DNA Methylation: Basic Principles
DNA methylation is a stable yet reversible epigenetic modification that regulates gene expression. New technologies have provided deep insights into the distribution and function of DNA methylation in humans, including the Human Roadmap Epigenome Project that defined genomewide methylation profiles across tissues and developmental stages, with the data available to anyone with Internet access. Exciting recent discoveries have revealed that 5-methylcytosine can be modified by ten-eleven translocase dioxygenases (TET1, 2, and 3) to form 5-hydroxymethylcytosine (5hmC). 5hmC is enriched in brain tissues and in embryonic stem cells and appears to have a regulatory role distinct from that of 5-methylcytosine (5mC). 5hmC also acts as a substrate for further modifications by the TET enzymes (5-formylcytosine and 5-carboxylcytosine) which undergo base excision repair by thymine DNA glycosylase (TDG) with replacement by unmethylated cytosine. These revelations present new challenges, including the need for technologies to quantify these modifications, determine their role in pathologies, and ways to target these modified bases and involved pathways to improve patient outcomes. Strategies to reverse abnormal hypermethylation of 5mC at specific loci are being developed and will eventually improve on the generalized toxicity associated with current DNA methyltransferase inhibitor therapies. Finally, exposures to endogenous and exogenous agents can lead to changes in methylation levels that increase disease risk. The sum combinatorial changes comprise what we refer to as each individual's unique "epigenoprint" that may be useful for determining risk of disease, best strategies for prevention and individualized interventions, likelihood of positive therapeutic response, and lead to improved prognoses.