Molecular mechanisms of cellular response to age-associated chromatin changes

细胞对年龄相关染色质变化反应的分子机制

• 批准号: 10635632
• 负责人: Weiwei Dang
• 金额: $ 33.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635632
• 关键词: Address; Affect; Age; Aging; Architecture; Biological Models; Cells; Cellular Stress; Chromatin; DNA Transposable Elements; Defect; Disease; Elements; Euchromatin; Event; Gene Silencing; Genes; Genetic; Genetic Transcription; Genome; Genomic approach; Heat Stress Disorders; Heterochromatin; Histones; Intervention; Knock-out; Lead; Link; Longevity; Longevity Pathway; Mediating; Metabolic; Metabolic Pathway; Modeling; Molecular; Molecular Conformation; Mothers; Names; Nucleosomes; Oxidative Stress; Pathway interactions; Physiological; Process; Regulation; Repetitive Sequence; Retrotransposition; Retrotransposon; Role; Series; Stress; Testing; Tissues; Yeasts; age related; aged; biological adaptation to stress; cell age; dosage; gene function; histone demethylase; histone modification; insight; mutant; novel; overexpression; oxidation; prevent; response; tool; transcription factor; transcriptomics

PROJECT SUMMARY Profound changes in chromatin occur in aged cells and tissues. These changes, such as altered histone modifications and chromatin conformation, lead to loss of heterochromatin, reduced nucleosome stability, and aberrant transcription, all of which have been causally linked to the aging process. Using yeast strains with reduced histone dosage, a model mimicking the situation of aged cells, we uncovered a cellular response to such chromatin defects, named chromatin architectural defects (CAD) response or simply chromatin stress response. Like cellular stress to heat and oxidation where moderate levels of stress can lead to hormesis, a beneficial effect, activating CAD response with moderate chromatin defects extends lifespan, offering a new intervention strategy to antagonize aging and age-related diseases. However, many mechanistic details of this response remain unexplored. This project will focus on these mechanistic questions. Does the CAD response directly mitigate age-associated chromatin changes and defects, such as disrupted heterochromatin, loss of transcription silencing and cryptic transcription? TOR inhibition is critical for the longevity effect of CAD response. How does the CAD response crosstalk with other TOR-related stress response pathways? In particular, does the CAD response interact with Isw2-regulated longevity-promoting stress responses? How does CAD response interact with metabolic changes? What are the regulators and effectors of CAD response? Importantly, how does the previously identified CAD response transcription factor Gis1 function to activate the transcriptional response? Addressing these questions pertaining to detailed molecular mechanisms will help characterize CAD response with molecular regulators and effectors, physiological effects to the cell, and relationships with other stress response and metabolic pathways. These mechanistic details will establish CAD response as a novel form of stress response with hormetic effects that promote longevity.

项目概要 衰老细胞和组织中染色质发生深刻变化。这些变化，例如组蛋白改变 修饰和染色质构象，导致异染色质丢失，核小体稳定性降低， 转录异常，所有这些都与衰老过程有因果关系。使用酵母菌株 减少组蛋白剂量，模拟衰老细胞情况的模型，我们发现了细胞反应 这种染色质缺陷，称为染色质结构缺陷 (CAD) 反应或简称为染色质应激 回复。就像细胞对热和氧化的应激一样，中等水平的应激会导致毒物兴奋效应， 有益效果，激活具有中度染色质缺陷的 CAD 反应，延长寿命，提供新的 对抗衰老和与年龄相关的疾病的干预策略。然而，这其中的许多机械细节 反应仍有待探索。该项目将重点关注这些机械问题。 CAD有反应吗 直接减轻与年龄相关的染色质变化和缺陷，例如异染色质破坏、染色质缺失 转录沉默和神秘转录？ TOR 抑制对于 CAD 反应的长期效果至关重要。 CAD 反应如何与其他 TOR 相关的应激反应途径相互干扰？特别是，是否 CAD 反应与 Isw2 调节的长寿应激反应相互作用吗？ CAD 如何响应 与代谢变化相互作用？ CAD响应的调节器和效应器是什么？重要的是，如何 先前确定的CAD反应转录因子Gis1有激活转录反应的功能吗？ 解决这些与详细分子机制相关的问题将有助于表征 CAD 反应 与分子调节器和效应器、对细胞的生理效应以及与其他应激的关系 反应和代谢途径。这些机械细节将使 CAD 响应成为一种新颖的形式 具有促进长寿的毒物兴奋效应的应激反应。