Combinatorial regulation of the enhancer codes in senescence

衰老过程中增强子密码的组合调控

基本信息

项目摘要

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.
摘要

项目成果

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MICHAEL G ROSENFELD其他文献

MICHAEL G ROSENFELD的其他文献

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{{ truncateString('MICHAEL G ROSENFELD', 18)}}的其他基金

Viral IncRNAs Regulate Host Genomic Transcriptional Programs Associated with Sporadic Alzheimer's Disease
病毒 IncRNA 调节与散发性阿尔茨海默病相关的宿主基因组转录程序
  • 批准号:
    10446865
  • 财政年份:
    2022
  • 资助金额:
    $ 54.59万
  • 项目类别:
Viral IncRNAs Regulate Host Genomic Transcriptional Programs Associated with Sporadic Alzheimer's Disease
病毒 IncRNA 调节与散发性阿尔茨海默病相关的宿主基因组转录程序
  • 批准号:
    10650398
  • 财政年份:
    2022
  • 资助金额:
    $ 54.59万
  • 项目类别:
Revealing the roles of HSV1 lytic and latent transcripts in AD pathogenesis and therapy
揭示 HSV1 裂解转录物和潜伏转录物在 AD 发病机制和治疗中的作用
  • 批准号:
    10621810
  • 财政年份:
    2021
  • 资助金额:
    $ 54.59万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10441547
  • 财政年份:
    2020
  • 资助金额:
    $ 54.59万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10646190
  • 财政年份:
    2020
  • 资助金额:
    $ 54.59万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10264170
  • 财政年份:
    2020
  • 资助金额:
    $ 54.59万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10091772
  • 财政年份:
    2020
  • 资助金额:
    $ 54.59万
  • 项目类别:
A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction
心肌细胞中应激诱导的启动子暂停释放程序可预防心肌梗死
  • 批准号:
    10521252
  • 财政年份:
    2019
  • 资助金额:
    $ 54.59万
  • 项目类别:
A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction
心肌细胞中应激诱导的启动子暂停释放程序可预防心肌梗死
  • 批准号:
    10318093
  • 财政年份:
    2019
  • 资助金额:
    $ 54.59万
  • 项目类别:
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:
    10017129
  • 财政年份:
    2019
  • 资助金额:
    $ 54.59万
  • 项目类别:

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