Cytosine methylation (WP3585)

DNA, namely cytosine, methylation is the key event in epigentics. The degree of methylation influences gene expression and methylation disorders are known to be major causes of some diseases like Rett syndrome and some cancer types. Epigenetic effects also contribute to the development of Alzheimers' disease, developmental retardation by alcohol, Huntington's disease and ischemia-reperfusion injury. Methylation is not a static event but a highly dynamic and therefore highly regulated procedure. Cytosine is methylated by DNA methyltransferases (DNMTs) forming 5-methylcytosine (5mC). In a second step, 5mC is transformed to 5-hydroxymethylcytosine (5hmC) by ten-eleven-translocation enzymes (TET1-3). These enzymes are sensitive to regulation by a variety of metabolites (ethanol, a-ketoglutarate, 2-hydroxyglutarate), miRNA and MeCP2 (targeting directly TET1). Proteins binding methylated DNA like MeCP2 or Mbd3 (as part of the NURD complex) also inhibit the conversion by blocking the target. MeCP2 also binds on 5hmC and block the transition to 5-formylcytosine (5fC) which is also catalyzed by the TET enzymes. The conversion back to cytosine is done by tymine DNA glycosylase (TGD) and base excision repair mechanism either directly or over another TET catalyzed step forming 5-carboxylcytosine (5caC).

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