细胞内支链氨基酸稳态的表观遗传调控维持了正常的寿命

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-06-07 DOI:10.1016/j.isci.2025.112846

Sejung Park , Yan Liu , Suji Lim , Hong-Yeoul Ryu , Seong Hoon Ahn

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引用次数: 0

摘要

细胞经历功能和寿命的逐渐下降，伴随着表观遗传变化。在这里，我们发现出芽酵母的细胞内BCAA （icBCAA）稳态是由组蛋白H3K4和H3K121调节的。利用全面的H3/H4突变文库，我们确定了与BCAA代谢相关的生命维持所必需的残基。其中，H3K4A/R和H3K121A突变导致BCAA生物合成和分解代谢相关基因的转录发生显著变化，并伴有icBCAA水平异常升高。与H3K121A突变体中BAT1、ILV6和ADH1基因的上调一致，染色质免疫沉淀显示其启动子上的H3K4me3增加。BAT1和BAT2的遗传扰动恢复了icBCAA平衡，部分挽救了H3K4或H3K121突变体的寿命缺陷。此外，H3K4和H3K121突变通过TORC1信号影响寿命调节。我们的研究结果表明，BCAA代谢的表观遗传控制，特别是通过修饰组蛋白残基，有助于维持代谢稳态和复制寿命。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan

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Epigenetic regulation of intracellular branched-chain amino acid homeostasis maintains a normal lifespan

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 BAT1, ILV6, and ADH1 genes in the H3K121A mutant, chromatin immunoprecipitation revealed increased H3K4me3 at their promoters. The genetic perturbation of BAT1 and BAT2 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.

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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