Editing Epigenetics (section)

==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|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=|pmc=11146814 }}</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.svg|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 | 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===
{{See also|Epigenetics of human 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 | 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 | vauthors = 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 | 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 | 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 | 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 | 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 | 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 | 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 }}
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