Editing Epigenetics (section)

==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 | 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 | vauthors = Khan FA }}</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 | pmc = 11147257 }}</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> 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>

===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 name="pmid32300195">{{cite journal | vauthors = Barbieri I, Kouzarides T | title = Role of RNA modifications in cancer | journal = Nature Reviews. Cancer | volume = 20 | issue = 6 | pages = 303–322 | date = June 2020 | pmid = 32300195 | doi = 10.1038/s41568-020-0253-2}}</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, once activated, transcribes a product that directly or indirectly sustains its own activity. 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 | 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 | 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 | 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 | 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 | vauthors = Bresnahan ST, Lee E, Clark L, Ma R, Rangel J, Grozinger CM, Li-Byarlay H | title = Examining parent-of-origin effects on transcription and RNA methylation in mediating aggressive behavior in honey bees (Apis mellifera) | journal = BMC Genomics | volume = 24 | issue = 1 | pages = 315 | date = June 2023 | pmid = 37308882 | pmc = 10258952 | doi = 10.1186/s12864-023-09411-4 | doi-access = free }}</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 | 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>