DNA methylation: past, present and future directions.

DNA methylation, or the covalent addition of a methyl group to cytosine within the context of the CpG dinucleotide, has profound effects on the mammalian genome. These effects include transcriptional repression via inhibition of transcription factor binding or the recruitment of methyl-binding proteins and their associated chromatin remodeling factors, X chromosome inactivation, imprinting and the suppression of parasitic DNA sequences. DNA methylation is also essential for proper embryonic development; however, its presence can add an additional burden to the genome. Normal methylation patterns are frequently disrupted in tumor cells with global hypomethylation accompanying region-specific hypermethylation. When these hypermethylation events occur within the promoter of a tumor suppressor gene they will silence the gene and provide the cell with a growth advantage in a manner akin to deletions or mutations. Recent work indicating that DNA methylation is an important player in both DNA repair and genome stability as well as the discovery of a new family of DNA methyltransferases makes now a very exciting period for the methylation field. This review will highlight the major findings in the methylation field over the past 20 years then summarize the most important and interesting future directions the field is likely to take in the next millennium.