Abstract
In Caenorhabditis elegans, mutations in WDR-5 and other components of the COMPASS H3K4 methyltransferase complex extend lifespan and enable its inheritance. Here, we show that wdr-5 mutant longevity is itself a transgenerational trait that corresponds with a global enrichment of the heterochromatin factor H3K9me2 over twenty generations. In addition, we find that the transgenerational aspects of wdr-5 mutant longevity require the H3K9me2 methyltransferase MET-2, and can be recapitulated by removal of the putative H3K9me2 demethylase JHDM-1. Finally, we show that the transgenerational acquisition of longevity in jhdm-1 mutants is associated with accumulating genomic H3K9me2 that is inherited by their long-lived wild-type descendants at a subset of loci. These results suggest that heterochromatin facilitates the transgenerational establishment and inheritance of a complex trait. Based on these results, we propose that transcription-coupled H3K4me via COMPASS limits lifespan by encroaching upon domains of heterochromatin in the genome.
Highlights
Lifespan is governed by complex interactions between genetics and the environment
It has previously been reported that animals mutant for genes encoding components of the COMPASS complex have a lifespan extension of up to 28% (Greer et al, 2010).This lifespan extension is inherited by wild-type descendants of these mutants, before reverting back to wild-type levels in the fifth generation (Greer et al, 2011)
We used homozygous wdr-5 mutant progeny descended from F5 wdr-5/+ heterozygotes as our P0 founding population, comparing them to P0 wild-type animals descended from survivors recovered from a thaw
Summary
Lifespan is governed by complex interactions between genetics and the environment. Despite its complexity as a trait, lifespan is limited by the germline in a wide range of metazoans. Genetic or physical ablation of the germline extends lifespan in C. elegans (Arantes-Oliveira, 2002; Flatt et al, 2008; Hsin and Kenyon, 1999; Kenyon, 2010). Subsequent work showed that reducing COMPASS solely in the germline activates a fatty acid desaturation pathway in the intestine that increases lifespan, in part by down-regulating an S6 kinase normally expressed in the germline (Han et al, 2017). Activation of this pathway causes the accumulation of mono-unsaturated fatty acids, and this increase is sufficient to extend lifespan (Han et al, 2017)
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