DNA methylation and demethylation probed by small molecules

DNA methylation is a covalent modification of DNA that plays an important role in setting gene expression programs during development. Recent evidence suggests that changes in DNA methylation patterns are involved in human disease through altering normal gene expression programming. In contrast to genetic changes aberrant DNA methylation patterns are potentially reversible raising the hope for DNA methylation based therapeutics. It was previously believed that the only relevant DNA methylation reaction in mature cells is DNA methyltransferase (DNMT), which accurately copies the DNA methylation pattern during cell division. The major effort in the field has therefore focused on developing DNMT inhibitors for cancer a disease of mitotic cells. However, recent evidence suggests that the DNA methylation state in both mitotic and postmitotic cells is a balance of DNA methylating and demethylating activities. This expands the scope of DNMT inhibitors to postmitotic tissues such as the brain. Since the identity of the DNA demethylating activity is still a mystery, the development of DNA demethylation inhibitors has been lagging. This review will discuss DNA methylation and demethylation machineries, and their therapeutic potentials as targets for small molecule inhibitors.

Research Highlights
► DNA methylation is a balance of methylation and demethylation activities.
► DNA methylation patterns are altered in disease.
► Cancer is distinguished by hypermethylation of certain genes and hypomethylation of other genes.
► DNA methylation inhibitors are used clinically as anticancer agents.
► DNA demethylation inhibitors are potential new therapeutics.