Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans.
Bottom Line: Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation.The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants.Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression.
Affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.Show MeSH
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Mentions: We next determined if transgenerational inheritance of lifespan was associated with heritable changes in H3K4me3. Western blot and immunocytochemistry revealed that global H3K4me3 levels were not decreased in F3 and F4 generation genetically wildtype descendents from wdr-5 and set-2 parents or in F1 and F2 generation descendents from ash-2 or wdr-5 knock-down only in parents (Fig. 6a, b, Supplementary Fig. 6, 7). Thus, transgenerational inheritance of lifespan is unlikely to be mediated by a heritable global decrease in H3K4me3 levels. Transgenerational inheritance of lifespan might be associated with heritable local changes of H3K4me3 at certain loci, which could affect expression of certain genes involved in longevity. To test this idea, we compared gene expression genome-wide in wildtype descendents from wdr-5 mutant and wildtype ancestors, and pure wdr-5 mutant descendents in the F4 and F5 generations (Fig. 6c). For each condition, we collected triplicates of L3 stage worms from the first or second day of egg-laying (Fig. 6c), with the first day of egg-laying corresponding to the samples used for lifespan assays. Statistical analysis of microarray (SAM) identified 759 genes that were differentially regulated in wdr-5 pure mutants compared to wildtype worms, regardless of the generation (Supplementary Table 7) and egg-laying day (Supplementary Fig. 8a) (p = 2.38×10−116, hypergeometric probability). These WDR-5 regulated genes are enriched for longevity, development, and growth Gene Ontology (GO) terms (Supplementary Fig. 8b), consistent with WDR-5’s reported functions12,21,22. As expected, WDR-5 regulated genes significantly overlap with ASH-2 regulated genes12 (p = 6.14×10−12, hypergeometric probability, Supplementary Fig. 8c) and are enriched for H3K4me3 (ref. 34,35) (p = 2.49×10−34, hypergeometric probability, Supplementary Fig. 8d). These observations suggest that WDR-5 functions together with ASH-2 to regulate a subset of genes by modulating H3K4me3 at these loci.
Affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.