Editing DNA methylation (section)

=== Repression of CpG-dense promoters ===

DNA methylation was probably present at some extent in early eukaryote ancestors. In virtually every organism analyzed, methylation in promoter regions correlates negatively with gene expression.<ref name=":1" /><ref name=":2">{{cite journal | vauthors = Feng S, Cokus SJ, Zhang X, Chen PY, Bostick M, Goll MG, Hetzel J, Jain J, Strauss SH, Halpern ME, Ukomadu C, Sadler KC, Pradhan S, Pellegrini M, Jacobsen SE | display-authors = 6 | title = Conservation and divergence of methylation patterning in plants and animals | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 19 | pages = 8689–8694 | date = May 2010 | pmid = 20395551 | pmc = 2889301 | doi = 10.1073/pnas.1002720107 | doi-access = free }}</ref> CpG-dense promoters of actively transcribed genes are never methylated, but, reciprocally, transcriptionally silent genes do not necessarily carry a methylated promoter. In mouse and human, around 60–70% of genes have a CpG island in their promoter region and most of these CpG islands remain unmethylated independently of the transcriptional activity of the gene, in both differentiated and undifferentiated cell types.<ref>{{cite journal | vauthors = Mohn F, Weber M, Rebhan M, Roloff TC, Richter J, Stadler MB, Bibel M, Schübeler D | display-authors = 6 | title = Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors | journal = Molecular Cell | volume = 30 | issue = 6 | pages = 755–766 | date = June 2008 | pmid = 18514006 | doi = 10.1016/j.molcel.2008.05.007 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Weber M, Hellmann I, Stadler MB, Ramos L, Pääbo S, Rebhan M, Schübeler D | title = Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome | journal = Nature Genetics | volume = 39 | issue = 4 | pages = 457–466 | date = April 2007 | pmid = 17334365 | doi = 10.1038/ng1990 | s2cid = 22446734 }}</ref> Of note, whereas DNA methylation of CpG islands is unambiguously linked with transcriptional repression, the function of DNA methylation in CG-poor promoters remains unclear; albeit there is little evidence that it could be functionally relevant.<ref>{{cite journal | vauthors = Schübeler D | title = Function and information content of DNA methylation | journal = Nature | volume = 517 | issue = 7534 | pages = 321–326 | date = January 2015 | pmid = 25592537 | doi = 10.1038/nature14192 | s2cid = 4403755 | bibcode = 2015Natur.517..321S }}</ref>

DNA methylation may affect the transcription of genes in two ways. First, the methylation of DNA itself may physically impede the binding of [[transcription factor|transcriptional proteins]] to the gene,<ref name="pmid20875111">{{cite journal | vauthors = Choy MK, Movassagh M, Goh HG, Bennett MR, Down TA, Foo RS | title = Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated | journal = BMC Genomics | volume = 11 | issue = 1 | pages = 519 | date = September 2010 | pmid = 20875111 | pmc = 2997012 | doi = 10.1186/1471-2164-11-519 | doi-access = free }}</ref> and second, and likely more important, methylated DNA may be bound by proteins known as [[methyl-CpG-binding domain]] proteins (MBDs). [[Methyl-CpG-binding domain protein 2|MBD]] proteins then recruit additional proteins to the locus, such as [[histone deacetylase]]s and other [[chromatin remodeling]] proteins that can modify [[histone]]s, thereby forming compact, inactive chromatin, termed [[heterochromatin]]. This link between DNA methylation and chromatin structure is important. In particular, loss of [[Methyl CpG binding protein 2|methyl-CpG-binding protein 2]] (MeCP2) has been implicated in [[Rett syndrome]]; and [[Methyl-CpG-binding domain protein 2|methyl-CpG-binding domain protein 2 (MBD2)]] mediates the transcriptional silencing of hypermethylated genes in "cancer."{{cn|date=March 2024}}