz RJ, Colomé-Tatché M, Johannes F | display-authors = 6 | title = Rate, spectrum, and evolutionary dynamics of spontaneous epimutations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 21 | pages = 6676–81 | date = May 2015 | pmid = 25964364 | pmc = 4450394 | doi = 10.1073/pnas.1424254112 | bibcode = 2015PNAS..112.6676V | doi-access = free }}</ref> An epigenetically inherited element such as the [[PSI (prion)|PSI+]] 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 [[genetic assimilation|genetically assimilate]] the adaptive phenotypic change.<ref>{{cite journal | vauthors = Griswold CK, Masel J | title = Complex adaptations can drive the evolution of the capacitor [PSI], even with realistic rates of yeast sex | journal = PLOS Genetics | volume = 5 | issue = 6 | pages = e1000517 | date = June 2009 | pmid = 19521499 | pmc = 2686163 | doi = 10.1371/journal.pgen.1000517 | doi-access = free }}</ref> The existence of this possibility increases the [[evolvability]] of a species. More than 100&nbsp;cases of [[transgenerational epigenetic inheritance]] phenomena have been reported in a wide range of organisms, including prokaryotes, plants, and animals.<ref name="Jablonka09">{{cite journal | vauthors = Jablonka E, Raz G | title = Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution | journal = The Quarterly Review of Biology | volume = 84 | issue = 2 | pages = 131–76 | date = June 2009 | pmid = 19606595 | doi = 10.1086/598822 | url = http://compgen.unc.edu/wiki/images/d/df/JablonkaQtrRevBio2009.pdf | citeseerx = 10.1.1.617.6333 | s2cid = 7233550 | access-date = 1 November 2017 | archive-date = 15 July 2011 | archive-url = https://web.archive.org/web/20110715111243/http://compgen.unc.edu/wiki/images/d/df/JablonkaQtrRevBio2009.pdf | url-status = dead }}</ref> For instance, [[Nymphalis antiopa|mourning-cloak butterflies]] will change color through hormone changes in response to experimentation of varying temperatures.<ref>Davies, Hazel (2008). Do Butterflies Bite?: Fascinating Answers to Questions about Butterflies and Moths (Animals Q&A). Rutgers University Press.</ref> The filamentous fungus ''Neurospora crassa'' is a prominent model system for understanding the control and function of cytosine methylation. In this organism, 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.<ref name="pmid19092133">{{cite journal | vauthors = Lewis ZA, Honda S, Khlafallah TK, Jeffress JK, Freitag M, Mohn F, Schübeler D, Selker EU | display-authors = 6 | title = Relics of repeat-induced point mutation direct heterochromatin formation in Neurospora crassa | journal = Genome Research | volume = 19 | issue = 3 | pages = 427–37 | date = March 2009 | pmid = 19092133 | pmc = 2661801 | doi = 10.1101/gr.086231.108 }}</ref> The [[yeast prion]] 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, exemplifying epigenetic regulation which enables 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.<ref name=JorgTost>{{cite book | vauthors = Tost J | title= Epigenetics | publisher= Caister Academic Press | location= Norfolk, England | year= 2008 | isbn= 978-1-904455-23-3 }}</ref> Direct detection of epigenetic marks in microorganisms is possible with [[single molecule real time sequencing]], in which polymerase sensitivity allows for measuring methylation and other modifications as a DNA molecule is being sequenced.<ref>{{cite journal | vauthors = Schadt EE, Banerjee O, Fang G, Feng Z, Wong WH, Zhang X, Kislyuk A, Clark TA, Luong K, Keren-Paz A, Chess A, Kumar V, Chen-Plotkin A, Sondheimer N, Korlach J, Kasarskis A | display-authors = 6 | title = Modeling kinetic rate variation in third generation DNA sequencing data to detect putative modifications to DNA bases | journal = Genome Research | volume = 23 | issue = 1 | pages = 129–41 | date = January 2013 | pmid = 23093720 | pmc = 3530673 | doi = 10.1101/gr.136739.111 }}</ref> Several projects have demonstrated the ability to collect genome-wide epigenetic data in bacteria.<ref>{{cite journal | vauthors = Davis BM, Chao MC, Waldor MK | title = Entering the era of bacterial epigenomics with single molecule real time DNA sequencing | journal = Current Opinion in Microbiology | volume = 16 | issue = 2 | pages = 192–8 | date = April 2013 | pmid = 23434113 | pmc = 3646917 | doi = 10.1016/j.mib.2013.01.011 }}</ref><ref>{{cite journal | vauthors = Lluch-Senar M, Luong K, Lloréns-Rico V, Delgado J, Fang G, Spittle K, Clark TA, Schadt E, Turner SW, Korlach J, Serrano L | display-authors = 6 | title = Comprehensive methylome characterization of Mycoplasma genitalium and Mycoplasma pneumoniae at single-base resolution | journal = PLOS Genetics | volume = 9 | issue = 1 | pages = e1003191 | year = 2013 | pmid = 23300489 | pmc = 3536716 | doi = 10.1371/journal.pgen.1003191 | veditors = Richardson PM | doi-access = free }}</ref><ref>{{cite journal | vauthors = Murray IA, Clark TA, Morgan RD, Boitano M, Anton BP, Luong K, Fomenkov A, Turner SW, Korlach J, Roberts RJ | display-authors = 6 | title = The methylomes of six bacteria | journal = Nucleic Acids Research | volume = 40 | issue = 22 | pages = 11450–62 | date = December 2012 | pmid = 23034806 | pmc = 3526280 | doi = 10.1093/nar/gks891 }}</ref><ref> {{cite journal | vauthors = Fang G, Munera D, Friedman DI, Mandlik A, Chao MC, Banerjee O, Feng Z, Losic B, Mahajan MC, Jabado OJ, Deikus G, Clark TA, Luong K, Murray IA, Davis BM, Keren-Paz A, Chess A, Roberts RJ, Korlach J, Turner SW, Kumar V, Waldor MK, Schadt EE | display-authors = 6 | title = Genome-wide mapping of methylated adenine residues in pathogenic Escherichia coli using single-molecule real-time sequencing | journal = Nature Biotechnology | volume = 30 | issue = 12 | pages = 1232–9 | date = December 2012 | pmid = 23138224 | pmc = 3879109 | doi = 10.1038/nbt.2432 }} </ref> == Epigenetics in bacteria == [[File:Escherichia coli flagella TEM.png|thumb|150px|''Escherichia coli'' bacteria]] While epigenetics is of fundamental importance in [[eukaryote]]s, especially [[Multicellular organism|metazoans]], it plays a different role in bacteria.<ref>{{cite journal | vauthors = Oliveira PH | title = Bacterial Epigenomics: Coming of Age | journal = mSystems | volume = 6 | issue = 4 | pages = e0074721 | date = August 2021 | pmid = 34402642 | doi = 10.1128/mSystems.00747-21 | pmc = 8407109 | s2cid = 237149441 | doi-access = free }}</ref> Most importantly, eukaryotes use epigenetic mechanisms primarily to regulate gene expression which bacteria rarely do. However, bacteria make widespread use of postreplicative DNA methylation for the epigenetic control of DNA-protein interactions. Bacteria also use DNA [[adenine]] methylation (rather than DNA [[cytosine]] methylation) as an epigenetic signal. DNA adenine methylation is important in bacteria virulence in organisms such as ''[[Escherichia coli]]'', ''[[Salmonella]], [[Vibrio]], [[Yersinia]], [[Haemophilus]]'', and ''[[Brucella]]''. In ''[[Alphaproteobacteria]]'', methylation of adenine regulates the cell cycle and couples gene transcription to DNA replication. In ''[[Gammaproteobacteria]]'', adenine methylation provides signals for DNA replication, chromosome segregation, mismatch repair, packaging of bacteriophage, transposase activity and regulation of gene expression.<ref name="JorgTost" /><ref name="Casadesus">{{cite journal | vauthors = Casadesús J, Low D | title = Epigenetic gene regulation in the bacterial world | journal = Microbiology and Molecular Biology Reviews | volume = 70 | issue = 3 | pages = 830–56 | date = September 2006 | pmid = 16959970 | pmc = 1594586 | doi = 10.1128/MMBR.00016-06 }}</ref> There exists a genetic switch controlling ''[[Streptococcus pneumoniae]]'' (the pneumococcus) that allows the bacterium to randomly change its characteristics into six alternative states that could pave the way to improved vaccines. Each form is randomly generated by a phase variable methylation system. The ability of the pneumococcus to cause deadly infections is different in each of these six states. Similar systems exist in other bacterial genera.<ref name="MansoOggioni2014">{{cite journal | vauthors = Manso AS, Chai MH, Atack JM, Furi L, De Ste Croix M, Haigh R, Trappetti C, Ogunniyi AD, Shewell LK, Boitano M, Clark TA, Korlach J, Blades M, Mirkes E, Gorban AN, Paton JC, Jennings MP, Oggioni MR | display-authors = 6 | title = A random six-phase switch regulates pneumococcal virulence via global epigenetic changes | journal = Nature Communications | volume = 5 | pages = 5055 | date = September 2014 | pmid = 25268848 | pmc = 4190663 | doi = 10.1038/ncomms6055 | bibcode = 2014NatCo...5.5055M }}</ref> In [[Bacillota]] such as ''[[Clostridioides difficile (bacteria)|Clostridioides difficile]],'' adenine methylation regulates [[Spore|sporulation]], [[biofilm]] formation and host-adaptation.<ref>{{cite journal | vauthors = Oliveira PH, Ribis JW, Garrett EM, Trzilova D, Kim A, Sekulovic O, Mead EA, Pak T, Zhu S, Deikus G, Touchon M, Lewis-Sandari M, Beckford C, Zeitouni NE, Altman DR, Webster E, Oussenko I, Bunyavanich S, Aggarwal AK, Bashir A, Patel G, Wallach F, Hamula C, Huprikar S, Schadt EE, Sebra R, van Bakel H, Kasarskis A, Tamayo R, Shen A, Fang G | display-authors = 6 | title = Epigenomic characterization of Clostridioides difficile finds a conserved DNA methyltransferase that mediates sporulation and pathogenesis | journal = Nature Microbiology | volume = 5 | issue = 1 | pages = 166–180 | date = January 2020 | pmid = 31768029 | pmc = 6925328 | doi = 10.1038/s41564-019-0613-4 }}</ref> ==Medicine== Epigenetics has many and varied potential medical applications.<ref name="pmid21447282">{{cite journal | vauthors = Chahwan R, Wontakal SN, Roa S | title = The multidimensional nature of epigenetic information and its role in disease | journal = Discovery Medicine | volume = 11 | issue = 58 | pages = 233–43 | date = March 2011 | pmid = 21447282 }}</ref> ===Twins=== Direct comparisons of identical twins constitute an optimal model for interrogating [[environmental epigenetics]]. In the case of humans with different environmental exposures, monozygotic (identical) twins were epigenetically indistinguishable during their early years, while older twins had remarkable differences in the overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation.<ref name="Moore_2015"/> 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 [[5-methylcytosine]] DNA and [[acetylation]] of [[histones]] H3 and H4.<ref name="pmid16009939" /> Dizygotic (fraternal) and monozygotic (identical) twins show evidence of epigenetic influence in humans.<ref name="pmid16009939">{{cite journal | vauthors = 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 | display-authors = 6 | title = Epigenetic differences arise during the lifetime of monozygotic twins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 30 | pages = 10604–9 | date = July 2005 | pmid = 16009939 | pmc = 1174919 | doi = 10.1073/pnas.0500398102 | bibcode = 2005PNAS..10210604F | doi-access = free }}</ref><ref name="pmid19151718">{{cite journal | vauthors = 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 | display-authors = 6 | title = DNA methylation profiles in monozygotic and dizygotic twins | journal = Nature Genetics | volume = 41 | issue = 2 | pages = 240–5 | date = February 2009 | pmid = 19151718 | doi = 10.1038/ng.286 | s2cid = 12688031 }}</ref><ref>{{cite news|title=The Claim: Identical Twins Have Identical DNA|newspaper=New York Times|url=https://www.nytimes.com/2008/03/11/health/11real.html| vauthors = O'Connor A | date=11 March 2008 | access-date=2 May 2010}}</ref> DNA sequence differences that would be abundant in a singleton-based study do not interfere with the analysis. Environmental differences 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.<ref name="pmid19653134">{{cite journal | vauthors = Ballestar E | title = Epigenetics lessons from twins: prospects for autoimmune disease | journal = Clinical Reviews in Allergy & Immunology | volume = 39 | issue = 1 | pages = 30–41 | date = August 2010 | pmid = 19653134 | doi = 10.1007/s12016-009-8168-4 | s2cid = 25040280 }}</ref> A [[High-throughput screening|high-throughput]] study, which denotes technology that looks at extensive genetic markers, focused on epigenetic differences between monozygotic twins to compare global and locus-specific changes in [[DNA methylation]] and histone modifications in a sample of 40 monozygotic twin pairs.<ref name="pmid16009939" /> 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". ''Epigenetic drift'' is the term given to epigenetic modifications as they occur as a direct function with age. While age is a known risk factor for many diseases, age-related methylation has been found to occur differentially at specific sites along the genome. Over time, this can result in measurable differences between biological and chronological age. Epigenetic changes have been found to be reflective of [[Lifestyle (social sciences)|lifestyle]] and may act as functional [[biomarker]]s of disease before clinical [[reference range|threshold]] is reached.<ref>{{cite journal | vauthors = Wallace RG, Twomey LC, Custaud MA, Moyna N, Cummins PM, Mangone M, Murphy RP | title = Potential Diagnostic and Prognostic Biomarkers of Epigenetic Drift within the Cardiovascular Compartment | journal = BioMed Research International | volume = 2016 | pages = 2465763 | year = 2016 | pmid = 26942189 | pmc = 4749768 | doi = 10.1155/2016/2465763 | doi-access = free }}</ref> 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 (biology)|microenvironment]] at early stages of embryonic development can be quite important for the establishment of epigenetic marks.<ref name="pmid19151718"/> Congenital genetic disease is well understood and it is clear that epigenetics can play a role, for example, in the case of [[Angelman syndrome]] and [[Prader–Willi syndrome]]. These are normal genetic diseases caused by gene deletions or inactivation of the genes but are unusually common because individuals are essentially [[hemizygous]] because of [[genomic imprinting]], and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.<ref>{{OMIM|105830}}</ref> ===Genomic imprinting=== {{Further|Genomic imprinting}} Some human disorders are associated with genomic imprinting, a phenomenon in mammals where the father and mother contribute different epigenetic patterns for specific genomic loci in their [[germ cells]].<ref name="pmid17121465">{{cite journal | vauthors = Wood AJ, Oakey RJ | title = Genomic imprinting in mammals: emerging themes and established theories | journal = PLOS Genetics | volume = 2 | issue = 11 | pages = e147 | date = November 2006 | pmid = 17121465 | pmc = 1657038 | doi = 10.1371/journal.pgen.0020147 | doi-access = free }}</ref> The best-known case of imprinting in human disorders is that of [[Angelman syndrome]] and [[Prader–Willi syndrome]] – both can be produced by the same genetic mutation, [[chromosome 15q partial deletion]], and the particular syndrome that will develop depends on whether the mutation is inherited from the child's mother or from their father.<ref name="pmid2564739">{{cite journal | vauthors = Knoll JH, Nicholls RD, Magenis RE, Graham JM, Lalande M, Latt SA | title = Angelman and Prader–Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion | journal = American Journal of Medical Genetics | volume = 32 | issue = 2 | pages = 285–90 | date = February 1989 | pmid = 2564739 | doi = 10.1002/ajmg.1320320235 }}</ref> In the [[Överkalix study]], paternal (but not maternal) grandsons<ref name="paternal-grandson">A person's paternal grandson is the son of a son of that person; a maternal grandson is the son of a daughter.</ref> 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 [[diabetes]] mortality in the grandchildren increased, suggesting that this was a transgenerational epigenetic inheritance.<ref name="pmid16391557">{{cite journal |vauthors=Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjöström M, Golding J |date=February 2006 |title=Sex-specific, male-line transgenerational responses in humans |journal=European Journal of Human Genetics |volume=14 |issue=2 |pages=159–66 |doi=10.1038/sj.ejhg.5201538 |pmid=16391557 |doi-access=free}} [[Robert Winston]] refers to this study in a {{cite web | url = http://www.dundee.ac.uk/externalrelations/events/lectures.html | title = Lecture | archive-url = https://web.archive.org/web/20070523074254/http://www.dundee.ac.uk/externalrelations/events/lectures.html| archive-date = 23 May 2007}}</ref> 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.<ref>{{cite web|url=https://www.pbs.org/wgbh/nova/transcripts/3413_genes.html |title=NOVA &#124; Transcripts &#124; Ghost in Your Genes |publisher=PBS |date=16 October 2007 |access-date=26 July 2012}}</ref> ===Examples of drugs altering gene expression from epigenetic events=== {{See also|Epigenetic Priming|label 1=Epigenetic Priming}} The use of beta-lactam [[antibiotics]] can alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. Additionally, [[lithium]] can impact autophagy of aberrant proteins, and [[opioid]] drugs via chronic use can increase the expression of genes associated with addictive phenotypes.<ref>{{cite journal | vauthors = Anderson SJ, Feye KM, Schmidt-McCormack GR, Malovic E, Mlynarczyk GS, Izbicki P, Arnold LF, Jefferson MA, de la Rosa BM, Wehrman RF, Luna KC, Hu HZ, Kondru NC, Kleinhenz MD, Smith JS, Manne S, Putra MR, Choudhary S, Massey N, Luo D, Berg CA, Acharya S, Sharma S, Kanuri SH, Lange JK, Carlson SA | display-authors = 6 | title = Off-Target drug effects resulting in altered gene expression events with epigenetic and "Quasi-Epigenetic" origins | journal = Pharmacological Research | volume = 107 | pages = 229–233 | date = May 2016 | pmid = 27025785 | doi = 10.1016/j.phrs.2016.03.028 }}</ref> Parental [[nutrition]], in utero exposure to stress or [[Endocrine disruptor|endocrine disrupting chemicals]],<ref>{{cite journal | vauthors = Alavian-Ghavanini A, Rüegg J | title = Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: From Mechanisms to Novel Test Methods | journal = Basic & Clinical Pharmacology & Toxicology | volume = 122 | issue = 1 | pages = 38–45 | date = January 2018 | pmid = 28842957 | doi = 10.1111/bcpt.12878 | doi-access = free }}</ref> male-induced maternal effects such as the attraction of differential mate quality, and maternal as well as paternal age, and offspring gender could all possibly influence whether a germline epimutation is ultimately expressed in offspring and the degree to which intergenerational inheritance remains stable throughout posterity.<ref name="ReferenceB">{{cite book |doi=10.1016/B978-0-12-809324-5.02862-5 |chapter=Persistence of Early-Life Stress on the Epigenome: Nonhuman Primate Observations☆ |title=Reference Module in Neuroscience and Biobehavioral Psychology |year=2017 | vauthors = Coplan J, Chanatry ST, Rosenblum LA |isbn=9780128093245 }}</ref> However, whether and to what extent epigenetic effects can be transmitted across generations remains unclear, particularly in humans.<ref name="PlominDeFries2012">{{cite book | vauthors = Plomin R, DeFries JC, Knopik VS, Neiderhiser JM | title = Behavioral Genetics | edition = Seventh | url = https://books.google.com/books?id=OytMMAEACAAJ | date = 2017 | publisher = Worth Publishers | isbn = 978-1-4292-4215-8 | pages = 152–153 }}</ref><ref>{{cite journal | vauthors = Heard E, Martienssen RA | title = Transgenerational epigenetic inheritance: myths and mechanisms | journal = Cell | volume = 157 | issue = 1 | pages = 95–109 | date = March 2014 | pmid = 24679529 | pmc = 4020004 | doi = 10.1016/j.cell.2014.02.045 | doi-access = free }}</ref> ===Addiction=== [[Addiction]] is a disorder of the brain's [[reward system]] which arises through [[transcriptional]] and neuroepigenetic mechanisms and occurs over time from chronically high levels of exposure to an addictive stimulus (e.g., morphine, cocaine, sexual intercourse, gambling).<ref name="Nestler">{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–37 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}</ref><ref name="G9a reverses ΔFosB plasticity">{{cite journal | vauthors = Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T | title = Epigenetic regulation in drug addiction | journal = Annals of Agricultural and Environmental Medicine | volume = 19 | issue = 3 | pages = 491–6 | year = 2012 | pmid = 23020045}}</ref> Transgenerational epigenetic inheritance of addictive [[phenotypes]] has been noted to occur in preclinical studies.<ref name="pmid23920159">{{cite journal | vauthors = Vassoler FM, Sadri-Vakili G | title = Mechanisms of transgenerational inheritance of addictive-like behaviors | journal = Neuroscience | volume = 264 | pages = 198–206 | date = April 2014 | pmid = 23920159 | pmc = 3872494 | doi = 10.1016/j.neuroscience.2013.07.064 }}</ref><ref name="pmid26572641">{{cite journal | vauthors = Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB, Arias-Carrión O, Machado S, Hou G, So KF | display-authors = 6 | title = Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism | journal = Molecular Neurobiology | volume = 53 | issue = 9 | pages = 6367–6376 | date = November 2016 | pmid = 26572641 | doi = 10.1007/s12035-015-9526-2 | hdl = 10400.22/7331 | s2cid = 25694221 | hdl-access = free }}</ref> However, robust evidence in support of the persistence of epigenetic effects across multiple generations has yet to be established in humans; for example, an epigenetic effect of prenatal exposure to smoking that is observed in great-grandchildren who had not been exposed.<ref name="PlominDeFries2012" /> ==Research== The two forms of heritable information, namely genetic and epigenetic, are collectively called dual inheritance. Members of the APOBEC/AID family of [[cytosine deaminase]]s may concurrently influence genetic and epigenetic inheritance using similar molecular mechanisms, and may be a point of crosstalk between these conceptually compartmentalized processes.<ref name="pmid20800313">{{cite journal | vauthors = Chahwan R, Wontakal SN, Roa S | title = Crosstalk between genetic and epigenetic information through cytosine deamination | journal = Trends in Genetics | volume = 26 | issue = 10 | pages = 443–8 | date = October 2010 | pmid = 20800313 | doi = 10.1016/j.tig.2010.07.005 }}</ref> [[Fluoroquinolone]] antibiotics induce epigenetic changes in [[mammalian]] cells through iron [[chelation]]. This leads to epigenetic effects through inhibition of α-ketoglutarate-dependent [[dioxygenases]] that require [[iron]] as a co-factor.<ref>{{cite journal | vauthors = Badal S, Her YF, Maher LJ | title = Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells | journal = The Journal of Biological Chemistry | volume = 290 | issue = 36 | pages = 22287–97 | date = September 2015 | pmid = 26205818 | pmc = 4571980 | doi = 10.1074/jbc.M115.671222 | doi-access = free }}</ref> Various pharmacological agents are applied for the production of induced pluripotent stem cells (iPSC) or maintain the embryonic stem cell (ESC) phenotypic via epigenetic approach. Adult stem cells like bone marrow stem cells have also shown a potential to differentiate into cardiac competent cells when treated with G9a histone methyltransferase inhibitor BIX01294.<ref>{{cite journal | vauthors = Mezentseva NV, Yang J, Kaur K, Iaffaldano G, Rémond MC, Eisenberg CA, Eisenberg LM | title = The histone methyltransferase inhibitor BIX01294 enhances the cardiac potential of bone marrow cells | journal = Stem Cells and Development | volume = 22 | issue = 4 | pages = 654–67 | date = February 2013 | pmid = 22994322 | pmc = 3564468 | doi = 10.1089/scd.2012.0181 }}</ref><ref>{{cite journal | vauthors = Yang J, Kaur K, Ong LL, Eisenberg CA, Eisenberg LM | title = Inhibition of G9a Histone Methyltransferase Converts Bone Marrow Mesenchymal Stem Cells to Cardiac Competent Progenitors | journal = Stem Cells International | volume = 2015 | pages = 270428 | date = 2015 | pmid = 26089912 | pmc = 4454756 | doi = 10.1155/2015/270428 | doi-access = free }}</ref> Cell plasticity, which is the adaptation of cells to stimuli without changes in their genetic code, requires epigenetic changes. These have been observed in cell plasticity in cancer cells during epithelial-to-mesenchymal transition<ref>{{cite journal | vauthors = Müller S, Sindikubwabo F, Cañeque T, Lafon A, Versini A, Lombard B, Loew D, Wu TD, Ginestier C, Charafe-Jauffret E, Durand A, Vallot C, Baulande S, Servant N, Rodriguez R | display-authors = 6 | title = CD44 regulates epigenetic plasticity by mediating iron endocytosis | journal = Nature Chemistry | volume = 12 | issue = 10 | pages = 929–938 | date = October 2020 | doi = 10.1038/s41557-020-0513-5 | pmid = 32747755 | pmc = 7612580 | bibcode = 2020NatCh..12..929M }}</ref> and also in immune cells, such as macrophages.<ref>{{cite journal | vauthors = Solier S, Müller S, Cañeque T, Versini A, Mansart A, Sindikubwabo F, Baron L, Emam L, Gestraud P, Pantoș GD, Gandon V, Gaillet C, Wu TD, Dingli F, Loew D, Baulande S, Durand S, Sencio V, Robil C, Trottein F, Péricat D, Näser E, Cougoule C, Meunier E, Bègue AL, Salmon H, Manel N, Puisieux A, Watson S, Dawson MA, Servant N, Kroemer G, Annane D, Rodriguez R | display-authors = 6 | title = A druggable copper-signalling pathway that drives inflammation | journal = Nature | volume = 617 | issue = 7960 | pages = 386–394 | date = May 2023 | pmid = 37100912 | doi = 10.1038/s41586-023-06017-4 | pmc = 10131557 | bibcode = 2023Natur.617..386S }}</ref> Interestingly, metabolic changes underly these adaptations, since various metabolites play crucial roles in the chemistry of epigenetic marks. This includes for instance alpha-ketoglutarate, which is required for histone demethylation, and acetyl-Coenzyme A, which is required for histone acetylation. ===Epigenome editing=== {{Main|Epigenome editing}} Epigenetic regulation of gene expression that could be altered or used in [[epigenome editing]] are or include [[mRNA modification|mRNA/lncRNA modification]], [[DNA methylation]] modification and [[histone modification]].<ref>{{cite journal | vauthors = Liu N, Pan T | title = RNA epigenetics | journal = Translational Research | volume = 165 | issue = 1 | pages = 28–35 | date = January 2015 | pmid = 24768686 | pmc = 4190089 | doi = 10.1016/j.trsl.2014.04.003 }}</ref><ref>{{cite journal | vauthors = Rong D, Sun G, Wu F, Cheng Y, Sun G, Jiang W, Li X, Zhong Y, Wu L, Zhang C, Tang W, Wang X | display-authors = 6 | title = Epigenetics: Roles and therapeutic implications of non-coding RNA modifications in human cancers | journal = Molecular Therapy. Nucleic Acids | volume = 25 | pages = 67–82 | date = September 2021 | pmid = 34188972 | pmc = 8217334 | doi = 10.1016/j.omtn.2021.04.021 | s2cid = 235558945 }}</ref><ref>{{cite journal | vauthors = Shin H, Choi WL, Lim JY, Huh JH | title = Epigenome editing: targeted manipulation of epigenetic modifications in plants | journal = Genes & Genomics | volume = 44 | issue = 3 | pages = 307–315 | date = March 2022 | pmid = 35000141 | doi = 10.1007/s13258-021-01199-5 | s2cid = 245848779 }}</ref> === CpG sites, SNPs and biological traits === Methylation is a widely characterized mechanism of genetic regulation that can determine biological traits. However, strong experimental evidences correlate methylation patterns in SNPs as an important additional feature for the classical activation/inhibition epigenetic dogma. Molecular interaction data, supported by colocalization analyses, identify multiple nuclear regulatory pathways, linking sequence variation to disturbances in DNA methylation and molecular and phenotypic variation.<ref name="Hawe_2022">{{cite journal | vauthors = Hawe JS, Wilson R, Schmid KT, Zhou L, Lakshmanan LN, Lehne BC, Kühnel B, Scott WR, Wielscher M, Yew YW, Baumbach C, Lee DP, Marouli E, Bernard M, Pfeiffer L, Matías-García PR, Autio MI, Bourgeois S, Herder C, Karhunen V, Meitinger T, Prokisch H, Rathmann W, Roden M, Sebert S, Shin J, Strauch K, Zhang W, Tan WL, Hauck SM, Merl-Pham J, Grallert H, Barbosa EG, Illig T, Peters A, Paus T, Pausova Z, Deloukas P, Foo RS, Jarvelin MR, Kooner JS, Loh M, Heinig M, Gieger C, Waldenberger M, Chambers JC | display-authors = 6 | title = Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function | journal = Nature Genetics | volume = 54 | issue = 1 | pages = 18–29 | date = January 2022 | pmid = 34980917 | doi = 10.1038/s41588-021-00969-x | s2cid = 245654240 | url = https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=64018 | access-date = 20 January 2023 | archive-date = 29 October 2022 | archive-url = https://web.archive.org/web/20221029233638/https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=64018 | url-status = dead }}</ref> ==== ''UBASH3B'' locus ==== ''UBASH3B'' encodes a protein with tyrosine phosphatase activity, which has been previously linked to advanced neoplasia.<ref>{{cite journal | vauthors = Lee ST, Feng M, Wei Y, Li Z, Qiao Y, Guan P, Jiang X, Wong CH, Huynh K, Wang J, Li J, Karuturi KM, Tan EY, Hoon DS, Kang Y, Yu Q | display-authors = 6 | title = Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 27 | pages = 11121–11126 | date = July 2013 | pmid = 23784775 | doi = 10.1073/pnas.1300873110 | pmc = 3704014 | bibcode = 2013PNAS..11011121L | doi-access = free }}</ref> SNP rs7115089 was identified as influencing DNA methylation and expression of this locus, as well as and Body Mass Index (BMI).<ref name="Hawe_2022" /> In fact, SNP rs7115089 is strongly associated with BMI<ref>{{cite journal | vauthors = Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, Frayling TM, Hirschhorn J, Yang J, Visscher PM | display-authors = 6 | title = Meta-analysis of genome-wide association studies for height and body mass index in ~700000 individuals of European ancestry | journal = Human Molecular Genetics | volume = 27 | issue = 20 | pages = 3641–3649 | date = October 2018 | pmid = 30124842 | doi = 10.1093/hmg/ddy271 | pmc = 6488973 }}</ref> and with genetic variants linked to other cardiovascular and metabolic traits in GWASs.<ref>{{cite journal | vauthors = Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, Yengo L, Ferreira T, Marouli E, Ji Y, Yang J, Jones S, Beaumont R, Croteau-Chonka DC, Winkler TW, Hattersley AT, Loos RJ, Hirschhorn JN, Visscher PM, Frayling TM, Yaghootkar H, Lindgren CM | display-authors = 6 | title = Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry | journal = Human Molecular Genetics | volume = 28 | issue = 1 | pages = 166–174 | date = January 2019 | pmid = 30239722 | doi = 10.1093/hmg/ddy327 | pmc = 6298238 }}</ref><ref>{{cite journal | vauthors = Zhu Z, Guo Y, Shi H, Liu CL, Panganiban RA, Chung W, O'Connor LJ, Himes BE, Gazal S, Hasegawa K, Camargo CA, Qi L, Moffatt MF, Hu FB, Lu Q, Cookson WO, Liang L | display-authors = 6 | title = Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank | journal = The Journal of Allergy and Clinical Immunology | volume = 145 | issue = 2 | pages = 537–549 | date = February 2020 | pmid = 31669095 | doi = 10.1016/j.jaci.2019.09.035 | pmc = 7010560 }}</ref><ref>{{cite journal | vauthors = Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Davey Smith G, Holmes MV | title = Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis | journal = PLOS Medicine | volume = 17 | issue = 3 | pages = e1003062 | date = March 2020 | pmid = 32203549 | doi = 10.1371/journal.pmed.1003062 | pmc = 7089422 | doi-access = free }}</ref> New studies suggesting ''UBASH3B'' as a potential mediator of adiposity and cardiometabolic disease.<ref name="Hawe_2022" /> In addition, animal models demonstrated that ''UBASH3B'' expression is an indicator of caloric restriction that may drive programmed susceptibility to obesity and it is associated with other measures of adiposity in human peripherical blood.<ref>{{cite journal | vauthors = Konieczna J, Sánchez J, Palou M, Picó C, Palou A | title = Blood cell transcriptomic-based early biomarkers of adverse programming effects of gestational calorie restriction and their reversibility by leptin supplementation | journal = Scientific Reports | volume = 5 | issue = 1 | pages = 9088 | date = March 2015 | pmid = 25766068 | doi = 10.1038/srep09088 | pmc = 4357898 | bibcode = 2015NatSR...5E9088K }}</ref> ==== ''NFKBIE'' locus ==== SNP rs730775 is located in the first intron of ''NFKBIE'' and is a ''cis'' eQTL for ''NFKBIE'' in whole blood.<ref name="Hawe_2022" /> Nuclear factor (NF)-κB inhibitor ε (NFKBIE) directly inhibits NF-κB1 activity and is significantly co-expressed with NF-κB1, also, it is associated with rheumatoid arthritis.<ref>{{cite journal | vauthors = Okada Y | title = From the era of genome analysis to the era of genomic drug discovery: a pioneering example of rheumatoid arthritis | journal = Clinical Genetics | volume = 86 | issue = 5 | pages = 432–440 | date = November 2014 | pmid = 25060537 | doi = 10.1111/cge.12465 | s2cid = 8499325 }}</ref> Colocalization analysis supports that variants for the majority of the CpG sites in SNP rs730775 cause genetic variation at the ''NFKBIE'' locus which is suggestible linked to rheumatoid arthritis through ''trans'' acting regulation of DNA methylation by NF-κB.<ref name="Hawe_2022" /> ==== ''FADS1'' locus ==== Fatty acid desaturase 1 (FADS1) is a key enzyme in the metabolism of fatty acids.<ref>{{cite journal | vauthors = He Z, Zhang R, Jiang F, Zhang H, Zhao A, Xu B, Jin L, Wang T, Jia W, Jia W, Hu C | display-authors = 6 | title = FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression | journal = Clinical Epigenetics | volume = 10 | issue = 1 | pages = 113 | date = August 2018 | pmid = 30157936 | pmc = 6114248 | doi = 10.1186/s13148-018-0545-5 | doi-access = free }}</ref> Moreover, rs174548 in the ''FADS1'' gene shows increased correlation with DNA methylation in people with high abundance of CD8+ T cells.<ref name="Hawe_2022" /> SNP rs174548 is strongly associated with concentrations of arachidonic acid and other metabolites in fatty acid metabolism,<ref>{{cite journal | vauthors = Guan W, Steffen BT, Lemaitre RN, Wu JH, Tanaka T, Manichaikul A, Foy M, Rich SS, Wang L, Nettleton JA, Tang W, Gu X, Bandinelli S, King IB, McKnight B, Psaty BM, Siscovick D, Djousse L, Chen YI, Ferrucci L, Fornage M, Mozafarrian D, Tsai MY, Steffen LM | display-authors = 6 | title = Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium | journal = Circulation: Cardiovascular Genetics | volume = 7 | issue = 3 | pages = 321–331 | date = June 2014 | pmid = 24823311 | doi = 10.1161/circgenetics.113.000208 | pmc = 4123862 }}</ref><ref name="pmid24816252">{{cite journal | vauthors = Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J, Arnold M, Erte I, Forgetta V, Yang TP, Walter K, Menni C, Chen L, Vasquez L, Valdes AM, Hyde CL, Wang V, Ziemek D, Roberts P, Xi L, Grundberg E, Waldenberger M, Richards JB, Mohney RP, Milburn MV, John SL, Trimmer J, Theis FJ, Overington JP, Suhre K, Brosnan MJ, Gieger C, Kastenmüller G, Spector TD, Soranzo N | display-authors = 6 | title = An atlas of genetic influences on human blood metabolites | journal = Nature Genetics | volume = 46 | issue = 6 | pages = 543–550 | date = June 2014 | pmid = 24816252 | pmc = 4064254 | doi = 10.1038/ng.2982 }}</ref> blood eosinophil counts.<ref>{{Cite journal | vauthors = Astle WJ, ((UK Blood Trait GWAS Team)), ((Cambridge BLUEPRINT epigenome)) |date=2016-12-02 |title=A GWAS of 170,000 Individuals Identifies Thousands of Alleles Perturbing Blood Cell Traits, Many of Which Are in Super Enhancers Setting Cell Identity |journal=Blood |volume=128 |issue=22 |pages=2652 |doi=10.1182/blood.v128.22.2652.2652 |issn=0006-4971}}</ref> and inflammatory diseases such as asthma.<ref>{{cite journal | vauthors = Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, Butterworth AS, Staley JR | display-authors = 6 | title = PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations | journal = Bioinformatics | volume = 35 | issue = 22 | pages = 4851–4853 | date = November 2019 | pmid = 31233103 | doi = 10.1093/bioinformatics/btz469 | pmc = 6853652 }}</ref> Interaction results indicated a correlation between rs174548 and asthma, providing new insights about fatty acid metabolism in CD8+ T cells with immune phenotypes.<ref name="Hawe_2022" /> ==Pseudoscience== As epigenetics is in the early stages of development as a science and is surrounded by [[sensationalism]] in the public media, [[David Gorski]] and geneticist [[Adam Rutherford]] have advised caution against the proliferation of false and [[Pseudoscience|pseudoscientific]] conclusions by [[new age]] authors making unfounded suggestions that a person's genes and health can be manipulated by [[brainwashing|mind control]]. Misuse of the scientific term by [[quackery|quack authors]] has produced misinformation among the general public.<ref name =science/><ref>{{cite web | vauthors = Gorski D | date = 4 February 2013 | url = https://www.sciencebasedmedicine.org/epigenetics-it-doesnt-mean-what-quacks-think-it-means/ | title = Epigenetics: It doesn't mean what quacks think it means | work = Science-Based Medicine }}</ref> == See also == {{Portal|Biology|Medicine}} {{Div col}} * [[Baldwin effect]] * [[Behavioral epigenetics]] * [[Biological effects of radiation on the epigenome]] * [[Computational epigenetics]] * [[Contribution of epigenetic modifications to evolution]] * [[DAnCER (database)|DAnCER]] database (2010) * [[Epigenesis (biology)]] * [[Epigenetics in forensic science]] * [[Epigenetics of autoimmune disorders]] *[[Epiphenotyping]] * [[Epigenetic therapy]] * [[Epigenetics of neurodegenerative diseases]] * [[Genetics]] * [[Lamarckism]] * [[Nutriepigenomics]] * [[Position-effect variegation]] * [[Preformationism]] * [[Somatic epitype]] * [[Synthetic genetic array]] * [[Sleep epigenetics]] * [[Transcriptional memory]] * [[Transgenerational epigenetic inheritance]] {{div col end}} {{clear}} == References == {{Reflist}} == Further reading == {{refbegin}} * {{cite journal | vauthors = Haque FN, Gottesman II, Wong AH | title = Not really identical: epigenetic differences in monozygotic twins and implications for twin studies in psychiatry | journal = American Journal of Medical Genetics. Part C, Seminars in Medical Genetics | volume = 151C | issue = 2 | pages = 136–41 | date = May 2009 | pmid = 19378334 | doi = 10.1002/ajmg.c.30206 | s2cid = 205327825 }} * {{cite web | title=What is Epigenetics? | website=Centers for Disease Control and Prevention | date=15 Aug 2022 | url=https://www.cdc.gov/genomics/disease/epigenetics.htm | access-date=11 Sep 2023}} {{refend}} == External links == {{Wiktionary}} {{Commons}} <!--======================== {{No more links}} ============================ | PLEASE BE CAUTIOUS IN ADDING MORE LINKS TO THIS ARTICLE. Wikipedia | | is not a collection of links nor should it be used for advertising. | | | | Excessive or inappropriate links WILL BE DELETED. | | See [[Wikipedia:External links]] & [[Wikipedia:Spam]] for details. | | | | If there are already plentiful links, please propose additions or | | replacements on this article's discussion page, or submit your link | | to the relevant category at the Open Directory Project (dmoz.org) | | and link back to that category using the {{dmoz}} template. | ======================= {{No more links}} =============================--> * {{Cite web|url=https://learn.genetics.utah.edu/content/epigenetics/inheritance/|title=Epigenetics & Inheritance|website=learn.genetics.utah.edu|access-date=17 April 2019}} * [http://www.epigenome.org/ The Human Epigenome Project (HEP)] * [https://web.archive.org/web/20100503172418/http://www.epigenome-noe.net/index.php The Epigenome Network of Excellence (NoE)] * [http://www.epigenomes.ca/ Canadian Epigenetics, Environment and Health Research Consortium (CEEHRC)] * [http://www.epigenome.eu/ The Epigenome Network of Excellence (NoE) – public international site] * [http://discovermagazine.com/2006/nov/cover "DNA Is Not Destiny"] – ''Discover'' magazine cover story * [http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ghostgenes.shtml "The Ghost In Your Genes"], ''Horizon'' (2005), BBC * [https://web.archive.org/web/20080509124439/http://www.hopkinsmedicine.org/press/2002/November/epigenetics.htm Epigenetics article] at Hopkins Medicine * [https://web.archive.org/web/20110721032750/http://genome.wellcome.ac.uk/doc_WTX036556.html Towards a global map of epigenetic variation ] {{Genetics}} {{MolBioGeneExp}} {{genarch}} {{Molecular Biology}} {{Branches of biology}} {{Authority control}} [[Category:Epigenetics| ]] [[Category:Genetic mapping]] [[Category:Lamarckism]]'