DNA methylation is one of the most prevalent epigenetic modifications of DNA in mammalian genomes. It is achieved by DNA methyltransferases that catalyze the addition of a methyl group from S-adenosyl-L-methionine to the 5-carbon position of cytosine. Methylation at cytosine plays an important role in regulating transcription and chromatin structure. Three families of DNA methyltransferase genes have been identified in mammals. They include Dnmt1, Dnmt2 and Dnmt3. Dnmt1 is constitutively expressed in proliferating cells and its inactivation results in demethylation of genomic DNA and embryonic death. Dnmt2 is expressed at low levels in adult tissues. Its inactivation does not affect DNA methylation or maintenance of methylation. The Dnmt3 (Dnmt3a and Dnmt3b) is strongly expressed in embryonic stem cells, but is down-regulated in differentiating embryonic stem cells and in adult somatic cells. Most mammalian transcription factors bind GC-rich DNA elements. Methylation of these elements abolishes binding. CpG methylation is shown to induce histone deacetylation, chromatin remodeling, and gene silencing through a transcription repressor complex. CpG islands are often located around the promoters of housekeeping genes and are not methylated. In contrast, the CG sequences in inactive genes are usually methylated to suppress their expression. Aberrant DNA methylation has been linked to several pathological conditions. Mutations in DNA methyltransferase 3b are known to cause ICF (immunodeficiency, centromere instability and facial anomalies) syndrome. Over expression of DNA methyltransferases has been implicated in the development of several types of tumors. About 25% of all mutations in the p53 gene in human cancers are reported to occur at CpG sites. Methylation of these sites can inactivate and silence tumor suppressor genes. Abnormal DNA methylation also occurs during aging and alters the activity of affected genes, thus affecting a variety of cellular functions.
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