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.

项目摘要 染色质的深刻变化发生在老化的细胞和组织中。这些变化，例如改变组蛋白 修饰和染色质构象，导致异染色质的丧失，核小体稳定性降低和 异常转录，所有这些都与衰老过程有因果关系。使用酵母菌菌株与 减少组蛋白剂量，一种模仿老化细胞状况的模型，我们发现了细胞的反应 这种染色质缺陷，命名为染色质结构缺陷（CAD）反应或简单的染色质应激 回复。像细胞应力对热量和氧化，中等压力会导致荷尔特的氧化，a 有益的效果，用中等染色质缺陷激活CAD响应会延长寿命，提供新的寿命 干预策略与衰老和与年龄有关的疾病对抗。但是，许多机械细节 响应仍未开发。该项目将重点放在这些机械问题上。 CAD响应吗 直接减轻与年龄相关的染色质变化和缺陷，例如杂染色质中断，丧失 转录沉默和神秘转录？ TOR抑制对于CAD反应的寿命效应至关重要。 CAD响应如何与其他与TOR相关的应力反应途径串扰？特别是 CAD响应与ISW2调节的寿命促进应力反应相互作用？ CAD如何响应 与代谢变化相互作用？ CAD响应的调节器和效应因素是什么？重要的是，如何 先前鉴定的CAD响应转录因子GIS1功能激活转录响应？ 解决与详细分子机制有关的这些问题将有助于表征CAD响应 使用分子调节剂和效应子，对细胞的生理效应，以及与其他压力的关系 反应和代谢途径。这些机械细节将建立CAD响应作为一种新颖的形式 压力反应伴随着促进寿命的刺激性效应。