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 then asked if the transgenerational inheritance of longevity is specific to H3K4me3 modifiers or if it is also observed with chromatin modifiers of other marks (set-9, set-15, and utx-1), and more generally with genes in known longevity pathways: insulin signaling (age-1 and dod-23), mitochondria (cco-1 and cyc-1), and stress resistance (asm-3)12,17,18,26–32. In contrast to what we observed for ash-2 and wdr-5, knock-down of set-9, set-15, utx-1, age-1, asm-3, cco-1, cyc-1, and dod-23 only in parents did not extend the lifespan of the F1 generation (Fig. 5a, b, Supplementary Fig. 5). Similarly, genetically wildtype F3 descendents from long-lived daf-2(e1370)33 mutant worms (+/+ from P0 daf-2 parents) had no significant extension of lifespan (6% p = 0.1955) (Fig. 5c, d). Collectively, these findings indicate that transgenerational extension of longevity is relatively specific to H3K4me3 chromatin modifiers, and further suggest that the H3K4me3 mark may be important for epigenetic memory of lifespan between generations. As SET-9, SET-15, and UTX-1, unlike members of the ASH-2 complex, regulate lifespan in a manner that is independent of the germline12,17,18, it is also possible that transgenerational inheritance of longevity is specific to chromatin regulators that act in the germline.
Affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.