Mechanisms of enhancer regulation in aging and age-related diseases

项目摘要/摘要 我的首要目标是理解三维(3D)增强器对衰老和与年龄相关的调节 疾病。衰老伴随着组织的功能衰退和许多 疾病。表观遗传改变是衰老的一个标志。有几条证据表明，组蛋白 衰老细胞中乙酰化水平升高，增强子格局在衰老过程中发生整体重塑 和衰老。然而，人们对三维(3D)增强剂的影响知之甚少 在衰老过程中，调节发生了变化。我的初步数据显示，许多增强剂与 聚集在一起形成大的集群，称为中枢。中枢中包含的促进剂和促进剂是不同的 在增殖和衰老之间。衰老特有的中枢确保了关键的转录程序 衰老的表型。然而，增强子中心如何改变对压力的反应以及机制和 这些改变的功能仍有待阐明。拟议研究的主要目标是揭示 不同应激源下增强子中心3D调控机制的研究 老龄化和老年相关疾病。我假设(1)在衰老过程中，关键的增强子聚集在一起 调节应激特定基因表达程序的中枢；(2)存在两条增强子调控途径 正常衰老：一种是细胞内源性衰老，另一种是环境炎症引起的细胞外源性衰老 加速内在途径的信号。在指导的K99阶段(目标1)，我将学习表观遗传学 衰老过程中3D增强子中心的调控机制(目标1a)及其在 不同类型的衰老(目标1b)。这些目标的实现将为我的独立奠定基础 老龄化和老年相关代谢紊乱的研究。在R00阶段(目标2)，在肝脏的自然老化中， 利用一种独特的小鼠模型，我将剖析肝细胞中内在的增强子调节途径和 受环境炎症信号刺激的外在途径。这将为以下目标提供潜在目标 在我的独立实验室未来的方向上改善与年龄相关的代谢紊乱。最终，拟议的 研究将揭示炎症和增强剂调节之间相互作用的新机制 并为年龄相关疾病提供新的治疗靶点。职业发展与培训 K99期组份将扩展我在衰老、新陈代谢和免疫学方面的经验，提供丰富的 为我成功过渡到独立的职业生涯奠定了基础。

PROJECT SUMMARY/ABSTRACT My overarching goal is to understand the three-dimensional (3D) enhancer regulation of aging and age-related diseases. Aging is accompanied by functional decline of tissues and an increased probability of many diseases. Epigenetic alteration is one hallmark of aging. Several lines of evidence demonstrate that histone acetylation levels elevate in senescent cells and global remodeling of the enhancer landscape occurs in aging and senescence. However, there is poor understanding of the influence of three-dimensional (3D) enhancer regulation changes during senescence. My preliminary data demonstrate that many enhancers connect together to form large clusters, termed hubs. The enhancers and promoters included in hubs are different between proliferation and senescence. The senescence-specific hubs ensure critical transcription programs for senescent phenotypes. However, how enhancer hubs change in response to stress and the mechanisms and functions of these alterations remain to be elucidated. The main goal of the proposed studies is to uncover mechanisms underlying the 3D regulation of enhancer hubs under different sources of stress during aging and age-related disease. I hypothesize that (1) during aging, key enhancers cluster together within hubs to regulate stress-specific gene expression programs; (2) two enhancer regulatory pathways exist during normal aging: one is cell intrinsic, and the other is cell extrinsic deriving from environmental inflammatory signals which accelerate the intrinsic pathway. In the mentored K99 phase (Aim 1), I will study epigenetic mechanisms regulating 3D enhancer hubs in senescence (Aim 1a) and test their generalization among different types of senescence (Aim 1b). Completion of these aims will set the stage for my independent research in aging and age-related metabolic disorder. In the R00 phase (Aim 2), in natural aging in liver, utilizing a unique mouse model, I will dissect the intrinsic enhancer regulatory pathway in hepatocytes and the extrinsic pathway stimulated by environmental inflammatory signals. This will provide potential targets to ameliorate age-related metabolic disorders in future direction of my independent lab. Ultimately, the proposed research will unveil new mechanisms underlying the interplay between inflammation and enhancer regulation in aging and provide novel therapeutic targets for age-related diseases. The career development and training components in K99 phase will expand my experience in aging, metabolism and immunology to provide a rich foundation for my successful transition to an independent career.