Coordinated regulation of vascular smooth muscle phenotype by p300, CBP, and TET2

p300、CBP 和 TET2 对血管平滑肌表型的协调调节

基本信息

  • 批准号:
    10308706
  • 负责人:
  • 金额:
    $ 54.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-12-15 至 2024-10-31
  • 项目状态:
    已结题

项目摘要

Mature vascular smooth muscle cells (SMC) retain the ability to reversibly dedifferentiate and dramatically alter their phenotype in response to environmental cues. This plasticity allows for vascular repair and growth, but also contributes to cardiovascular pathologies including atherosclerosis, intimal hyperplasia, aneurysm, transplant arteriosclerosis, and others. Little is known about the epigenetic control of SMC phenotypic switching. We have recently identified TET2 as a novel master epigenetic regulator of SMC phenotype that promotes SMC differentiation and is downregulated in diseased vessels. TET2 promotes expression of key transcriptional drivers of SMC differentiation including myocardin and SRF while simultaneously inhibiting expression of KLF4, a transcription factor associated with dedifferentiation in SMC and pluripotency in stem cells. In addition to its known function of generating the epigenetic mark 5 hydroxymethylcytosine (5hmC), we have determined that TET2 also influences histone methylation, indicating that TET2 is involved in global chromatin remodeling in SMC. Others have shown association between TET2 and HDACs in hematopoietic cells. Our new preliminary data indicate a physical and functional association between TET2 and histone acetyltransferases (HATs). HATs acetylate histones in enhancer regions to promote cell type-specific gene expression. We have made the surprising observation that the HATs p300 and CBP, often considered to be interchangeable, have opposing roles in regulating SMC gene expression. We find that p300 is required to induce SMC differentiation in culture, while CBP is required for de-differentiation. Notably, these HATs also oppositely influence 5hmC at contractile promoters in SMC, and we detect a differentiation-dependent association between p300 and TET2. We hypothesize that p300 and CBP regulate distinct enhancers at contractile- and synthetic phenotype-specific genes, respectively, and are critical factors in SMC phenotypic switching. We further propose that TET2/p300 interactions may coordinately regulate chromatin conformation. The overall goal of this proposal is to identify the mechanisms by which p300, CBP, and TET coordinately regulate SMC phenotypic plasticity. We will employ state-of-the art molecular biology approaches, animal models, and advanced genomics techniques to address the central hypothesis that p300 and CBP regulate opposing programs of gene expression by acetylating distinct cis regulatory elements, and that HATs and TET2 work in concert to remodel chromatin during SMC phenotype modulation. Aim 1 will determine the mechanistic roles of p300 and CBP in SMC phenotypic modulation. Aim 2 will aim to define the opposing roles of p300 and CBP on vascular injury response in vivo. Aim 3 will determine how enhancers are regulated by p300, CBP, and TET2 using deletion approaches in vitro and in vivo. Collectively, these studies will lead to new understanding of SMC phenotypic modulation, which has potential for generating new preventive and therapeutic strategies for cardiovascular diseases.
成熟的血管平滑肌细胞(SMC)保留可逆去分化的能力,并显着改变 它们的表型对环境的反应。这种可塑性允许血管修复和生长,但也 导致心血管病变,包括动脉粥样硬化、内膜增生、动脉瘤、移植 动脉硬化等。关于SMC表型转换的表观遗传控制知之甚少。我们有 最近发现TET 2是一种新的SMC表型的主要表观遗传调节因子, 分化,并在患病血管中下调。TET 2促进关键转录因子的表达 SMC分化的驱动因子,包括心肌蛋白和SRF,同时抑制KLF 4的表达, 一种与SMC去分化和干细胞多能性相关的转录因子。除了其 已知产生表观遗传标记5羟甲基胞嘧啶(5 hmC)的功能,我们已经确定, TET 2还影响组蛋白甲基化,表明TET 2参与了细胞的整体染色质重塑。 SMC。其他人已经显示TET 2和造血细胞中的HDAC之间的关联。我们新的初步调查 数据表明TET 2和组蛋白乙酰转移酶(HAT)之间的物理和功能关联。帽子 乙酰化增强子区域中的组蛋白以促进细胞类型特异性基因表达。我以黑夜做 令人惊讶的观察是,HAT p300和CBP通常被认为是可以互换的,但它们却相反 调节SMC基因表达的作用。我们发现p300是诱导培养SMC分化所必需的, 而CBP是去分化所必需的。值得注意的是,这些HAT也相反地影响收缩时的5 hmC。 启动子SMC,我们检测到p300和TET 2之间的分化依赖性协会。我们 假设p300和CBP在收缩和合成表型特异性上调节不同增强子 基因,分别是SMC表型转换的关键因素。我们进一步建议TET 2/p300 相互作用可以协调调节染色质构象。本提案的总体目标是确定 p300、CBP和泰特协同调节SMC表型可塑性的机制。我们将 采用最先进的分子生物学方法、动物模型和先进的基因组学技术, 解决了中心假设,即p300和CBP调节基因表达的相反程序, 乙酰化不同的顺式调节元件,并且HAT和TET 2协同工作以在细胞周期中重塑染色质。 SMC表型调节。目的1探讨p300和CBP在平滑肌细胞表型分化中的作用机制。 调变目的2旨在确定p300和CBP在体内血管损伤反应中的相反作用。 目的3将确定如何增强调控p300,CBP,和TET 2在体外缺失的方法 和体内。总的来说,这些研究将导致对SMC表型调节的新理解, 为心血管疾病产生新的预防和治疗策略的潜力。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hippo and Hyperplasia.
河马和增生。
  • DOI:
    10.1161/circresaha.119.314968
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    Ostriker,AllisonC;Martin,KathleenA
  • 通讯作者:
    Martin,KathleenA
TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.
  • DOI:
    10.1161/circulationaha.120.050553
  • 发表时间:
    2021-08-10
  • 期刊:
  • 影响因子:
    37.8
  • 作者:
    Ostriker AC;Xie Y;Chakraborty R;Sizer AJ;Bai Y;Ding M;Song WL;Huttner A;Hwa J;Martin KA
  • 通讯作者:
    Martin KA
TCF21: Flipping the Phenotypic Switch in SMC.
  • DOI:
    10.1161/circresaha.120.316533
  • 发表时间:
    2020-02
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    Yi Xie;K. Martin
  • 通讯作者:
    Yi Xie;K. Martin
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PATRICK G GALLAGHER其他文献

PATRICK G GALLAGHER的其他文献

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{{ truncateString('PATRICK G GALLAGHER', 18)}}的其他基金

Novel Mechanisms of Congenital Dyserythropoietic Anemia
先天性红细胞生成不良性贫血的新机制
  • 批准号:
    10454333
  • 财政年份:
    2020
  • 资助金额:
    $ 54.85万
  • 项目类别:
Novel Mechanisms of Congenital Dyserythropoietic Anemia
先天性红细胞生成不良性贫血的新机制
  • 批准号:
    9887377
  • 财政年份:
    2020
  • 资助金额:
    $ 54.85万
  • 项目类别:
Novel Mechanisms of Congenital Dyserythropoietic Anemia
先天性红细胞生成不良性贫血的新机制
  • 批准号:
    10192709
  • 财政年份:
    2020
  • 资助金额:
    $ 54.85万
  • 项目类别:
Nonenzymatic Gene Editing in Treatment of Heredity Spherocytosis
非酶基因编辑治疗遗传性球形红细胞增多症
  • 批准号:
    10305603
  • 财政年份:
    2019
  • 资助金额:
    $ 54.85万
  • 项目类别:
Responsiveness and non-responsiveness to transfused RBCs in mice and humans.
小鼠和人类对输注红细胞的反应性和无反应性。
  • 批准号:
    9918440
  • 财政年份:
    2017
  • 资助金额:
    $ 54.85万
  • 项目类别:
Yale Cooperative Center of Excellence in Hematology
耶鲁大学血液学卓越合作中心
  • 批准号:
    10454355
  • 财政年份:
    2015
  • 资助金额:
    $ 54.85万
  • 项目类别:
Yale Cooperative Hematology Specialized Core Center
耶鲁大学合作血液学专业核心中心
  • 批准号:
    9987207
  • 财政年份:
    2015
  • 资助金额:
    $ 54.85万
  • 项目类别:
Yale Cooperative Center of Excellence in Hematology
耶鲁大学血液学卓越合作中心
  • 批准号:
    10249339
  • 财政年份:
    2015
  • 资助金额:
    $ 54.85万
  • 项目类别:
Yale Cooperative Hematology Specialized Core Center
耶鲁大学合作血液学专业核心中心
  • 批准号:
    8972977
  • 财政年份:
    2015
  • 资助金额:
    $ 54.85万
  • 项目类别:
Yale Cooperative Hematology Specialized Core Center
耶鲁大学合作血液学专业核心中心
  • 批准号:
    9325318
  • 财政年份:
    2015
  • 资助金额:
    $ 54.85万
  • 项目类别:

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