Molecular mechanisms of cellular response to age-associated chromatin changes

项目总结 在老化的细胞和组织中，染色质发生了深刻的变化。这些变化，如组蛋白的改变 修饰和染色质构象，导致异染色质丢失，降低核小体稳定性，以及 异常转录，所有这些都与衰老过程有因果关系。使用酵母菌和 减少组蛋白剂量，这是一个模拟衰老细胞情况的模型，我们发现了细胞对 这种染色质缺陷，称为染色质结构缺陷(CAD)反应或简称染色质应激 回应。就像细胞应激到高温和氧化一样，适度的应激可以导致兴奋，一种 有益效果，激活中度染色质缺陷的CAD反应可延长寿命，提供一种新的 对抗老龄化和老年相关疾病的干预策略。然而，这方面的许多机械细节 对此的回应仍未得到探索。这个项目将集中于这些机械性的问题。CAD是否会做出响应 直接减轻与年龄相关的染色质变化和缺陷，如异染色质中断、 转录沉默和隐秘转录？Tor抑制对于CAD反应的长寿效应至关重要。 CAD反应如何与其他与TOR相关的应激反应途径产生串扰？尤其是，是否 CAD反应与Isw2调节的促进长寿的应激反应相互作用？CAD如何应对 与新陈代谢变化相互作用？什么是CAD反应的调节者和效应者？重要的是，如何 先前发现的CAD反应转录因子Gis1是否具有激活转录反应的功能？ 解决这些与详细的分子机制有关的问题将有助于表征CAD的反应 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响应成为一种新的形式 具有刺激效应的应激反应，可延长寿命。

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.