Mechanisms of enhancer regulation in aging and age-related diseases

项目概要/摘要 我的首要目标是了解衰老和年龄相关的三维（3D）增强剂调节。 疾病衰老伴随着组织的功能衰退和许多组织功能衰退的可能性增加。 疾病表观遗传改变是衰老的一个标志。有几条证据表明， 乙酰化水平在衰老细胞中升高，增强子景观的整体重塑在衰老中发生 和衰老。然而，人们对三维（3D）增强剂的影响了解甚少 衰老过程中的调节变化。我的初步数据表明，许多增强子连接 一起形成大型集群，称为枢纽。集线器中包含的增强子和启动子是不同的 在增殖和衰老之间。衰老特异性枢纽确保关键转录程序， 衰老表型然而，增强子中枢如何响应压力而改变，以及增强子中枢的机制和作用机制。 这些改变的功能仍有待阐明。这项研究的主要目的是揭示 在不同的压力来源下，增强子中心的3D调节机制 衰老和与年龄有关的疾病。我假设（1）在衰老过程中，关键增强子聚集在一起， 枢纽调节胁迫特异性基因表达程序;（2）两个增强子调控途径存在期间 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K99阶段（目标1），我将研究表观遗传学 机制调节衰老中的3D增强子枢纽（Aim 1a），并测试它们在 不同类型的衰老（目标1b）。这些目标的实现将为我的独立工作奠定基础。 研究衰老和与年龄相关的代谢紊乱。在R 00阶段（目标2），在肝脏的自然老化中， 利用一个独特的小鼠模型，我将剖析肝细胞中的内在增强子调节途径， 由环境炎症信号刺激的外源性途径。这将提供潜在的目标， 改善与年龄相关的代谢紊乱是我独立实验室的未来方向。最后，建议 研究将揭示炎症和增强子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。职业发展和培训 K99阶段的成分将扩大我在衰老，代谢和免疫学方面的经验， 这是我成功过渡到独立职业的基础。

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.