Figure 3. Locus-specific active DNa demethylation in somatic cells.

a | Active demethylation at the brain-derived neurotrophic factor (BDNF) promoter. In neurons, BDNF is maintained in a repressed state through DNA methylation and binding of the repressive methylcytosine (meC)-binding protein MeCP2. On depolarization with KCl, DNA methylation and MeCP2 binding are lost, concomitant with increased BDNF expression. This demethylation event is considered to be active because it occurs in post-mitotic neurons. b | Active demethylation at nuclear receptor target promoters. The promoter of the oestrogen receptor (ER) target gene pS2 (also known as TFF1) undergoes cyclical rounds of methylation and demethylation that correspond to the repression and expression of the gene, respectively. Transcriptional activation of pS2 occurs in the presence of oestrogens (E2) and coincides with demethylation of the promoter. This is achieved by deamination of 5meC by DNA methyltransferase 3 (DNMT3) followed by base excision repair (BER) of the T•G mismatch by T DNA glycosylase (TDG). To revert to repression, DNMT3 re-methylates the promoter. Although DNMT3 is involved in both methylation and demethylation, it is important to note that DNMT3 can only carry out the deamination step in the absence or at low concentrations of the methyl donor S-adenosylmethionine (SAM).