Fig. 5

Proposed model that highlights the role of H3K36 methylation maintenance on epigenetic aging. The H3K36me2/3 mark allows recruiting de novo DNA methyltransferases DNMT3A (in green) and DNMT3B (not shown) through their PWWP domain (in blue) to different genomic regions (such as gene bodies or pericentric heterochromatin) [60, 68, 69], which leads to the methylation of the cytosines in the DNA of these regions (5-mC, black lollipops). On the contrary, DNA methylation valleys (DMVs) are conserved genomic regions that are normally found hypomethylated and associated with Polycomb-regulated developmental genes [64,65,66,67]. During aging, the H3K36 methylation machinery could become less efficient at maintaining the H3K36me2/3 landscape. This would lead to a relocation of de novo DNA methyltransferases from their original genomic reservoirs (which would become hypomethylated) to other non-specific regions such as DMVs (which would become hypermethylated and potentially lose their normal boundaries), with functional consequences for the tissues. This is also partially observed in patients with Sotos syndrome, where mutations in NSD1 potentially affect H3K36me2/3 patterns and accelerate the epigenetic aging clock as measured with the Horvath model [8]. Given that DNMT3B is enriched in the gene bodies of highly transcribed genes [60] and that we found these regions depleted in our differential methylation analysis, we hypothesize that the hypermethylation of DMVs could be mainly driven by DNMT3A instead. However, it is important to mention that our analysis does not discard a role of DNMT3B during epigenetic aging