Park Sejung, Liu Yan, Lim Suji, Ryu Hong-Yeoul, Ahn Seong Hoon
Department of Medicinal and Life Science, College of Science and Convergence Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea.
BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, College of National Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
iScience. 2025 Jun 7;28(7):112846. doi: 10.1016/j.isci.2025.112846. eCollection 2025 Jul 18.
Cells experience a progressive decline in function and lifespan, accompanied by epigenetic changes. Here, we show that intracellular BCAA (icBCAA) homeostasis is regulated by histone H3K4 and H3K121 in budding yeast. Using a comprehensive H3/H4 mutant library, we identified residues essential for lifespan maintenance linked to BCAA metabolism. Among these, H3K4A/R and H3K121A mutations led to significant transcriptional changes in genes involved in BCAA biosynthesis and catabolism, accompanied by abnormally elevated icBCAA levels. Consistent with the upregulation of , , and genes in the H3K121A mutant, chromatin immunoprecipitation revealed increased H3K4me3 at their promoters. The genetic perturbation of and restored icBCAA balance and partially rescued lifespan defects in H3K4 or H3K121 mutants. Additionally, H3K4 and H3K121 mutations affected lifespan regulation through TORC1 signaling. Our findings suggest that the epigenetic control of BCAA metabolism, specifically through the modification of histone residues, contributes to maintaining metabolic homeostasis and replicative lifespan.
细胞功能和寿命会逐渐下降，并伴有表观遗传变化。在此，我们表明在出芽酵母中，细胞内支链氨基酸（icBCAA）稳态受组蛋白H3K4和H3K121调控。利用一个全面的H3/H4突变体文库，我们鉴定出了与支链氨基酸代谢相关的维持寿命所必需的残基。其中，H3K4A/R和H3K121A突变导致参与支链氨基酸生物合成和分解代谢的基因发生显著转录变化，同时伴有icBCAA水平异常升高。与H3K121A突变体中、和基因的上调一致，染色质免疫沉淀显示其启动子处的H3K4me3增加。对和的基因干扰恢复了icBCAA平衡，并部分挽救了H3K4或H3K121突变体中的寿命缺陷。此外，H3K4和H3K121突变通过TORC1信号传导影响寿命调控。我们的研究结果表明，支链氨基酸代谢的表观遗传调控，特别是通过组蛋白残基的修饰，有助于维持代谢稳态和复制寿命。
