DNA demethylation

DNA demethylation is the process of removal of a methyl group from nucleotides in DNA. DNA demethylation could be passive or active. The passive process takes place in the absence of methylation of newly synthesised DNA strands by DNMT1 during several replication rounds (for example, upon 5-Azacytidine treatment). Active DNA demethylation occurs via direct removal of a methyl group independently of DNA replication.

All the cases of DNA demethylation can be divided as global (genome wide) or locus-specific (when just specific sequences are demethylated). The genome-wide DNA demethylation occurs:

Examples of specific DNA demethylation:

There are several proposed hypothetical mechanisms of active DNA demethylation:

A Direct removal of 5-methylcytosine

B Removal of 5-methylcytosine via further modified cytosine bases

Oxidation of the methyl group generates 5-Hydroxymethylcytosine. Several mechanisms have been proposed to mediate demethylation of 5-hydroxymethylcytosines. This base can be either deaminated by AID/Apobec enzymes to give 5-Hydroxymethyluracil. Alternatively, TET enzymes can further oxidize 5-hydroxymethylcytosine to 5-Formylcytosine and 5-Carboxylcytosine.

DNA hydroxymethylation has been proposed to act as a specific epigenetic mark opposing DNA methylation, rather than a passive intermediate in the de-methylation pathway. DNA hydroxymethylation in vivo is sometimes associated with labile nucleosomes, which are more easy to disassemble and to out-compete by transcription factors during cell development Hydroxymethylation has been associated with pluripotency of stem cells. Further, Changes in hydroxymethylation have been associated with cancer.

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