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
Mentions: We first focused on WDR-5, a conserved regulatory component of the ASH-2 complex19 whose depletion decreases H3K4me3 levels12,20–22 and extends lifespan in worms12. To test if longevity could be inherited in a transgenerational epigenetic manner, we crossed wildtype males with wdr-5(ok1417) mutant hermaphrodites to generate F1 heterozygous hermaphrodites (Fig. 1a). These F1 heterozygous hermaphrodites were genotyped and then self-crossed to generate F2 hermaphrodites (wildtype, heterozygous, and homozygous at the wdr-5 locus), which were genotyped after they had laid F3 generation progeny. In parallel, we crossed a wildtype male with a wildtype hermaphrodite to generate pure wildtype descendents and control for any beneficial longevity effects that could come from crossing rather than self-mating (Fig. 1a). Longevity of the F3, F4, and F5 generations of worms was examined. Interestingly, genetically wildtype F3 descendents from P0 wdr-5 parents (+/+ from P0 wdr-5 parents) still exhibited a ~20% extension of lifespan (p<0.0001) compared to descendents from pure wildtype parents (+/+ from P0 N2 parents) (Fig. 1b). This 20% lifespan extension was similar in magnitude to the lifespan extension of pure F3 wdr-5(ok1417) mutants (wdr-5/wdr-5) (Fig. 1b). The lifespan of genetically wildtype descendents from wdr-5(ok1417) mutant parents (+/+ from P0 wdr-5 parents) was still extended in the F4 generation (Fig. 1c), but was no longer extended in the F5 generation (Fig. 1d). Thus, wdr-5 deficiency only in the parental generation can extend the lifespan of subsequent generations. Since the lifespan of F5 generation wildtype descendents from wdr-5 mutant parents is no longer extended, the lifespan extension observed in the F3 and F4 generations is unlikely to be due to extraneous mutations that might have been present in the parental wdr-5 mutant strain. Instead, the transgenerational inheritance of longevity may be due to epigenetic changes in H3K4me3 itself or in another molecule that can only be inherited for a limited number of generations.
Affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.