Editing 5-Methylcytosine (section)

== Role in humans ==
=== In cancer ===
In cancer, DNA can become both overly methylated, termed [[hypermethylation]], and under-methylated, termed hypomethylation.<ref name=":22">{{cite journal|last=Ehrlich|first=Melanie|date=2009-12-01|title=DNA hypomethylation in cancer cells|journal=Epigenomics|volume=1|issue=2|pages=239–259|doi=10.2217/epi.09.33|issn=1750-1911|pmc=2873040|pmid=20495664}}</ref> CpG islands overlapping gene promoters are ''de novo'' methylated resulting in aberrant inactivation of genes normally associated with growth inhibition of tumors (an example of hypermethylation).<ref>{{cite journal|last=Jones|first=Peter A.|date=1996-06-01|title=DNA Methylation Errors and Cancer|url=https://cancerres.aacrjournals.org/content/56/11/2463|journal=Cancer Research|language=en|volume=56|issue=11|pages=2463–2467|issn=0008-5472|pmid=8653676}}</ref> Comparing tumor and normal tissue, the former had elevated levels of the methyltransferases DNMT1, DNMT3A, and mostly DNMT3B, all of which are associated with the abnormal levels of 5mC in cancer.<ref name=":1" /> Repeat sequences in the genome, including satellite DNA, Alu, and long interspersed elements (LINE), are often seen hypomethylated in cancer, resulting in expression of these normally silenced genes, and levels are often significant markers of tumor progression.<ref name=":22" /> It has been hypothesized that there a connection between the hypermethylation and hypomethylation; over activity of DNA methyltransferases that produce the abnormal ''de novo'' 5mC methylation may be compensated by the removal of methylation, a type of epigenetic repair. However, the removal of methylation is inefficient resulting in an overshoot of genome-wide hypomethylation. The contrary may also be possible; over expression of hypomethylation may be silenced by genome-wide hypermethylation.<ref name=":22" />  Cancer hallmark capabilities are likely acquired through epigenetic changes that alter the 5mC in both the cancer cells and in surrounding tumor-associated stroma within the tumor microenvironment.<ref>{{cite journal|last1=Hanahan|first1=Douglas|last2=Weinberg|first2=Robert A.|date=2011-03-04|title=Hallmarks of Cancer: The Next Generation|journal=Cell|language=en|volume=144|issue=5|pages=646–674|doi=10.1016/j.cell.2011.02.013|issn=0092-8674|pmid=21376230|doi-access=free|url=https://infoscience.epfl.ch/record/171696/files/1-s2.0-S0092867411001279-main.pdf}}</ref> The anticancer drug [[Cisplatin]] has been reported to react with 5mC.<ref>{{cite journal|last1=Menke|first1=Annika|last2=Dubini|first2=Romeo C.A.|last3=Mayer|first3=Peter|last4=Rovó|first4=Petra|last5=Daumann|first5=Lena|date=2020-10-23|title=Formation of Cisplatin Adducts with the Epigenetically-relevant Nucleobase 5-Methylcytosine|journal=European Journal of Inorganic Chemistry|volume=2021|pages=30–36|doi=10.1002/ejic.202000898|issn=1434-1948|doi-access=free}}</ref>

=== As a biomarker of aging ===
"Epigenetic age" refers to the connection between chronological age and levels of DNA methylation in the genome.<ref>{{cite journal|last1=Horvath|first1=Steve|last2=Raj|first2=Kenneth|date=June 2018|title=DNA methylation-based biomarkers and the epigenetic clock theory of ageing|journal=Nature Reviews Genetics|language=en|volume=19|issue=6|pages=371–384|doi=10.1038/s41576-018-0004-3|pmid=29643443|s2cid=4709691|issn=1471-0064}}</ref> Coupling the levels of DNA methylation, in specific sets of CpGs called "clock CpGs", with algorithms that regress the typical levels of collective genome-wide methylation at a given chronological age, allow for epigenetic age prediction. During youth (0–20 years old), changes in DNA methylation occur at a faster rate as development and growth progresses, and the changes begin to slow down at older ages. Multiple epigenetic age estimators exist. Horvath's clock measures a multi-tissue set of 353 CpGs, half of which positively correlate with age, and the other half negatively, to estimate the epigenetic age.<ref>{{cite journal|last=Horvath|first=Steve|date=2013-12-10|title=DNA methylation age of human tissues and cell types|journal=Genome Biology|volume=14|issue=10|pages=3156|doi=10.1186/gb-2013-14-10-r115|issn=1474-760X|pmc=4015143|pmid=24138928 |doi-access=free }}{{Erratum|doi=10.1186/s13059-015-0649-6|pmid=25968125|http://retractionwatch.com/2015/06/15/high-profile-aging-paper-posts-old-erratum-requested-by-author-more-than-one-year-prior/ ''Retraction Watch''|checked=yes}}</ref> Hannum's clock utilizes adult blood samples to calculate age based on an orthogonal basis of 71 CpGs.<ref>{{cite journal|last1=Hannum|first1=Gregory|last2=Guinney|first2=Justin|last3=Zhao|first3=Ling|last4=Zhang|first4=Li|last5=Hughes|first5=Guy|last6=Sadda|first6=SriniVas|last7=Klotzle|first7=Brandy|last8=Bibikova|first8=Marina|last9=Fan|first9=Jian-Bing|last10=Gao|first10=Yuan|last11=Deconde|first11=Rob|date=2013-01-24|title=Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates|journal=Molecular Cell|volume=49|issue=2|pages=359–367|doi=10.1016/j.molcel.2012.10.016|issn=1097-2765|pmc=3780611|pmid=23177740}}</ref> Levine's clock, known as DNAm PhenoAge, depends on 513 CpGs and surpasses the other age estimators in predicting mortality and lifespan, yet displays bias with non-blood tissues.<ref>{{cite journal|last1=Levine|first1=Morgan E.|last2=Lu|first2=Ake T.|last3=Quach|first3=Austin|last4=Chen|first4=Brian H.|last5=Assimes|first5=Themistocles L.|last6=Bandinelli|first6=Stefania|last7=Hou|first7=Lifang|last8=Baccarelli|first8=Andrea A.|last9=Stewart|first9=James D.|last10=Li|first10=Yun|last11=Whitsel|first11=Eric A.|date=2018-04-17|title=An epigenetic biomarker of aging for lifespan and healthspan|journal=Aging (Albany NY)|volume=10|issue=4|pages=573–591|doi=10.18632/aging.101414|issn=1945-4589|pmc=5940111|pmid=29676998}}</ref> There are reports of age estimators with the methylation state of only one CpG in the gene ELOVL2.<ref>{{cite journal|last1=Garagnani|first1=Paolo|last2=Bacalini|first2=Maria G.|last3=Pirazzini|first3=Chiara|last4=Gori|first4=Davide|last5=Giuliani|first5=Cristina|last6=Mari|first6=Daniela|last7=Blasio|first7=Anna M. Di|last8=Gentilini|first8=Davide|last9=Vitale|first9=Giovanni|last10=Collino|first10=Sebastiano|last11=Rezzi|first11=Serge|date=2012|title=Methylation of ELOVL2 gene as a new epigenetic marker of age|journal=Aging Cell|language=en|volume=11|issue=6|pages=1132–1134|doi=10.1111/acel.12005|pmid=23061750|issn=1474-9726|hdl=11585/128353|s2cid=8775590|hdl-access=free}}</ref> Estimation of age allows for prediction lifespan through expectations of age related conditions that individuals may be subject to based on their 5mC methylation markers.{{cn|date=March 2024}}