Cardiac interaction networks as determinants of transcriptional specificity

心脏相互作用网络作为转录特异性的决定因素

• 批准号: 10159116
• 负责人: Frank Leo Conlon
• 金额: $ 54.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159116
• 关键词: Address; Atrial Heart Septal Defects; Binding Sites; Biochemical; Cardiac; Cardiac Myocytes; Cardiac development; Complex; Congenital Abnormality; Conserved Sequence; Coupled; Data; Deacetylase; Disease; Ectopic Expression; Embryo; Europe; Fibroblasts; GATA4 gene; Genes; Genetic; Genetic Transcription; Heart; Heart Abnormalities; Heart Septal Defects; Holt Oram syndrome; Homeostasis; Human; Infant Mortality; Lead; Molecular; Mus; Mutation; Nucleic Acid Regulatory Sequences; Nucleosomes; Pattern; Phase; Proteins; Proteomics; Repression; Role; Set protein; Specificity; Structural Congenital Anomalies; System; Testing; Time; Tissues; Transcription Coactivator; Transcriptional Regulation; Work; base; cardiogenesis; cell type; congenital heart disorder; gene repression; genetic corepressor; human disease; in vivo; insight; liquid chromatography mass spectrometry; novel; programs; protein complex; protein function; septal defect; transcription factor

ABSTRACT Congenital malformations, or structural birth defects, are now the leading cause of infant mortality in the US and Europe. Of the congenital malformations, congenital heart disease (CHD) is the most common. Mutations in the T-box transcription factor TBX5 have been found to be causative to a range of human cardiac abnormalities including Tetrology of Fallot and Holt Oram Syndrome (HOS), disease states associated associated with cardiac septal defects. While TBX5 is an essential transcription factor for heart development and its disease relevance is well established, there are many critical questions unanswered about the mechanism of how TBX5 functions. We do not understand what proteins complex with TBX5 during different stages of cardiac development and homeostasis, how these interactions regulate TBX5's choice of distinct transcriptional targets at different times, or how these interactions function to activate and/or repress target gene transcription. To this end, our labs recently initiated a directed proteomic-based approach to identify proteins that function in association with TBX5. These studies demonstrate TBX5 interacts with the transcriptional repression machinery of the Nucleosome Remodeling and Deacetylase (NuRD) complex. We further demonstrated that TBX5 human disease mutations disrupt this interaction, leading to ectopic expression of non-cardiac genes normally repressed by TBX5 and septal defects associated with Holt Oram syndrome. Collectively, this work led to the central hypothesis that TBX5 function and thus its suites of target genes are regulated during cardiac development through changes in the components of the TBX5 interactome. To address this hypothesis, we will used an integrated systems based approach to determine the mechanisms by which Tbx5 regulates distinct gene programs in the heart by defining the endogenous cardiac TBX5 transcriptional complexes, establish the mechanisms of TBX5 repression and activation and by determining the potential role of co-factors in TBX5 transcriptional regulation.

抽象的 先天性畸形或结构性先天缺陷现在是婴儿死亡率的主要原因 美国和欧洲。在先天性畸形中，先天性心脏病（CHD）是最大的 常见的。 T-box转录因子TBX5中的突变对A是病因 人类心脏异常范围包括法洛和霍尔特·奥兰综合征（HOS）的术语， 与心脏间隔缺陷相关的疾病状态。而TBX5是必不可少的 心脏发育及其疾病相关性的转录因子已经确定了 关于TBX5如何运作的机制，许多关键的问题都没有得到解决。我们没有 了解心脏发育不同阶段中与TBX5的蛋白质​​复合物以及 稳态，这些相互作用如何调节TBX5选择不同的转录目标 不同的时间，或这些相互作用如何激活和/或抑制靶基因转录。 为此，我们的实验室最近启动了一种基于蛋白质组学的方法，以识别蛋白质 与TBX5相关的功能。这些研究表明TBX5与转录相互作用 核小体重塑和脱乙酰基酶（NURD）复合物的抑制机制。我们进一步 证明TBX5人类疾病突变破坏了这种相互作用，导致异位 通常被TBX5抑制的非心脏基因的表达和与Holt相关的中间缺陷的表达 奥兰综合征。总的来说，这项工作导致了一个中心假设，即TBX5功能及其。 靶基因的套件在心脏发育过程中通过变化在心脏发展过程中受到调节 TBX5相互作用。为了解决这一假设，我们将使用基于集成的系统的 确定TBX5调节心脏不同基因程序的机制的方法 通过定义内源性心脏TBX5转录复合物，建立机制 TBX5抑制和激活，并通过确定副因素在TBX5中的潜在作用 转录调节。