Project 3: Control of cardiac transcription by MEF2 and myocardin

项目3:MEF2和心肌素控制心脏转录

基本信息

  • 批准号:
    10006190
  • 负责人:
  • 金额:
    $ 51.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT PROJECT 3 Cardiovascular disease, including heart failure, is the most common cause of mortality in adults, and congenital heart defects are the most common form of birth defects in the US. An important concept that has emerged in recent years is that disruptions of cardiac transcription factor networks play important roles in congenital heart defects and in heart failure in adults. MEF2C is one of the core cardiac transcription factors and is required for cardiac development and for postnatal cardiac gene expression and homeostasis. MEF2C functions as signal responsive transcription factor that interacts with numerous co-regulator proteins to control gene expression, yet much remains to be determined about how MEF2C functions in the heart. The most potent transcriptional coactivator for MEF2C described to date is myocardin. MEF2C specifically interacts with a long isoform of myocardin (myocardin-935) to synergistically activate cardiac transcription. Preliminary studies identified a novel bridging mechanism whereby two myocardin-935 molecules interact with MEF2C and with each other via a leucine zipper (LZ) dimerization motif to cooperatively activate paired MEF2 sites, supporting a central role for myocardin dimerization for activation of MEF2-dependent cardiac genes. Furthermore, in silico analyses of cardiac enhancers suggests that paired MEF2 sites are prevalent and occur more frequently than predicted by chance specifically in cardiac enhancers. However, whether these enhancers are bona fide targets of the MEF2C-myocardin complex and how myocardin dimerization influences activity of these enhancers and gene expression in vivo remains to be determined. Additional, unpublished preliminary studies have identified a family with congenital heart defects likely caused by an in-frame microdeletion that results in loss of the myocardin LZ dimerization motif. Similarly, unpublished work shows that mice with an analogous deletion the leucine zipper domain of myocardin die with congenital heart defects. This project will test the hypothesis that the MEF2C-myocardin complex recruits a larger transcriptional coregulatory complex, which is influenced by upstream signaling and myocardin dimerization to regulate cardiac gene expression. To test this overall hypothesis, this project will define the interaction partners of MEF2C and myocardin in the embryonic and adult heart and will identify the phosphorylation sites and other modifications on MEF2C and myocardin. This will provide critical insight into the post-translational regulation of these key cardiac transcription factors. This project will also utilize RNA-seq, ChIP-seq, and other genome- wide approaches from embryos and endogenous tissues to identify transcriptional targets of the MEF2C- myocardin complex and will determine how myocardin dimerization influences the complex and downstream gene expression. Finally, this project will determine the requirement for myocardin dimerization for heart development in vivo by examining the lethal heart development phenotype in myocardin leucine zipper mutant mice and will identify gene expression changes associated with loss of myocardin dimerization.
项目总结/摘要 项目3 心血管疾病,包括心力衰竭,是成人死亡的最常见原因, 先天性心脏缺陷是美国最常见的出生缺陷。一个重要的概念, 心脏转录因子网络的破坏在心脏疾病中起重要作用, 先天性心脏病和成人心力衰竭。MEF 2C是心脏的核心转录因子之一 并且是心脏发育和出生后心脏基因表达和体内平衡所必需的。MEF2c 作为信号应答转录因子,与许多辅助调节蛋白相互作用, 基因表达,但仍有很多关于MEF 2C在心脏中的功能有待确定。最 迄今为止描述的MEF 2C的有效转录共激活因子是心肌素。MEF 2C特异性地与 心肌素的长同种型(心肌素-935)以协同激活心脏转录。初步 研究确定了一种新的桥接机制,其中两个心肌素-935分子与MEF 2C相互作用, 通过亮氨酸拉链(LZ)二聚化基序相互作用以协同激活成对的MEF 2位点, 支持心肌蛋白二聚化对MEF 2依赖性心脏基因激活的中心作用。 此外,对心脏增强子的计算机分析表明,成对的MEF 2位点是普遍存在的, 比偶然预测的更频繁,特别是在心脏增强剂中。然而,无论这些 增强子是MEF 2C-心肌素复合物的真正靶点,以及心肌素二聚化如何影响 这些增强子的活性和体内基因表达仍有待确定。其他,未发表 初步研究已经确定了一个先天性心脏缺陷的家庭, 微缺失导致心肌蛋白LZ二聚化基序的丢失。同样,未发表的研究表明, 具有类似缺失的小鼠(心肌蛋白亮氨酸拉链结构域)死于先天性心脏缺陷。 该项目将测试MEF 2C-心肌蛋白复合物招募更大的转录因子的假设。 共调节复合物,其受上游信号传导和心肌蛋白二聚化的影响以调节 心脏基因表达为了检验这一总体假设,本项目将定义 MEF 2C和myocardin在胚胎和成人心脏,并将确定磷酸化位点和其他 对MEF 2C和心肌素的修饰。这将为翻译后调控提供重要的见解 这些关键的心脏转录因子。该项目还将利用RNA-seq,ChIP-seq和其他基因组- 从胚胎和内源性组织中鉴定MEF 2C转录靶点的广泛方法- 心肌蛋白复合物,并将确定心肌蛋白二聚化如何影响复合物和下游 基因表达。最后,该项目将确定心脏对心肌蛋白二聚化的要求 通过检查心肌蛋白亮氨酸拉链突变体中致死心脏发育表型的体内发育 小鼠,并将鉴定与心肌蛋白二聚化丧失相关的基因表达变化。

项目成果

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Brian L Black其他文献

Brian L Black的其他文献

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{{ truncateString('Brian L Black', 18)}}的其他基金

Project 3: Control of cardiac transcription by MEF2 and myocardin
项目3:MEF2和心肌素控制心脏转录
  • 批准号:
    10471991
  • 财政年份:
    2019
  • 资助金额:
    $ 51.63万
  • 项目类别:
Project 3: Control of cardiac transcription by MEF2 and myocardin
项目3:MEF2和心肌素控制心脏转录
  • 批准号:
    10245031
  • 财政年份:
    2019
  • 资助金额:
    $ 51.63万
  • 项目类别:
NAVBO Workshops at Vascular Biology 2017
2017 年血管生物学 NAVBO 研讨会
  • 批准号:
    9331793
  • 财政年份:
    2017
  • 资助金额:
    $ 51.63万
  • 项目类别:
NAVBO Workshops at Vascular Biology 2014
2014 年血管生物学 NAVBO 研讨会
  • 批准号:
    8785754
  • 财政年份:
    2014
  • 资助金额:
    $ 51.63万
  • 项目类别:
Molecular and Genetic Regulation of Craniofacial Development
颅面发育的分子和遗传调控
  • 批准号:
    8499043
  • 财政年份:
    2009
  • 资助金额:
    $ 51.63万
  • 项目类别:
Molecular and Genetic Regulation of Craniofacial Development
颅面发育的分子和遗传调控
  • 批准号:
    7792319
  • 财政年份:
    2009
  • 资助金额:
    $ 51.63万
  • 项目类别:
Molecular and Genetic Regulation of Craniofacial Development
颅面发育的分子和遗传调控
  • 批准号:
    7938865
  • 财政年份:
    2009
  • 资助金额:
    $ 51.63万
  • 项目类别:
Molecular and Genetic Regulation of Craniofacial Development
颅面发育的分子和遗传调控
  • 批准号:
    8103255
  • 财政年份:
    2009
  • 资助金额:
    $ 51.63万
  • 项目类别:
Molecular and Genetic Regulation of Craniofacial Development
颅面发育的分子和遗传调控
  • 批准号:
    8291115
  • 财政年份:
    2009
  • 资助金额:
    $ 51.63万
  • 项目类别:
Regulation of cardiac gene expression by MEF2-Myocardin transcription complexes
MEF2-Myocardin 转录复合物对心脏基因表达的调节
  • 批准号:
    8590744
  • 财政年份:
    2008
  • 资助金额:
    $ 51.63万
  • 项目类别:

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