DNA methylation

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Homo sapiens
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Methylation of cytosine is catalyzed by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B transfer methyl groups from S-adenosylmethionine to cytosine, producing 5-methylcytosine and homocysteine (reviewed in Klose and Bird 2006, Ooi et al. 2009, Jurkowska et al. 2011, Moore et al. 2013). (DNMT2 appears to methylate RNA rather than DNA.) DNMT1, the first enzyme discovered, preferentially methylates hemimethylated CG motifs that are produced by replication (template strand methylated, synthesized strand unmethylated). Thus it maintains existing methylation through cell division. DNMT3A and DNMT3B catalyze de novo methylation at unmethylated sites that include both CG dinucleotides and non-CG motifs.
DNA from adult humans contains about 0.76 to 1.00 mole percent 5-methylcytosine (Ehrlich et al. 1982, reviewed in Klose and Bird 2006, Ooi et al. 2009, Moore et al. 2013). Methylation of DNA occurs at cytosines that are mainly located in CG dinucleotides. CG dinucleotides are unevenly distributed in the genome. Promoter regions tend to have a high CG-content, forming so-called CG-islands (CGIs), while the CG-content in the remaining part of the genome is much lower. CGIs tend to be unmethylated, while the majority of CGs outside CGIs are methylated. Methylation in promoters and first exons tends to repress transcription while methylation in gene bodies (regions of genes downstream of the promoter and first exon) correlates with transcription (reviewed in Ehrlich and Lacey 2013, Kulis et al. 2013). Proteins such as MeCP2 and MBDs specifically bind 5-methylcytosine and may recruit other factors.
Mammalian development has two major episodes of genome-wide demethylation and remethylation (reviewed in Zhou 2012, Guibert and Weber 2013, Hackett and Surani 2013, Dean 2014). In mice about 1 day after fertilization the paternal genome is actively demethylated by TET proteins together with thymine DNA glycosylase and the maternal genome is demethylated by passive dilution during replication, however methylation at imprinted sites is maintained. The genome has its lowest methylation level about 3.5 days post-fertilization. Remethylation occurs by 6.5 days post-fertilization. The second demethylation-remethylation event occurs in primordial germ cells of the developing embryo about 12.5 days post-fertilization. DNMT3A and DNMT3B, together with the non-catalytic DNMT3L, play major roles in the remethylation events (reviewed in Chen and Chan 2014). How the methyltransferases are directed to particular regions of the genome remains an area of active research. The mechanisms at each locus may differ in detail but a connection between histone modifications and DNA methylation has been observed (reviewed in Rose and Klose 2014).
Literature References
PubMed ID Title Journal Year
22781841 DNA methylation and its basic function

Le, T, Moore, LD, Fan, G

Neuropsychopharmacology 2013
7079182 Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells

McCune, RA, Gehrke, C, Midgett, RM, Kuo, KC, Gama-Sosa, MA, Huang, LH, Ehrlich, M

Nucleic Acids Res. 1982
24214338 DNA methylation and demethylation: A pathway to gametogenesis and development

Dean, W

Mol. Reprod. Dev. 2014
23687512 DNA methylation program during development

Zhou, FC

Front Biol (Beijing) 2012
24589714 The de novo DNA methyltransferase DNMT3A in development and cancer

Chen, BF, Chan, WY

Epigenetics 2014
16403636 Genomic DNA methylation: the mark and its mediators

Bird, AP, Klose, RJ

Trends Biochem. Sci. 2006
24560929 Understanding the relationship between DNA and histone lysine methylation

Klose, RJ, Rose, NR

Biochim. Biophys. Acta 2014
23938249 Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer

Queirós, AC, Martín-Subero, JI, Kulis, M, Beekman, R

Biochim. Biophys. Acta 2013
21243710 Structure and function of mammalian DNA methyltransferases

Jurkowski, TP, Jurkowska, RZ, Jeltsch, A

Chembiochem 2011
23587238 Functions of DNA methylation and hydroxymethylation in mammalian development

Weber, M, Guibert, S

Curr. Top. Dev. Biol. 2013
19657014 Mammalian cytosine methylation at a glance

Ooi, SK, Bestor, TH, O'Donnell, AH

J. Cell. Sci. 2009
23166392 DNA methylation dynamics during the mammalian life cycle

Surani, MA, Hackett, JA

Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2013
24059801 DNA methylation and differentiation: silencing, upregulation and modulation of gene expression

Lacey, M, Ehrlich, M

Epigenomics 2013
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