Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
The Rowett Institute, University of Aberdeen, Foresterhill Campus, Aberdeen AB25 2ZD, UK.
Aging (Albany NY). 2023 Oct 23;15(20):10915-10937. doi: 10.18632/aging.205109.
Compared to replicative lifespan, epigenetic regulation of chronological lifespan (CLS) is less well understood in yeast. Here, by screening all the viable mutants of histone acetyltransferase (HAT) and histone deacetylase (HDAC), we demonstrate that Gcn5, functioning in the HAT module of the SAGA/SLIK complex, exhibits an epistatic relationship with the HDAC Hda1 to control the expression of starvation-induced stress response and respiratory cell growth. Surprisingly, the mutants lose their colony-forming potential early in the stationary phase but display a longer maximum CLS than their WT counterparts, suggesting the contradictory roles of Gcn5 in lifespan regulation. Integrative analyses of the transcriptome, metabolome and ChIP assays reveal that Gcn5 is necessary for the activation of two regulons upon glucose starvation: the Msn2/4-/Gis1-dependent stress response and the Cat8-/Adr1-mediated metabolic reprogramming, to enable pro-longevity characteristics, including redox homeostasis, stress resistance and maximal storage of carbohydrates. The activation of Cat8-/Adr1-dependent regulon also promotes the pyruvate dehydrogenase (PDH) bypass, leading to acetyl-CoA synthesis, global and targeted H3K9 acetylation. Global H3K9 acetylation levels mediated by Gcn5 and Hda1 during the transition into stationary phase are positively correlated with senescent cell populations accumulated in the aged cell cultures. These data suggest that Gcn5 lies in the centre of a feed-forward loop between histone acetylation and starvation-induced gene expression, enabling stress resistance and homeostasis but also promoting chronological ageing concomitantly.
与复制寿命相比，酵母中细胞时程寿命（CLS）的表观遗传调控了解较少。在这里，通过筛选所有组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）的可行突变体，我们证明了 Gcn5 在 SAGA/SLIK 复合物的 HAT 模块中发挥作用，与 HDAC Hda1 表现出上位关系，以控制饥饿诱导的应激反应和呼吸细胞生长的表达。令人惊讶的是，突变体在静止期早期失去其集落形成能力，但显示出比其 WT 对应物更长的最大 CLS，表明 Gcn5 在寿命调节中的矛盾作用。对转录组、代谢组和 ChIP 分析的综合分析表明，Gcn5 是葡萄糖饥饿后两个调控子激活所必需的：Msn2/4-/Gis1 依赖性应激反应和 Cat8-/Adr1 介导的代谢重编程，以实现延长寿命的特征，包括氧化还原平衡、应激抗性和碳水化合物的最大储存。Cat8-/Adr1 依赖性调控子的激活也促进了丙酮酸脱氢酶（PDH）旁路，导致乙酰辅酶 A 合成、全局和靶向 H3K9 乙酰化。在进入静止期的过程中，Gcn5 和 Hda1 介导的全局 H3K9 乙酰化水平与在老化细胞培养物中积累的衰老细胞群体呈正相关。这些数据表明，Gcn5 位于组蛋白乙酰化和饥饿诱导的基因表达之间的正反馈回路的中心，从而实现应激抗性和动态平衡，但同时也促进了细胞时程老化。
