DNA hydroxymethylation in aging

The authors first quantified global 5mC or 5hmC levels in seven organs from young (aged 2–5 months) or old (aged 18–20 months) mice. Of these organs, only the liver displayed an age-dependent increase in global 5hmC levels, which prompted the authors to sequence genomic DNA from old versus young mouse livers in order to profile the distribution of 5mC and 5hmC marks. The authors observed a significant accumulation of 5hmC, but not 5mC, in the gene bodies of old mice — particularly in genes linked to metabolism. Next, the authors paired these epigenomic data with existing transcriptomic data from the livers of age-matched animals. Although the authors observed age-dependent changes in gene expression, these differences were less prominent in genes with higher levels of 5hmC in old compared to young mice. In the words of the study’s corresponding author, Payel Sen, and first author James Occean, the researchers found that “elevated levels of DNA hydroxymethylation restricted gene expression changes with age.”

To explore why 5hmC might dampen age-related changes in gene expression, the authors next incubated mouse liver nuclear protein extract with DNA probes that were unmodified, methylated or hydroxymethylated. From proteomic analysis of the nuclear proteins that bound each of these probes, the authors found that RNA splicing-related factors were less likely to interact with hydroxymethylated than with methylated DNA. Referring back to their liver transcriptomic data, the authors reported that genes with higher levels of 5hmC were more likely to undergo alternative splicing. Sen and Occean concluded that these results suggest a role for 5hmC “in maintaining gene expression stability with age, potentially through a mechanism involving alternative splicing.”