Locus-specific H3K9me3 gain in aged somatic tissues in Caenorhabditis elegans

Abstract

Epigenetic 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.

How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span

“…Changes in histone methylation levels were also documented during aging. Recent work suggests that levels of the repressive histone mark H3K9me3 increased at heterochromatic regions and decreased at euchromatic regions in aged worms [41]. In line with the notion that decreasing histone methylation could be linked with prolonged life span, previous data showed that H3K9me3 was increased in the head of 40 days old versus 10 old male and female drosophila [23].…”