Linking Histone Modifications, HSF-1 activity and Lifespan

连接组蛋白修饰、HSF-1 活性和寿命

• 批准号: 10683390
• 负责人: Ursula H. Jakob
• 金额: $ 18.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683390
• 关键词: Adult; Affect; Age; Aging; Biological; Biological Assay; Biological Process; Biology; Biology of Aging; Biosensor; Caenorhabditis elegans; Cells; Climacteric; Communities; Complex; Data; Deposition; Development; Early identification; Embryo; Environment; Epigenetic Process; Eukaryota; Event; Future; Gene Expression; Genetic; Goals; HSF1; Heat shock factor; Heat-Shock Response; Histones; Imaging Device; Imaging Techniques; Individual; Individual Differences; Individuality; Larva; Life; Link; Longevity; Maternal Age; Methylation; Molecular; Monitor; Mothers; Motion; Oocytes; Organism; Outcome Study; Oxidation-Reduction; Physiological; Play; Population; Reactive Oxygen Species; Research; Resistance; Role; Sorting; Source; Stress; Testing; Time; Tissues; Variant; Work; experimental study; fascinate; follow-up; genetic makeup; healthspan; heat shock transcription factor; histone methylation; histone modification; imprint; insight; member; model organism; neuronal cell body; offspring; oxidation; sensor; spatiotemporal; tool

One of the most fascinating questions in the aging field is: Why do some organisms live longer than others? That lifespan variations are not solely based on the genetic makeup or the environment becomes clear when one studies isogenic organisms, such as Caenorhabditis elegans. Even when carefully age-synchronized and cultivated under uniform environmental conditions, the lifespan of individuals within a population of C. elegans varies several-fold. What causes this lifespan variation and when is the clock set? Our previous work demonstrated that individuals of a synchronized C. elegans population show high inter-individual differences in their levels of endogenous reactive oxygen species (ROS) during early development. Sorting of larval worms according to their endogenous redox states (i.e., oxidized vs. reduced) followed by longitudinal physiological and cell-biological assays revealed that larval worms that are more oxidized have significantly increased stress resistance, a more reduced redox state during adulthood and a longer lifespan. We found that this increase in stress resistance and lifespan is due to the ROS-dependent transient inactivation of Set2, a conserved member of the COMPASS complex, the complex which is responsible for the trimethylation of H3K4 (i.e., H3K4me3) in eukaryotes. To our knowledge, these studies not only provide the first demonstration of a redox- regulated histone methylation event in biology, but are the first to give mechanistic insights into how early life events can increase longevity. We will now investigate the mechanisms by which a decrease in H3K4me3 levels during development leads to increased stress resistance and extended lifespan. Our proposed studies are guided by preliminary results, which demonstrate a hitherto unknown link between the global reduction in H3K4me3 marks, and the increase in the levels and activity of the heat shock factor HSF1, one of the most conserved longevity factors known. We will exploit genetic tools in C. elegans to directly monitor the effects of H3K4me3 depletion on HSF1 synthesis, stability and turnover, and deplete H3K4me3 levels at defined time points and in specific tissues to reveal when, how and in what tissues the individuality in lifespan arises. To determine where developmental ROS variations come from, we will follow up on exciting preliminary data suggesting that the redox states in developing C. elegans larvae (and hence their lifespan) are inversely related to the age and redox state of the mother. These studies are likely to shed new mechanistic insights into the Lansing Effect, a long recognized but so far mostly descriptive phenomenon that describes the negative relationship between the maternal age and the lifespan of the offspring. The results of these studies will provide fundamentally new insights into the underlying mechanisms that lead to early life redox variations, and the subsequent events that delay aging.

衰老领域最令人着迷的问题之一是：为什么有些生物比其他生物活得更长？ 寿命的变化不仅仅是基于基因组成或环境， 一种研究同基因生物，如秀丽隐杆线虫。即使仔细的年龄同步， 在统一的环境条件下栽培，C. elegans 有好几倍的变化是什么导致了这种寿命的变化，时钟是什么时候设定的？我们以前的工作 证明了同步C.线虫种群在以下方面表现出很高的个体间差异： 内源性活性氧（ROS）的水平在早期发展。蠕虫分类 根据它们的内源氧化还原状态（即，氧化与还原），然后是纵向生理 细胞生物学分析显示，被氧化程度更高的幼虫压力显著增加， 电阻，在成年期更减少氧化还原状态和更长的寿命。我们发现， 胁迫抗性和寿命是由于Set 2的ROS依赖性瞬时失活，Set 2是一个保守的 COMPASS复合物的成员，该复合物负责H3 K4的三甲基化（即， H3K4me3）。据我们所知，这些研究不仅首次证明了氧化还原- 调节组蛋白甲基化事件在生物学中，但第一次给机制的见解，如何早期生命 事件可以延长寿命。我们现在将研究H3 K4 me 3减少的机制。 在发展过程中的水平导致增加的压力抵抗力和延长寿命。我们建议的研究 这些初步结果表明，全球温室气体排放量的减少与全球温室气体排放量的减少之间存在着迄今未知的联系， H3 K4 me 3标记，以及热休克因子HSF 1水平和活性的增加，这是最重要的因素之一。 已知的保守长寿因素。我们将利用C语言中的遗传工具。elegans直接监测的影响 H3 K4 me 3消耗对HSF 1合成、稳定性和周转的影响，并在规定时间消耗H3 K4 me 3水平 点和特定的组织，以揭示何时，如何和在什么组织中的个性在寿命产生。到 确定发育中的ROS变化来自哪里，我们将跟进令人兴奋的初步数据 表明C.线虫幼虫（以及它们的寿命）与 与母亲的年龄和氧化还原状态有关。这些研究很可能会揭示新的机制见解 兰辛效应，一个长期公认的，但迄今为止主要是描述性的现象，描述了 母亲年龄与后代寿命呈负相关。这些研究的结果 将为导致早期生命氧化还原变化的潜在机制提供全新的见解， 以及延迟衰老的后续事件。