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: ASH-2 is important for the conversion of H3K4 dimethylation (H3K4me2) to H3K4me3 (ref. 23). ash-2 knock-down in worms decreases global H3K4me3 levels at the L3 stage12,22 and extends longevity12. We asked if ash-2 knock-down only in the parental generation affected the lifespan of several generations of descendents. Wildtype parent worms (P0) were placed on plates with bacteria expressing RNAi to ash-2 from birth to the larval stage L4, then switched every day for three days onto plates containing OP50-1 bacteria and streptomycin to selectively prevent the growth of RNAi-expressing bacteria (Fig. 3a). Endogenous ash-2 mRNA and ASH-2 protein levels were significantly decreased in the P0 generation, but returned to normal levels in subsequent generations (Fig. 3b, c), indicating that ash-2 RNAi is not itself inherited. The lifespan of worms from the F1, F2, and F3 generations in which ash-2 had been knocked-down only in the P0 parental generation was still significantly extended (19–27%, p<0.0001) compared to that of descendents of worms treated with empty vector control in the P0 parental generation (Fig. 3d–g). By contrast, F4 generation descendents no longer had extended lifespan (Fig. 3h). We obtained similar results after bleaching P0 worms to avoid potential carry over of RNAi-expressing bacteria (data not shown). Thus, alteration of the components of the H3K4me3 methyltransferase complex (ASH-2, WDR-5, SET-2) in parents affects the lifespan of descendents, supporting the possibility that transgenerational inheritance of longevity is due to epigenetic changes that may only be inherited for a limited number of generations.
Affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.