DNA methylation

DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging, and carcinogenesis.

As of 2016, two nucleobases have been found on which natural, enzymatic DNA methylation takes place: adenine and cytosine. The modified bases are N⁶-methyladenine,^[1] 5-methylcytosine^[2] and N⁴-methylcytosine.^[3]

	Unmodified base
			Adenine, A		Cytosine, C
	Modified forms
			N6-Methyladenine, 6mA		5-Methylcytosine, 5mC		N4-Methylcytosine, 4mC

Cytosine methylation is widespread in both eukaryotes and prokaryotes, even though the rate of cytosine DNA methylation can differ greatly between species: 14% of cytosines are methylated in Arabidopsis thaliana, 4% to 8% in Physarum,^[4] 7.6% in Mus musculus, 2.3% in Escherichia coli, 0.03% in Drosophila; methylation is essentially undetectable in Dictyostelium;^[5][6] and virtually absent (0.0002 to 0.0003%) from Caenorhabditis^[7] or fungi such as Saccharomyces cerevisiae and S. pombe (but not N. crassa).^{[8][9]: 3699} Adenine methylation has been observed in bacterial and plant DNA, and recently also in mammalian DNA,^[10][11] but has received considerably less attention.

Methylation of cytosine to form 5-methylcytosine occurs at the same 5 position on the pyrimidine ring where the DNA base thymine's methyl group is located; the same position distinguishes thymine from the analogous RNA base uracil, which has no methyl group. Spontaneous deamination of 5-methylcytosine converts it to thymine. This results in a T:G mismatch. Repair mechanisms then correct it back to the original C:G pair; alternatively, they may substitute A for G, turning the original C:G pair into a T:A pair, effectively changing a base and introducing a mutation. This misincorporated base will not be corrected during DNA replication as thymine is a DNA base. If the mismatch is not repaired and the cell enters the cell cycle the strand carrying the T will be complemented by an A in one of the daughter cells, such that the mutation becomes permanent. The near-universal use of thymine exclusively in DNA and uracil exclusively in RNA may have evolved as an error-control mechanism, to facilitate the removal of uracils generated by the spontaneous deamination of cytosine.^[12] DNA methylation as well as a number of its contemporary DNA methyltransferases have been thought to evolve from early world primitive RNA methylation activity and is supported by several lines of evidence.^[13]

In plants and other organisms, DNA methylation is found in three different sequence contexts: CG (or CpG), CHG or CHH (where H correspond to A, T or C). In mammals however, DNA methylation is almost exclusively found in CpG dinucleotides, with the cytosines on both strands being usually methylated. Non-CpG methylation can however be observed in embryonic stem cells,^[14][15][16] and has also been indicated in neural development.^[17] Furthermore, non-CpG methylation has also been observed in hematopoietic progenitor cells, and it occurred mainly in a CpApC sequence context.^[18]