Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans

Abstract

The plasticity of aging suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and aging has mostly focused on histone deacetylation by the Sir2 family1,2, but less is known about the role of other histone modifications in longevity. Histone methylation plays a crucial role during development and in maintaining stem cell pluripotency in mammals3. Regulators of histone methylation have been associated with aging in worms4,5,6,7 and flies8, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex9, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in C. elegans in a directed RNAi screen in fertile worms. Deficiencies in members of the ASH-2 complex–ASH-2 itself, WDR-5, and the H3K4 methyltransferase SET-2 extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation–a mark associated with active chromatin–is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results suggest that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.

Mutation of C. elegans demethylase spr-5 extends transgenerational longevity

“…We first treated worms with 5-fluorodeoxyuridine (FUdR), which inhibits proliferation of germline stem cells, the production of intact eggs in adults, and extends longevity [13,14]. We found FUdR had similar effects on the lifespan of WT and early generation spr-5(by101) mutant worms (G5) (Supplementary information, Figure S2A).…”

Epigenetic regulation of aging stem cells

“…Nevertheless, both studies identify age-dependent alterations in the expression of select modifiers of chromatin state (Rossi et al, 2005;Chambers et al, 2007). Interestingly, chromatin modifiers have recently been found to control longevity in model organisms such as yeast, flies and worms Chen et al, 2009;Dang et al, 2009;Greer et al, 2010;Siebold et al, 2010). In addition, chromatin modifiers have been implicated in the control of a number of cellular processes that may contribute to longevity, including DNA damage repair, telomere maintenance and cellular metabolism (Vidanes et al, 2005;Longo and Kennedy, 2006;Blasco, 2007).…”

“…PcG proteins control levels of the repressive mark tri-methyl lysine 27 of histone H3 (H3K27me3), which inhibits gene expression (Ringrose and Paro, 2007). Members of both complexes have been implicated in organismal longevity (Greer et al, 2010;Siebold et al, 2010) and adult stem cell regulation (Molofsky et al, 2003;Park et al, 2003;Jude et al, 2007;McMahon et al, 2007;Lim et al, 2009), indicating that interplay between PcG and TrxG complexes may mediate transcriptional regulation of genes critical for adult stem cell function throughout an organism's lifespan.…”

“…TrxG proteins promote transcriptional activation through deposition and maintenance of the activating chromatin mark H3K4me3. In Caenorhabditis elegans (C. elegans), mutations in TrxG complex members extend organismal longevity in a manner dependent on the germline (Greer et al, 2010). The germline contains the only stem-like cells of the postmitotic nematode , raising the intriguing possibility that chromatin regulation by TrxG in stem cells is critical for controlling age-related phenotypes.…”

Integration of ‘omics’ data in aging research: from biomarkers to systems biology

“…Together, they form a global pattern of hypomethylation in repetitive sequences, hypermethylation in promoter regions and higher intercell variability (Cevenini et al ., 2008; Bacalini et al ., 2014). Besides DNA methylation, other epigenetic changes, such as histone methylation and acetylation, have been found to be associated with longevity in model organisms (Dang et al ., 2009; Greer et al ., 2010). Investigating these modifications in humans could shed light on so far unknown mechanisms of aging.…”