H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans.
H3K9me1/2 methylation limits the lifespan of daf-2 mutants in C. elegans.
复制标题
H3K9me1/2 甲基化限制了线虫中 daf-2 突变体的寿命
作者：
Huang M;Hong M;Hou X;Zhu C;Chen D;Chen X;Guang S;Feng X
组蛋白甲基化在哺乳动物干细胞多能性的发育、基因调控和维持中起着至关重要的作用。最近的研究表明，组蛋白甲基化与衰老有关，但其潜在机制仍不清楚。在这项工作中，我们确定了一类假定的组蛋白3赖氨酸9单/二甲基转移酶基因（met-2，set-6，set-19，set-20，set-21，set-32和set-33），突变诱导协同延长秀丽隐杆线虫中长寿的IGF-2（胰岛素生长因子1 [IGF-1]受体）突变体的寿命。这些假定的组蛋白甲基转移酶加daf-2双突变体不仅表现出平均寿命接近野生型动物的三倍，最大寿命约为100天，而且还显着增加抗氧化和热应激。协同寿命延长取决于转录因子foxo-16（FOXO）。mRNA-seq实验显示，在daf-2;set双突变体中，由DAF-16激活的DAF-16 I类基因的mRNA水平进一步升高。在这些基因中，tts-1、F35E8.7、ins-35、nhr-62、sod-3、asm-2和Y39G8B.7是daf-2;set-21双突变体寿命延长所必需的。此外，用H3 K9 me 1/2甲基转移酶G9 a抑制剂治疗daf-2动物也延长了寿命并增加了应激抗性。因此，研究H3 K9 me 1/2和H3 K9 me 1/2缺陷介导的协同长寿将有助于更好地理解衰老的分子机制和治疗应用。
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.