Project description:SET-9 and SET-26 are highly homologous paralogs that share redundant function in germline development, but SET-26 alone plays a key role in longevity and heat stress response. SET-26 is broadly expressed, but SET-9 is only detectable in the germline, which likely account for their different biological roles. SET-9 and SET-26 bind to H3K4me3 in vitro and in vivo, and their loss results in broadening of H3K4me3 domains. SET-9 and SET-26 also regulate the RNA expression of a subset of their target genes, irrespective of their H3K4me3 status. We propose that SET-9 and SET-26 function to organize local chromatin environment and to regulate the expression of specific target genes, and these activities together contribute to their critical roles in germline development, stress response, and longevity. SET-9 and SET-26 are highly homologous to human MLL5, a factor implicated in leukemia and glioblastoma, and our findings help to provide new insights into MLL5.
2018-05-31 | GSE100623 | GEO
Project description:SET-9 and SET-26, the C. elegans homologs of human MLL5, are critical for germline development and longevity
Project description:SET-9 and SET-26 are highly homologous paralogs that share redundant function in germline development, but SET-26 alone plays a key role in longevity and heat stress response. SET-26 is broadly expressed, but SET-9 is only detectable in the germline, which likely account for their different biological roles. SET-9 and SET-26 bind to H3K4me3 in vitro and in vivo, and their loss results in broadening of H3K4me3 domains. SET-9 and SET-26 also regulate the RNA expression of a subset of their target genes, irrespective of their H3K4me3 status. We propose that SET-9 and SET-26 function to organize local chromatin environment and to regulate the expression of specific target genes, and these activities together contribute to their critical roles in germline development, stress response, and longevity. SET-9 and SET-26 are highly homologous to human MLL5, a factor implicated in leukemia and glioblastoma, and our findings help to provide new insights into MLL5.
Project description:How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in C.CaenorhabditisC. elegans elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.
Project description:Insulin/IGF-1 Signaling (IIS) is known to constrain longevity by inhibiting the transcription factor FOXO. How phosphorylation mediated by IIS kinases regulates lifespan beyond FOXO remains unclear. Here, we profile IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant Caenorhabditis elegans strains. We quantify more than 15,000 phosphosites and find that 476 of these are differentially phosphorylated in the long-lived daf-2/insulin receptor mutant. We develop a machine learning-based method to prioritize 25 potential lifespan-related phosphosites. We perform validations to show that AKT-1 pT492 inhibits DAF-16/FOXO and compensates the loss of daf-2 function, that EIF-2α pS49 potently inhibits protein synthesis and daf-2 longevity, and that reduced phosphorylation of multiple germline proteins apparently transmits reduced DAF-2 signaling to the soma. In addition, an analysis of kinases with enriched substrates detects that casein kinase 2 (CK2) subunits negatively regulate lifespan. Our study reveals detailed functional insights into longevity.
Project description:SET-26, HCF-1, and HDA-1 are highly conserved chromatin factors with key roles in development and aging. Here we present mechanistic insights into how these factors regulate gene expression and modulate longevity in C. elegans. We show that SET-26 and HCF-1 cooperate to regulate a common set of genes, and both antagonize the histone deacetylase HDA-1 to limit longevity. We propose a model in which SET-26 recruits HCF-1 to chromatin in somatic cells, where they stabilize each other at the promoters of a subset of genes, particularly mitochondrial function genes, and regulate their expression. HDA-1 opposes SET-26 and HCF-1 on the regulation of a subset of their common target genes and in longevity. Our findings suggest that SET-26, HCF-1, and HDA-1 comprise a mechanism to fine-tune gene expression and longevity and likely have important implications for the mechanistic understanding of how these factors function in diverse organisms, particularly in aging biology.
Project description:SET-26, HCF-1, and HDA-1 are highly conserved chromatin factors with key roles in development and aging. Here we present mechanistic insights into how these factors regulate gene expression and modulate longevity in C. elegans. We show that SET-26 and HCF-1 cooperate to regulate a common set of genes, and both antagonize the histone deacetylase HDA-1 to limit longevity. We propose a model in which SET-26 recruits HCF-1 to chromatin in somatic cells, where they stabilize each other at the promoters of a subset of genes, particularly mitochondrial function genes, and regulate their expression. HDA-1 opposes SET-26 and HCF-1 on the regulation of a subset of their common target genes and in longevity. Our findings suggest that SET-26, HCF-1, and HDA-1 comprise a mechanism to fine-tune gene expression and longevity and likely have important implications for the mechanistic understanding of how these factors function in diverse organisms, particularly in aging biology.
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.