TY - JOUR TI - H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans AU - Huang, Meng AU - Hong, Minjie AU - Hou, Xinhao AU - Zhu, Chengming AU - Chen, Di AU - Chen, Xiangyang AU - Guang, Shouhong AU - Feng, Xuezhu A2 - Leiser, Scott F A2 - Isales, Carlos A2 - Katz, David VL - 11 PY - 2022 DA - 2022/09/20 SP - e74812 C1 - eLife 2022;11:e74812 DO - 10.7554/eLife.74812 UR - https://doi.org/10.7554/eLife.74812 AB - 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. KW - longevity KW - epigenetic KW - insulin pathway KW - FOXO transcription factor KW - aging KW - histone methyltransferases JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -