A biochemical modification adding a methyl group to DNA, typically affecting gene activity without changing the sequence.DNA methylation is a chemical tag added to DNA that does not change the sequence of letters but changes how the DNA is read. In most animals and plants, the tag is a methyl group attached to a cytosine base, usually where a cytosine is followed by a guanine (a CpG site). When methylation sits in or near a gene's control region, it typically makes that gene harder to switch on, because the methyl group can block or recruit proteins that regulate transcription. This makes methylation one of the main ways cells with identical genomes — a liver cell and a neuron, say — can behave so differently, and it is a central mechanism of epigenetics, the layer of regulation that sits 'on top of' the genetic code.
DNA methylation was identified in the mid-twentieth century, and its role in gene regulation and in X-chromosome inactivation was established in the 1970s and 1980s. The idea that methylation patterns could serve as a molecular record of age was proposed in the 2010s.
Enzymes called DNA methyltransferases recognize specific sequence contexts and transfer a methyl group from a donor molecule (S-adenosylmethionine) onto the carbon-5 position of cytosine. The pattern is copied when DNA replicates: a maintenance enzyme recognizes the methyl mark on the old strand and places the same mark on the new strand, so the pattern can be inherited through cell divisions. Methyl marks can also be actively removed by a series of oxidation and repair steps, allowing the pattern to change in response to development or environment.
Methylation is measured in research and clinical settings to study gene regulation, to classify tumors, and to estimate biological age from a tissue sample.
In mammals, most of the genome's CpG sites are methylated, but dense clusters of CpGs near gene start sites — called CpG islands — are usually kept unmethylated, which is the opposite of what one might naively expect.