Editing Epigenetics (section)

==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 | 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 | 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 | 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 = 623–637 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}</ref><ref name="Cheron2021">{{cite journal | vauthors = Cheron J, Kerchove d'Exaerde A | title = Drug addiction: from bench to bedside | journal = Translational Psychiatry | volume = 11 | issue = 1 | pages = 424 | date = August 2021 | pmid = 34385417 | pmc = 8361217 | doi = 10.1038/s41398-021-01542-0 }}</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 = 491–496 | 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 | 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-access = free | s2cid = 25694221 | hdl = 10400.22/7331 }}</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" />