Abstract
Tri-methylation on histone H3 lysine 4 (H3K4me3) is associated with active gene expression but its regulatory role in transcriptional activation is unclear. Here we used Caenorhabditis elegans to investigate the connection between H3K4me3 and gene expression regulation during aging. We uncovered around 30% of H3K4me3 enriched regions to show significant and reproducible changes with age. We further showed that these age-dynamic H3K4me3 regions largely mark gene-bodies and are acquired during adult stages. We found that these adult-specific age-dynamic H3K4me3 regions are correlated with gene expression changes with age. In contrast, H3K4me3 marking established during developmental stages remained largely stable with age, even when the H3K4me3 associated genes exhibited RNA expression changes during aging. Importantly, the genes associated with changes in H3K4me3 and RNA levels with age are enriched for functional groups commonly implicated in aging biology. Therefore, our findings suggested divergent roles of H3K4me3 in gene expression regulation during aging, with important implications on aging-dependent pathophysiologies.
Highlights
Aging in diverse organisms is accompanied by alterations in gene expression profiles that correlate with age-dependent physiological changes [1,2,3,4,5,6,7,8,9,10,11,12,13]
Recent studies in diverse model organisms demonstrated that the global alterations of particular histone modifications, for instance H3K4me3, extend the lifespan of the organism
We performed chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) to profile the genome-wide patterns of H3K4me3 in C. elegans somatic cells at the young and old age (S1 Table)
Summary
Aging in diverse organisms is accompanied by alterations in gene expression profiles that correlate with age-dependent physiological changes [1,2,3,4,5,6,7,8,9,10,11,12,13]. Previous studies in diverse models demonstrated that aging is accompanied by dynamic changes in DNA methylation, histone modifications, and small RNAs levels [16,17,18,19,20,21,22]. It was reported that over 80% of the genes marked with H3K4me at the promoter region are actively transcribed [24]. Studies in yeast and mammalian cells showed that defects in major H3K4me histone modification enzymes do not result in changes in gene expression [28,29,30]. Whether and how H3K4me contributes to gene expression regulation remain unclear. Recent studies in mammals indicated that atypical, broad domains of H3K4me are likely important for maintaining cell identity [31] and the expression of specific genes [32,33]
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