RRC ID 76196
Author Huang M, Hong M, Hou X, Zhu C, Chen D, Chen X, Guang S, Feng X.
Title H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans.
Journal Elife
Abstract Histone methylation plays crucial roles in the development, gene regulation, and maintenance of stem cell pluripotency in mammals. Recent work shows that histone methylation is associated with aging, yet the underlying mechanism remains unclear. In this work, we identified a class of putative histone 3 lysine 9 mono/dimethyltransferase genes (met-2, set-6, set-19, set-20, set-21, set-32, and set-33), mutations in which induce synergistic lifespan extension in the long-lived DAF-2 (insulin growth factor 1 [IGF-1] receptor) mutant in Caenorhabditis elegans. These putative histone methyltransferase plus daf-2 double mutants not only exhibited an average lifespan nearly three times that of wild-type animals and a maximal lifespan of approximately 100 days, but also significantly increased resistance to oxidative and heat stress. Synergistic lifespan extension depends on the transcription factor DAF-16 (FOXO). mRNA-seq experiments revealed that the mRNA levels of DAF-16 Class I genes, which are activated by DAF-16, were further elevated in the daf-2;set double mutants. Among these genes, tts-1, F35E8.7, ins-35, nhr-62, sod-3, asm-2, and Y39G8B.7 are required for the lifespan extension of the daf-2;set-21 double mutant. In addition, treating daf-2 animals with the H3K9me1/2 methyltransferase G9a inhibitor also extends lifespan and increases stress resistance. Therefore, investigation of DAF-2 and H3K9me1/2 deficiency-mediated synergistic longevity will contribute to a better understanding of the molecular mechanisms of aging and therapeutic applications.
Volume 11
Published 2022-9-20
DOI 10.7554/eLife.74812
PII 74812
PMID 36125117
PMC PMC9514849
MeSH Animals Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism Histone Methyltransferases / metabolism Histones / genetics Histones / metabolism Insulin / metabolism Insulin-Like Growth Factor I / metabolism Longevity / genetics Lysine / metabolism Mammals / genetics Methylation Methyltransferases / genetics Methyltransferases / metabolism RNA, Messenger / metabolism Receptor, Insulin / genetics Receptor, Insulin / metabolism
C.elegans tm1489 tm1624 tm3746 tm1818 tm2963 tm760