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DNA demethylation

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DNA demethylation is a process of removal of methyl group from nucleotide in DNA. DNA demethylation could be passive and active. 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 active dismiss of methyl group.

Examples of active DNA demethylation

All the cases of DNA demethylation could be divided on global (genome wide) and specific (when just specific sequences are demethylated). The genome wide DNA demethylation occurs:

  1. In mammals:
    1. In male pronucleus of zygote immediately after fertilization;
    2. Possibly in the primordial germ cells (PGCs) of 11.5-12.5 day old embryos;
  2. Possibly in amphibia - during midblastula transition

Examples of specific DNA demethylation:

  1. Gene imprinting during plant reproduction;
  2. Electroconvulsive stimulation-induced demethylation of neurotrophic factor genes in dentate gyrus neurons in the mouse brain [1][2]

Possible mechanisms of active DNA demethylation

There are several proposed hypothetical mechanisms of active DNA demethylation:

  1. Direct removal of methyl group. This process has quite low thermodynamic probability.
  2. Removal of methylated base (either by direct removal of methylcytosine, or through cytosine deamination followed by removal of thymine from thymine/guanosine mismatch), followed by insertion of unmethylated one using base excision repair machinery (BER).
  3. Removal of entire DNA patch and following filling it with new nucleotides by nucleotide excision repair (NER).
  4. Oxidation of the methyl group generates 5-Hydroxymethylcytosine. Presence of 5-hydroxymethylcytosine demethylase activity has been shown.[2] Several mechanisms have been proposed to mediate demethylation of 5-hydroxymethylcytosines.[3] For instance, 5-Hydroxymethylcytosine could be further oxidized to 5-Formylcytosine and 5-Carboxylcytosine which could then be decarboxylated to Cytosine. 5-Formylcytosine has been identified in DNA from embryonic stem cells.[4]

Reference

  1. ^ Ma, DK (2009-02-20). "Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis". Science. 323 (5917): 1074–7. doi:10.1126/science.1166859. PMC 2726986. PMID 19119186. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ a b Guo, JU (2011-04-29). "Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain". Cell. 145 (3): 423–34. doi:10.1016/j.cell.2011.03.022. PMC 3088758. PMID 21496894. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ Wu, SC (2010 Sep). "Active DNA demethylation: many roads lead to Rome". Nature reviews. Molecular cell biology. 11 (9): 607–20. doi:10.1038/nrm2950. PMID 20683471. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ Pfaffeneder, Toni (30 June 2011). "The Discovery of 5-Formylcytosine in Embryonic Stem Cell DNA". Angew. Chem., Int. Ed. PMID 21721093. {{cite journal}}: Text "doi: 10.1002/anie.201103899" ignored (help)CS1 maint: date and year (link)
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