Editing DNA methylation (section)

{{Short description|Biological process}}
[[File:DNA methylation.svg|class=skin-invert-image|thumb|302x302px]]
[[File:DNA methylation.jpg|thumb|300px|Representation of a [[DNA]] molecule that is methylated. The two white spheres represent [[methyl group]]s. They are bound to two [[cytosine]] [[nucleotide]] molecules that make up the DNA sequence.]]

'''DNA methylation''' is a biological process by which [[methyl group]]s are added to the [[DNA]] molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene [[promoter (genetics)|promoter]], DNA methylation typically acts to repress gene [[Transcription (genetics)|transcription]]. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including [[genomic imprinting]], [[X-chromosome inactivation]], repression of [[transposable element]]s, [[aging]], and [[carcinogenesis]].

As of 2016, two nucleobases have been found on which natural, enzymatic DNA methylation takes place: [[adenine]] and [[cytosine]]. The modified bases are N<sup>6</sup>-methyladenine,<ref name="Dunn_Smith_1958">D. B. Dunn, J. D. Smith: "The occurrence of 6-methylaminopurine in deoxyribonucleic acids". In: ''Biochem J.'' 68(4), Apr 1958, S. 627–636. [//www.ncbi.nlm.nih.gov/pubmed/13522672?dopt=Abstract PMID 13522672]. {{PMC|1200409}}.</ref><!--"Urlink" auf N6-Methyladenin--> [[5-methylcytosine]]<ref name="Vanyushin_etal1970">B. F. Vanyushin, S. G. Tkacheva, A. N. Belozersky: "Rare bases in animal DNA". In: ''Nature''. 225, 1970, S. 948–949. {{PMID|4391887}}.</ref><!-- "Urlink" auf N6-Methylcytosin --> and N<sup>4</sup>-methylcytosine.<ref name="Ehrlich_etal1985">Melanie Ehrlich, Miguel A. Gama-Sosa, Laura H. Carreira, Lars G. Ljungdahl, Kenneth C. Kuo, Charles W. Gehrke: "DNA methylation in thermophilic bacteria: N6-methylcytosine, 5-methylcytosine, and N6-methyladenine." In: ''Nucleic Acids Research''. 13, 1985, S.&nbsp;1399. [//www.ncbi.nlm.nih.gov/pubmed/4000939?dopt=Abstract PMID 4000939]. {{PMC|341080}}.</ref>

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| Unmodified base
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|[[File:Adenin.svg|class=skin-invert-image|100px]]
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|[[File:Cytosin.svg|class=skin-invert-image|80px]]
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| Adenine,&nbsp;'''[[Adenine|A]]'''
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| style="text-align:center" | Cytosine,&nbsp;'''[[Cytosine|C]]'''
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| Modified forms
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|[[File:6-methyladenine.svg|class=skin-invert-image|105px]]
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|[[File:5-Methylcytosine.svg|class=skin-invert-image|125px]]
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|[[File:N4-Methylcytosine.svg|class=skin-invert-image|110px]]
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| ''N''<sup>6</sup>-Methyladenine,&nbsp;'''[[:de:N6-Methyladenin|6mA]]'''
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| 5-Methylcytosine,&nbsp;'''[[5-Methylcytosine|5mC]]'''
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| ''N''<sup>4</sup>-Methylcytosine,&nbsp;'''[[:de:N4-Methylcytosin|4mC]]'''
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'''Cytosine methylation''' is widespread in both [[eukaryotes]] and [[prokaryotes]], even though the rate of cytosine DNA methylation can differ greatly between species: 14% of cytosines are methylated in ''[[Arabidopsis thaliana]]'', 4% to 8% in ''[[Physarum]]'',<ref name="ReferenceA">{{cite journal | vauthors = Evans HH, Evans TE | title = Methylation of the deoxyribonucleic acid of Physarum polycephalum at various periods during the mitotic cycle | journal = The Journal of Biological Chemistry | volume = 245 | issue = 23 | pages = 6436–6441 | date = December 1970 | pmid = 5530731 | doi = 10.1016/S0021-9258(18)62627-4 | doi-access = free }}{{open access}}</ref> 7.6% in ''[[Mus musculus]]'', 2.3% in ''[[Escherichia coli]]'', 0.03% in ''[[Drosophila]]''; methylation is essentially undetectable in ''[[Dictyostelium]]'';<ref name ="ReferenceZ">{{cite journal | vauthors = Smith SS, Rather DI | title = Lack of 5-methylcytosine in Dictyostelium discoideum DNA | journal = The Biochemical Journal | volume = 277 | issue = 1 | pages = 273–275 | date = July 1991 | pmid = 1713034 | doi = 10.1042/bj2770273 | pmc = 1151219 }}</ref><ref name="ReferenceB">{{cite journal | vauthors = Drewell RA, Cormier TC, Steenwyk JL, St Denis J, Tabima JF, Dresch JM, Larochelle DA | title = The ''Dictyostelium discoideum'' genome lacks significant DNA methylation and uncovers palindromic sequences as a source of false positives in bisulfite sequencing  | journal = NAR Genomics Bioinformatics | volume = 5 | issue = 2 | pages = lqad035| date = April 2023 | pmid =  37081864 | doi =  10.1093/nargab/lqad035 | pmc = 10111430 }}</ref> and virtually absent (0.0002 to 0.0003%) from ''[[Caenorhabditis]]''<ref>{{cite journal | vauthors = Hu CW, Chen JL, Hsu YW, Yen CC, Chao MR | title = Trace analysis of methylated and hydroxymethylated cytosines in DNA by isotope-dilution LC-MS/MS: first evidence of DNA methylation in Caenorhabditis elegans | journal = The Biochemical Journal | volume = 465 | issue = 1 | pages = 39–47 | date = January 2015 | pmid = 25299492 | doi = 10.1042/bj20140844 }}</ref> or fungi such as ''[[Saccharomyces cerevisiae]]'' and ''[[S. pombe]]'' (but not ''[[N. crassa]]'').<ref>{{cite journal | vauthors = Bird A | title = Molecular biology. Methylation talk between histones and DNA | journal = Science | volume = 294 | issue = 5549 | pages = 2113–2115 | date = December 2001 | pmid = 11739943 | doi = 10.1126/science.1066726 | hdl-access = free | quote = As a result of this process, known as repeat-induced point mutation (RIP), the wild-type ''Neurospora'' genome contains a small fraction of methylated DNA, the majority of the DNA remaining nonmethylated. | s2cid = 82947750 | department = Science's Compass | hdl = 1842/464 }}{{open access}}</ref><ref name=pmid24640988>{{cite journal | vauthors = Capuano F, Mülleder M, Kok R, Blom HJ, Ralser M | title = Cytosine DNA methylation is found in Drosophila melanogaster but absent in Saccharomyces cerevisiae, Schizosaccharomyces pombe, and other yeast species | journal = Analytical Chemistry | volume = 86 | issue = 8 | pages = 3697–3702 | date = April 2014 | pmid = 24640988 | pmc = 4006885 | doi = 10.1021/ac500447w }}</ref>{{Rp|3699}} [[Adenine methylation]] has been observed in bacterial and plant DNA, and recently also in mammalian DNA,<ref>{{cite journal | vauthors = Ratel D, Ravanat JL, Berger F, Wion D | title = N6-methyladenine: the other methylated base of DNA | journal = BioEssays | volume = 28 | issue = 3 | pages = 309–315 | date = March 2006 | pmid = 16479578 | pmc = 2754416 | doi = 10.1002/bies.20342 }}</ref><ref>{{cite journal | vauthors = Wu TP, Wang T, Seetin MG, Lai Y, Zhu S, Lin K, Liu Y, Byrum SD, Mackintosh SG, Zhong M, Tackett A, Wang G, Hon LS, Fang G, Swenberg JA, Xiao AZ | display-authors = 6 | title = DNA methylation on N(6)-adenine in mammalian embryonic stem cells | journal = Nature | volume = 532 | issue = 7599 | pages = 329–333 | date = April 2016 | pmid = 27027282 | pmc = 4977844 | doi = 10.1038/nature17640 | bibcode = 2016Natur.532..329W }}</ref> but has received considerably less attention.

Methylation of cytosine to form [[5-methylcytosine]] occurs at the same 5 position on the [[pyrimidine]] ring where the DNA base [[thymine]]'s methyl group is located; the same position distinguishes thymine from the analogous RNA base [[uracil]], which has no methyl group. Spontaneous [[deamination]] of [[5-methylcytosine]] converts it to thymine. This results in a T:G mismatch. Repair mechanisms then correct it back to the original C:G pair; alternatively, they may substitute A for G, turning the original C:G pair into a T:A pair, effectively changing a base and introducing a mutation. This misincorporated base will not be corrected during DNA replication as thymine is a DNA base. If the mismatch is not repaired and the cell enters the cell cycle the strand carrying the T will be complemented by an A in one of the daughter cells, such that the mutation becomes permanent. The near-universal use of [[thymine]] exclusively in DNA and [[uracil]] exclusively in RNA may have evolved as an error-control mechanism, to facilitate the removal of uracils generated by the spontaneous deamination of cytosine.<ref>Angéla Békési and Beáta G Vértessy [http://www.scienceinschool.org/2011/issue18/uracil  "Uracil in DNA: error or signal?"]</ref>  DNA methylation as well as a number of its contemporary DNA methyltransferases have been thought to evolve from early world primitive RNA methylation activity and is supported by several lines of evidence.<ref>{{cite journal | vauthors = Rana AK, Ankri S | title = Reviving the RNA World: An Insight into the Appearance of RNA Methyltransferases | journal = Frontiers in Genetics | volume = 7 | pages = 99 | date = 2016 | pmid = 27375676 | pmc = 4893491 | doi = 10.3389/fgene.2016.00099 | doi-access = free }}</ref>

In plants and other organisms, DNA methylation is found in three different sequence contexts: CG (or [[CpG site|CpG]]), CHG or CHH (where H correspond to A, T or C). In mammals however, DNA methylation is almost exclusively found in CpG dinucleotides, with the cytosines on both strands being usually methylated. Non-CpG methylation can however be observed in embryonic [[stem cell]]s,<ref>{{cite journal | vauthors = Dodge JE, Ramsahoye BH, Wo ZG, Okano M, Li E | title = De novo methylation of MMLV provirus in embryonic stem cells: CpG versus non-CpG methylation | journal = Gene | volume = 289 | issue = 1–2 | pages = 41–48 | date = May 2002 | pmid = 12036582 | doi = 10.1016/S0378-1119(02)00469-9 }}</ref><ref>{{cite journal | vauthors = Haines TR, Rodenhiser DI, Ainsworth PJ | title = Allele-specific non-CpG methylation of the Nf1 gene during early mouse development | journal = Developmental Biology | volume = 240 | issue = 2 | pages = 585–598 | date = December 2001 | pmid = 11784085 | doi = 10.1006/dbio.2001.0504 | doi-access = free }}</ref><ref name="ReferenceC">{{cite journal | vauthors = Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR | display-authors = 6 | title = Human DNA methylomes at base resolution show widespread epigenomic differences | journal = Nature | volume = 462 | issue = 7271 | pages = 315–322 | date = November 2009 | pmid = 19829295 | pmc = 2857523 | doi = 10.1038/nature08514 | bibcode = 2009Natur.462..315L }}</ref> and has also been indicated in [[neural development]].<ref>{{cite journal | vauthors = Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD, Yu M, Tonti-Filippini J, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM, Ecker JR | display-authors = 6 | title = Global epigenomic reconfiguration during mammalian brain development | journal = Science | volume = 341 | issue = 6146 | pages = 1237905 | date = August 2013 | pmid = 23828890 | pmc = 3785061 | doi = 10.1126/science.1237905 }}</ref> Furthermore, non-CpG methylation has also been observed in [[hematopoiesis|hematopoietic]] progenitor cells, and it occurred mainly in a CpApC sequence context.<ref name=":0">{{cite journal | vauthors = Kulis M, Merkel A, Heath S, Queirós AC, Schuyler RP, Castellano G, Beekman R, Raineri E, Esteve A, Clot G, Verdaguer-Dot N, Duran-Ferrer M, Russiñol N, Vilarrasa-Blasi R, Ecker S, Pancaldi V, Rico D, Agueda L, Blanc J, Richardson D, Clarke L, Datta A, Pascual M, Agirre X, Prosper F, Alignani D, Paiva B, Caron G, Fest T, Muench MO, Fomin ME, Lee ST, Wiemels JL, Valencia A, Gut M, Flicek P, Stunnenberg HG, Siebert R, Küppers R, Gut IG, Campo E, Martín-Subero JI | display-authors = 6 | title = Whole-genome fingerprint of the DNA methylome during human B cell differentiation | journal = Nature Genetics | volume = 47 | issue = 7 | pages = 746–756 | date = July 2015 | pmid = 26053498 | pmc = 5444519 | doi = 10.1038/ng.3291 }}</ref>