DNA demethylation

DNA methylation is the addition of a methyl group to the DNA that happens at cytosine. The image shows a cytosine single ring base and a methyl group added on to the 5 carbon. In mammals, DNA methylation occurs almost exclusively at a cytosine that is followed by a guanine.

For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C) (see figure of 5mC and C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequence or, in replicating cells, by preventing addition of methyl groups to DNA so that the replicated DNA will largely have cytosine in the DNA sequence (5mC will be diluted out).

Methylated cytosine is frequently present in the linear DNA sequence where a cytosine is followed by a guanine in a 5' → 3' direction (a CpG site). In mammals, DNA methyltransferases (which add methyl groups to DNA bases) exhibit a strong sequence preference for cytosines at CpG sites.[1] There appear to be more than 20 million CpG dinucleotides in the human genome (see genomic distribution). In mammals, on average, 70% to 80% of CpG cytosines are methylated,[2] though the level of methylation varies with different tissues. Methylated cytosines often occur in groups or CpG islands within the promoter regions of genes, where such methylation may reduce or silence gene expression (see gene expression). Methylated cytosines in the gene body, however, are positively correlated with expression.[3]

Almost 100% DNA demethylation occurs by a combination of passive dilution and active enzymatic removal during the reprogramming that occurs in early embryogenesis and in gametogenesis. Another large demethylation, of about 3% of all genes, can occur by active demethylation in neurons during formation of a strong memory.[4] After surgery, demethylations are found in peripheral blood mononuclear cells at sites annotated to immune system genes.[5] Demethylations also occur during the formation of cancers.[6] During global DNA hypomethylation of tumor genomes, there is a minor to moderate reduction of the number of methylated cytosines (5mC) amounting to a loss of about 5% to 20% on average of the 5mC bases.[7]

  1. ^ Ziller MJ, Müller F, Liao J, Zhang Y, Gu H, Bock C, Boyle P, Epstein CB, Bernstein BE, Lengauer T, Gnirke A, Meissner A (December 2011). "Genomic distribution and inter-sample variation of non-CpG methylation across human cell types". PLOS Genet. 7 (12): e1002389. doi:10.1371/journal.pgen.1002389. PMC 3234221. PMID 22174693.
  2. ^ Jabbari K, Bernardi G (May 2004). "Cytosine methylation and CpG, TpG (CpA) and TpA frequencies". Gene. 333: 143–9. doi:10.1016/j.gene.2004.02.043. PMID 15177689.
  3. ^ Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G (October 2014). "Gene body methylation can alter gene expression and is a therapeutic target in cancer". Cancer Cell. 26 (4): 577–90. doi:10.1016/j.ccr.2014.07.028. PMC 4224113. PMID 25263941.
  4. ^ Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD (July 2017). "Experience-dependent epigenomic reorganization in the hippocampus". Learn. Mem. 24 (7): 278–288. doi:10.1101/lm.045112.117. PMC 5473107. PMID 28620075.
  5. ^ Sadahiro R, Knight B, James F, Hannon E, Charity J, Daniels IR, Burrage J, Knox O, Crawford B, Smart NJ, Mill J (April 2020). "Major surgery induces acute changes in measured DNA methylation associated with immune response pathways". Sci Rep. 10 (1): 5743. Bibcode:2020NatSR..10.5743S. doi:10.1038/s41598-020-62262-x. PMC 7113299. PMID 32238836.
  6. ^ Ehrlich M (December 2009). "DNA hypomethylation in cancer cells". Epigenomics. 1 (2): 239–59. doi:10.2217/epi.09.33. PMC 2873040. PMID 20495664.
  7. ^ Pfeifer GP (April 2018). "Defining Driver DNA Methylation Changes in Human Cancer". Int J Mol Sci. 19 (4): 1166. doi:10.3390/ijms19041166. PMC 5979276. PMID 29649096.