Aging and DNA methylation

Abstract

In this Opinion article, we summarize how changes in DNA methylation occur during aging in mammals and discuss examples of how such events may contribute to the aging process. We explore mechanisms that could facilitate DNA methylation changes in a site-specific manner and highlight a model in which region-specific DNA hypermethylation during aging is facilitated in a competitive manner by destabilization of the Polycomb repressive complex.

Figure 1

De novo methylation by competition. Unmethylated CpG-rich DNA regions, termed CpG islands, are recognized and bound by KDM2B, which recruits PRC1, which in turn results in PRC2 binding and H3K27me3 formation. Our theory is that this complex degrades with age, allowing gradual access of DNA to the de novo methyltransferases DNMT3A and DNMT3B and leading to partial DNA methylation in older individuals. A subset of the Polycomb-marked genes will simultaneously carry an active chromatin mark, H3K4me3, and are referred to as bivalent genes. A similar process may be operative, but for bivalent genes both the H3K27me3 modification and the H3K4me3 mark need to be lost in order for DNA methylation to occur. White circles illustrate unmethylated CpG sites and black circles show methylated CpG sites.