Hypomethylation: One Side of a Larger Picture

Hypomethylation signifies one end of a spectrum of DNA methylation states. In most cases hypomethylation refers to a relative state that represents a change from the "normal" methylation level. Hypomethylation, when approached from a topographical perspective, has been used to describe either overall decreases in the methylation status of the entire genome (global hypomethylation) or more localized relative demethylation of specific subsets of the genome, such as the promoter regions of protooncogenes or normally highly methylated repetitive sequences. Global hypomethylation accompanied by gene-specific hypermethylation is observed in at least two important settings: cancer and aging. Global hypomethylation is generally reflective of decreased methylation in CpGs dispersed throughout repetitive sequences as well as the bodies of genes. Hypomethylation of repetitive and parasitic DNA sequences correlates with a number of adverse outcomes. For example, decreased methylation of repetitive sequences in the satellite DNA of the pericentric region of chromosomes is associated with increased chromosomal rearrangements, a hallmark of cancer. Decreased methylation of proviral sequences can lead to reactivation and increased infectivity. However, hypomethylation in cancer can also affect the CpGs in the promoters of specific genes-namely, protooncogenes-leading to their overexpression and resulting in the functional outcome of increased cell proliferation. Thus, hypomethylation, in a variety of settings in which it represents a deviation from "normal," appears to correlate with progression to cancer and offers potential mechanisms to explain the carcinogenic process.