Combinatorial regulation of the enhancer codes in senescence

衰老过程中增强子密码的组合调控

• 批准号: 10152492
• 负责人: MICHAEL G ROSENFELD
• 金额: $ 54.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152492
• 关键词: Activins; Address; Aging; Appearance; Area; Binding; Biology; CRISPR interference; Cell Aging; Cells; Code; DNA Binding; Data; Development; Enhancers; Event; Feedback; Genetic Transcription; Genomics; Goals; Growth Factor; Homeostasis; In Vitro; Knowledge; Laboratories; Licensing; MADH2 gene; Modality; Molecular; Motion; Outcome Study; Pathologic; Pathology; Peptide Hydrolases; Phenotype; Process; Production; Regulation; Research; Response Elements; Role; Seminal; Series; Signal Pathway; Signal Transduction; Sirolimus; Testing; Withdrawal; Work; activating transcription factor; base; cell growth regulation; cell type; chemokine; chromatin remodeling; cohort; combinatorial; cytokine; epigenomics; healthy aging; histone modification; in vivo; inhibitor/antagonist; insight; mTOR Inhibitor; novel; novel therapeutics; outcome prediction; programs; response; screening; senescence; transcription factor

Abstract Based on the importance of defining new insights into cellular senescence, we initiated studies to investigate whether there might be a specific enhancer activation “code” that underlies cellular senescence for identifying the responsible DNA binding transcription factors. While there is rapidly-emerging, and now unassailable evidence, on the role of the 40-70,000 enhancers in each cell type in development, homeostasis and, often, pathological events, their role in cellular senescence remains undefined. Furthermore, while cellular senescence represents a fundamental process of aging and a known driver of pathologies, the causative role of newly activated enhancer cohorts underlying progression of senescence remain poorly understood. Therefore, the goal of this proposal, supported by extensive preliminary data, is to test a novel hypothesis that the de novo appearance of two specific cohorts of enhancers sets into motion a progressive, functionally- important, alteration in gene transcription programs. Based on our study of the altered enhancer and chromosomal landscape during replicative senescence, we have begun to establish that the geroprotective mTOR inhibitor, Rapamycin, markedly delays all aspects of cellular senescence, including the appearance of new, functional, enhancers. Our focus is to elucidate the functional importance of a gained enhancer program underlying cellular senescence, and identify the critical DNA binding transcription factors underlying the transcriptional programs that are determinants of replicative senescence, based on the complementary expertise of the Suh and Rosenfeld laboratories. Specifically: i) We will use unbiased screens to document that at least two distinct activated enhancer networks independently regulate the proliferation arrest and SASP aspects of replicative senescence, respectively. ii) We will identify combinatorial factors synergizing with the previously-unrecognized transcription factors, NFI-A, NFI-C, to regulate the gained enhancers underling proliferation arrest, and those that, with SMAD2/3 and NFkB, to regulate the SASP program. In parallel, we can implicate the underlying signaling pathways. iii) We will identify previously unrecognized histone modification signatures of, and their functional importance in replicative senescence . iv) We will Identify Activin and Tgf2 as inhibitors of the proliferation and SASP enhancer programs, respectively. Our proposal promises to provide transformative insights into molecular events that initiate and perpetuate the senescent cell phenotypes, and help elucidate potential novel therapeutic modalities against the deleterious SASP program.

抽象的 基于将新见解定义到细胞感应的重要性，我们开始研究以研究 是否可能存在特定的增强子激活“代码”，其基础是细胞感应的基础 识别负责任的DNA结合转录因子。虽然有迅速的出现，现在 不可避免的证据，关于每种细胞类型中40-70,000个增强子在开发中的作用，体内平衡 而且，通常是病理事件，它们在细胞感应中的作用仍然不确定。此外，而细胞 感应代表了衰老的基本过程和已知的病理驱动力，这是病原体的作用 新近激活的增强子同类群的感应进展仍然很少了解。所以， 该提案的目的在广泛的初步数据的支持下，是为了检验一个新的假设。 两种特定组的增强子组的Novo出现，将运动渐进性，在功能上 - 重要的是，基因转录程序的改变。基于我们对改变的增强剂和 复制感应期间，我们已经开始确定凝胶保护层 mTOR抑制剂雷帕霉素显着延迟了细胞感应的所有方面，包括外观 新的，功能的增强剂。我们的重点是阐明获得的增强程序计划的功能重要性 潜在的细胞感应，并确定临界DNA结合转录因子 基于完整的专业知识，确定复制感应的转录程序 Suh和Rosenfeld实验室的工作。具体：i）我们将使用公正的屏幕来记录至少 两个独特的激活增强子网络独立调节扩散逮捕和SASP方面 分别复制感应。 ii）我们将确定与 以前未认可的转录因子NFI-A，NFI-C调节获得的增强子 扩散逮捕，以及与SMAD2/3和NFKB一起规范SASP计划的人。并行，我们 可以实现基础信号通路。 iii）我们将识别先前未识别的组蛋白 修改签名及其在复制感应中的功能重要性。 iv）我们将确定 激活素和TGF2分别作为增殖和SASP增强剂程序的抑制剂。我们的建议 有望提供对启动和永久启动的分子事件的变革性见解 表型，有助于阐明潜在的新型热模式，以针对有害的SASP程序。