Abstract
Changes in histone post-translational modifications are associated with aging through poorly defined mechanisms. Histone 3 lysine 4 (H3K4) methylation at promoters is deposited by SET1 family methyltransferases acting within conserved multiprotein complexes known as COMPASS. Previous work yielded conflicting results about the requirement for H3K4 methylation during aging. Here, we reassessed the role of SET1/COMPASS-dependent H3K4 methylation in Caenorhabditis elegans lifespan and fertility by generating set-2(syb2085) mutant animals that express a catalytically inactive form of SET-2, the C. elegans SET1 homolog. We show that set-2(syb2085) animals retain the ability to form COMPASS, but have a marked global loss of H3K4 di- and trimethylation (H3K4me2/3). Reduced H3K4 methylation was accompanied by loss of fertility, as expected; however, in contrast to earlier studies, set-2(syb2085) mutants displayed a significantly shortened, not extended, lifespan and had normal intestinal fat stores. Other commonly used set-2 mutants were also short-lived, as was a cfp-1 mutant that lacks the SET1/COMPASS chromatin-targeting component. These results challenge previously held views and establish that WT H3K4me2/3 levels are essential for normal lifespan in C. elegans.
Highlights
Epigenetic alterations, such as post-translational histone modification and DNA methylation, are well-established hallmarks of cellular senescence and organismal aging [1, 2]
Similar results were obtained when the germlines were immunostained for H3K4me2, which is mediated by SET1/complex of proteins associated with Set1 (COMPASS) in C. elegans (Fig 1B and C) [29]
Our results demonstrate that the levels of H3K4me2/ 3 in set-2(syb2085) animals are reduced to levels comparable to those seen in set-2 null animals, consistent with complete loss of set-2 catalytic activity
Summary
Epigenetic alterations, such as post-translational histone modification and DNA methylation, are well-established hallmarks of cellular senescence and organismal aging [1, 2]. The complexity of the aging epigenome, especially in mammals, has hampered efforts to establish whether and how individual epigenetic alterations contribute to the aging process. More recent studies in these model systems have sought to establish a causal link between specific epigenetic modifications and the aging process. Overexpression of H3 and H4 histones in WT budding yeast is sufficient to extend lifespan, suggesting that the observed loss of histones during replicative aging directly contributes to the aging process [5, 6]. Global loss of histones is observed in aging Caenorhabditis elegans, senescent human cells, and human fibroblasts undergoing replicative aging [7, 8, 9], suggesting that a decline in core histone proteins may represent a conserved aging mechanism
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