DNA Methylation

DNA methylation involves the modification of cytosine bases by methylation of the carbon at the fifth position in the pyrimidine ring (Fig. 3-9). Extensive DNA methylation is a mark of repressed genes and is a widespread mechanism associated with the establishment of specific programs of gene expression during cell differentiation and development. Typically, DNA methylation occurs on the C of CpG dinucleotides (see Fig. 3-8) and inhibits gene expression by recruitment of specific methyl-CpG–binding proteins that, in turn, recruit chromatin-modifying enzymes to silence transcription. The presence of 5-methylcytosine (5-mC) is considered to be a stable epigenetic mark that can be faithfully transmitted through cell division; however, altered methylation states are frequently observed in cancer, with hypomethylation of large genomic segments or with regional hypermethylation (particularly at CpG islands) in others (see Chapter 15).

Extensive demethylation occurs during germ cell development and in the early stages of embryonic development, consistent with the need to “re-set” the chromatin environment and restore totipotency or pluripotency of the zygote and of various stem cell populations. Although the details are still incompletely understood, these reprogramming steps appear to involve the enzymatic conversion of 5-mC to 5-hydroxymethylcytosine (5-hmC; see Fig. 3-9), as a likely intermediate in the demethylation of DNA. Overall, 5-mC levels are stable across adult tissues (approximately 5% of all cytosines), whereas 5-hmC levels are much lower and much more variable (0.1% to 1% of all cytosines). Interestingly, although 5-hmC is widespread in the genome, its highest levels are found in known regulatory regions, suggesting a possible role in the regulation of specific promoters and enhancers.