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PubMed1988

Hypomethylation of DNA in the regulation of gene expression.

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?

5-Methylcytosine↗
PubMed1984

SCE and DNA methylation.

The interrelationship between sister chromatid exchange (SCE) formation and DNA methylation was studied in Chinese hamster V79 and Indian muntjac cells. A DNA methylation inhibitor, 5-azacytidine (5AzaC), induced SCEs only when it had been present in cells for at least 2 rounds of DNA replication. This result suggests that SCEs are formed during replication of hemimethylated or demethylated DNA possessing 5AzaC, and that hypomethylated sites may become fully methylated after they pass 1 cell division. It also appears that hypomethylated DNA is not more sensitive to ultraviolet light (UV) or 3-aminobenzamide (3AMB) than normal chromosomes, but sensitized to mitomycin C (MMC) for the induction of SCEs. An analysis of sites of SCEs induced by 5AzaC within Indian muntjac chromosomes showed that the SCE frequency was enhanced at the 5 methylcytosine-rich regions where spontaneous SCEs were intensively suppressed. The SCE mechanism at the junction between contiguous replicons with different replication timing was discussed.

5-Methylcytosine↗