Hypomethylation of DNA in the regulation of gene expression

Abstract

Although numerous possible functions of eukaryotic DNA methylation have been proposed (Ehrlich and Wang, 1981), current evidence suggests an association between hypomethylation of specific gene regions and transcriptional activity (Doerfler, 1983; Riggs and Jones, 1983). Considerable excitement has been generated by the finding that potential methylation sites are often clustered at the 5' regions of genes (Bird et al., 1985). Furthermore, these clusters appear to be protected from methylation when associated with actively expressed genes. These findings have generated a new line of thinking among researchers, namely that genes may be regulated by domains of methylation sites (Jones, 1986). Although the evidence supporting a role for methylation in eukaryotic gene regulation is convincing, it is by no means unequivocal (Bird, 1984). To date, however, determination of the methylation status of specific cytosine residues in DNA has been limited by the experimental tools at hand. Therefore, development of a method that allows for evaluation of the methylation status of all CpG sites within, and in the vicinity of, genes may be necessary to elucidate the exact relationship between DNA methylation and gene expression. The emerging consensus is that DNA methylation is one component of a hierarchy of control mechanisms that regulate eukaryotic gene expression and cellular differentiation. Furthermore, the realization that methylation plays an important role in regulating gene expression during normal cellular differentiation suggests that aberrations in this potential controlling mechanism may be implicated in the abnormal gene expression seen in cancer. Indeed, a large body of experimental evidence demonstrates altered levels and patterns of methylation in tumor cells (Riggs and Jones, 1983; Jones, 1986). The regulatory function of 5-mCyt is most likely exerted via DNA-protein interactions. Two key questions remain unanswered: How does 5-mCyt affect these interactions? More importantly, what are the proteins that modulate DNA methylation during differentiation?