Project description:Chromatin state influences lifespan and may allow for the epigenetic inheritance of this complex trait. At sites of active transcription, the COMPASS complex methylates histone H3 at lysine 4 (H3K4me). In Caenorhabditis elegans, reductions in COMPASS extend lifespan, and wild-type descendants of COMPASS mutants inherit longevity for four generations. Here we show that the longevity of COMPASS mutants is itself a transgenerational trait caused by gradual changes in the repressive chromatin factor H3K9me2. H3K9me2 is required for longevity in COMPASS mutants and can confer longevity when increased in other chromatin modifier mutants. H3K9me2 levels also correlate with a transgenerational decline in wild-type lifespan after freezing or starvation. We propose that germline transcription-coupled H3K4me encroaches on H3K9me2 to limit lifespan. Loss of COMPASS complex alleviates the burden of H3K4me and therefore extends lifespan. This study suggests a causal role for a single heterochromatin factor in the establishment and inheritance of longevity.
Project description:Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendents. The histone H3 lysine 4 trimethylation (H3K4me3) complex composed of ASH-2, WDR-5, and the histone methyltransferase SET-2 regulates C. elegans lifespan. 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 descendents 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 descendents. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendents.
Project description:Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendents. The histone H3 lysine 4 trimethylation (H3K4me3) complex composed of ASH-2, WDR-5, and the histone methyltransferase SET-2 regulates C. elegans lifespan. 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 descendents 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 descendents. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendents. There are 35 samples in total. We found that genetically WT descendents from mutants of the H3K4me3 modifying complex had extended longevity up until the F4 generation. Their lifespan returned to WT levels in the F5 generation. We performed microarrays to examine what gene expression differences there were between N2(WT) worms, +/+ (from wdr-5 mutant) worms, and wdr-5/wdr-5 in the F4 and the F5 generation. We analyzed L3 samples from the first and second days of egg laying in triplicate each. Samples consist of ~1000 worms each.
Project description:Epigenetic inheritance provides mutation-free mechanisms for phenotypic adaptation, including modifications to DNA or DNA-associated proteins that create patterns of heritable gene regulation. However, the limits and regulation of this inheritance remain incompletely understood. Here, we developed a C. elegans system to study the transgenerational epigenetic inheritance of H3K27me3, a conserved histone posttranslational modification associated with gene repression. We find that induced alterations of the genome-wide H3K27me3 landscape and the associated fertility defects persist for many generations in genetically wildtype descendants under selective pressure. We uncover that the inheritance of the altered H3K27me3 landscape involves an initiation phase that relies on SET-32/H3K23me3 and a maintenance phase that requires MES-4/H3K36me3. Our results demonstrate that epigenetic inheritance can act as a mutation-independent, heritable mechanism of adaptation.