AbstractEpigenetic alterations occur as organisms age, and lead to chromatin deterioration, loss of transcriptional silencing and genomic instability. Dysregulated epigenome has been linked to increased susceptibility to age-related disorders. We aim to characterize the age-dependent changes of the epigenome and, in turn, to understand epigenetic processes that drive aging phenotypes. In this study, we focused on the aging-associated changes in the repressive histone marks H3K9me3 and H3K27me3 in C. elegans. We observed redistribution of of both histone marks, but the changes are more significant for H3K9me3. We further found alteration of heterochromatic boundaries in aged somatic tissues. Interestingly, we discovered that the most significant changes reflected H3K9me3-marked regions that are formed during aging, and are absent in developing worms, which we termed “aging-associated repressive domains” (AARDs). These AARDs preferentially occur in genic regions that are marked by high levels of H3K9me2 and H3K36me2 in larval stages. Interestingly, maintenance of high H3K9me2 levels in these regions have been shown to correlate with longer lifespan. Next, we examined whether the changes in repressive histone marks lead to de-silencing of repetitive DNA elements, as reported for several other organisms. We observed increased expression of active repetitive DNA elements but not global re-activation of silent repeats in old worms, likely due to the distributed nature of repetitive elements in the C. elegans genome. Intriguingly, CELE45, a putative short interspersed nuclear elements (SINE), was greatly overexpressed at old age and upon heat stress. SINEs have been suggested to regulate transcription in response to various cellular stresses in mammals, it is likely that CELE45 RNAs also play roles in stress response and aging in C. elegans. Taken together, our study revealed significant and specific age-dependent changes in repressive histone modifications and repetitive elements, providing important insights into aging biology.Author summaryHeterochromatin refers to the portion of the genome that is tightly packed where genes stay silent. Heterochromatin is typically decorated by particular chemical groups called histone modifications, such as trimethylation of lysine 9 or lysine 27 on histone 3 (H3K9me3 or H3K27me3). To understand how the heterochromatin landscape may change from a “youthful” to an “aged” state, we monitored the genome-wide patterns of H3K9me3 and H3K27me3 during aging using the genetic model soil worm C. elegans. We found that while H3K27me3 remained relatively stable with age, H3K9me3 showed profound genome-wide redistribution in aged worms. We observed that new H3K9me3-marked heterochromatin preferentially formed in specific gene-rich regions in aged worms. Interestingly, these particular regions were marked by high levels of three other histone modifications when worms were young. This result suggested that H3K9me3 gain during aging is influenced by the gene-specific landscape of histone modifications established at young age rather than occurs in a stochastic manner. In summary, our study discovered reproducible and gene-specific changes in histone modifications that likely contribute to the aging phenotypes.
Impact of Repetitive DNA Elements on Snake Genome Biology and Evolution