H3K9me2 protects lifespan against the transgenerational burden of germline transcription in C. elegans

Abstract

1During active transcription, the COMPASS complex methylates histone H3 at lysine 4 (H3K4me). In 2 Caenorhabditis elegans, mutations in COMPASS subunits, including WDR-5, extend lifespan and enable the 3 inheritance of increased lifespan in wild-type descendants. Here we show that the increased lifespan of 4 wdr-5 mutants is itself a transgenerational trait that manifests after eighteen generations and correlates 5 with changes in the heterochromatin factor H3K9me2. Additionally, we find that wdr-5 mutant longevity 6 and its inheritance requires the H3K9me2 methyltransferase MET-2 and can be recapitulated by a mutation 7 in the putative H3K9me2 demethylase JHDM-1. These data suggest that lifespan is constrained by reduced 8H3K9me2 due to transcription-coupled H3K4me. wdr-5 mutants alleviate this burden, extending lifespan 9 and enabling the inheritance of increased lifespan. Thus, H3K9me2 functions in the epigenetic 10 establishment and inheritance of a complex trait. Based on this model, we propose that lifespan is limited 11 by the germline in part because germline transcription reduces heterochromatin. 12 13 H3K9me2 in the longevity of wdr-5 mutants over generational time. 51 52 RESULTS 53Transgenerational longevity in wdr-5 mutants 54It has previously been reported that animals mutant for genes encoding components of the 55 COMPASS complex have a lifespan extension of up to 28% (Greer et al. 2010), and this lifespan extension is 56 inherited by wild-type descendants of these mutants before reverting back to wild-type levels in the fifth 57 generation . To investigate the nature of this inheritance, we first attempted to 58 recapitulate the original observation using fertile, homozygous wdr-5 (ok1417) mutants. Since the 59 transgenerational effects of a wdr-5 mutation lasts for four generations, we crossed wdr-5 mutants to wild 60 type to generate heterozygous wdr-5/+ progeny and maintained populations as wdr-5/+ heterozygotes for 61 five generations. We then used homozygous wdr-5 mutant progeny from F5 wdr-5/+ heterozygotes as our 62 P0 founding population, comparing them to P0 wild-type animals descended from survivors recovered from 63 a thaw. In contrast to prior observations, P0 wdr-5 mutants were never long-lived compared to their wild-64 type counterparts (as observed in eight biological replicates) (Figure 1, Figure 1 -figure supplement 1). 65The initial observations of wdr-5 mutant longevity did not report how many generations lacking 66 WDR-5 activity were required to reach the 28% lifespan extension in wdr-5 mutants, so we considered the 67 possibility that lifespan may gradually change over a number of generations in COMPASS mutants. Starting 68 with P0 as described above, we followed a single population of wdr-5 mutants and assessed lifespan every 69 three generations. For the first six generations (which are hereafter referred to as early-gen populations), 70 wdr-5 mutants had slightly shorter lifespans than wild-type populations of the same generation, though the 71 decrease was not statisticall...

Hop stunt viroid infection alters host heterochromatin

“…For example, DNA binding and kinase activity were predominantly associated with H3K27me3, while hydrolase and catalytic activities were in general related to H3K9me2 (Figure 5B). This observation is in line with the known roles of H3K27me3 in regulating the sensing of environmental signals (82) and a potential role of H3K9me2 in the control of housekeeping metabolic activities as observed in other species such as C.elegans or humans (83,84). Next, we explored the influence of the presence of gain or loss peaks over the transcriptional activation or repression of gene expression in response to HSVd infection.…”

Gene bookmarking by the heat shock transcription factor programs the insulin-like signaling pathway

“…We have yet to investigate whether the interaction between HSF-1 and MET-2 follows the biphasic dose-response relationship characteristic of hormetic responses Baldwin, 1998, 2001;Calabrese et al, 2020;Giordano et al, 2008). HSF-1 and MET-2 are essential during normal development (Akerfelt et al, 2007;Sridharan et al, 2013) and beneficial for lifespan extension (Lee et al, 2019) but detrimental when upregulated in cancer (Alasady and Mendillo, 2020;Zhang and Adams, 2007) or dysregulated in neurodegenerative diseases (Berson et al, 2018;Neef et al, 2011), suggesting that their interaction is unlikely to be monotonic.…”

“…88802, Pierce) pre-cleared with salmon sperm DNA was used. Worm lysates were first pre-cleared with pre-cleared magnetic beads and then the resulting precleared worm lysate was incubated at 4 C overnight with anti-H3K9me2 antibody (Lee et al, 2019) (catalog no. ab1220, Abcam, RRID:AB_449854).…”