Mechanism and Function of Cardiac Transcriptional Repression Networks

心脏转录抑制网络的机制和功能

基本信息

批准号：
10452617
负责人：
Frank Leo Conlon
金额：
$ 53.67万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-16 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10452617
关键词：
Address Adult Architecture Binding Binding Sites Biochemical Bioinformatics Biological Assay CHD4 gene Cardiac Cardiac Myocytes Cardiac development Catalytic Domain Cell Nucleus Chromatin Chromatin Remodeling Factor Clustered Regularly Interspaced Short Palindromic Repeats Complex Congenital Abnormality DNA Binding Deacetylase Defect Disease Embryo GATA4 gene Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Goals Health Heart Heart Atrium Heart Diseases Homeostasis Human Infant Mortality Lead Mass Spectrum Analysis Missense Mutation Modeling Mus Muscle Mutant Strains Mice Mutation Nature Nucleosomes Pathway interactions Patients Phenotype Proteins Reagent Role Structural Congenital Anomalies System Testing Tissues Transcription Repressor Transcriptional Activation Ventricular Ventricular Septal Defects base cardiogenesis cell type chromatin remodeling cohort congenital heart disorder gene repression genomic locus heart function histone methyltransferase improved improved outcome in vivo insight member mouse model mutant null mutation proband protein complex protein function recruit structural heart disease transcription factor transcriptomics ventricular hypertrophy

项目摘要

Abstract Congenital heart disease (CHD) remains the most common congenital malformation. Therefore, attaining a mechanistic understanding of cardiomyocyte formation is crucial for improving outcomes to structural heart disease. Though much emphasis in the last few years has been placed on transcription factor networks that control cardiomyocyte differentiation, these studies have mainly focused on transcriptional activation. However, there is growing recognition that alterations in transcriptional repression also lead to CHDs. Transcriptional repression involves not only cardiac transcription factors but also broadly expressed multiprotein machines that modify and remodel chromatin. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex. In this proposal we address the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic core component of the NuRD complex. The critical nature of CHD4 is highlighted by mutations in Chd4 being causative to CHDs. The goal of the current application is to test the central hypothesis that CHD4 functions with the NuRD complex to regulate cardiac chromatin architecture. This will be achieved by: 1) Determine whether CHD4 both represses and activates cardiac gene expression. 2) Delineate how CHD4 and NuRD are recruited to cardiac loci. 3) Establish how the human Chd4 missense mutations lead to cardiac disease.

抽象的先天性心脏病（CHD）仍然是最常见的先天性畸形。所以，对心肌细胞形成的机械理解对于改善至关重要结构性心脏病的结果。尽管最近几年的重点是这些研究放置在控制心肌细胞分化的转录因子网络上主要集中于转录激活。但是，人们越来越认识到转录抑制的改变也导致了CHD。转录抑制涉及不仅心脏转录因子，而且还广泛表达了多蛋白机器修饰和重塑染色质。其中突出的是核小体重塑和脱乙酰基酶（NURD）复合物。在此提案中，我们解决了染色体构酶解旋酶的作用 DNA结合蛋白4（CHD4），NURD复合物的催化核心成分。关键 CHD4的突变强调了CHD4对CHD的原因。目标的目标当前的应用是测试CHD4与NURD复合物一起发挥作用的中心假设调节心脏染色质结构。这将通过：1）确定是否CHD4 抑制和激活心脏基因表达。 2）描述CHD4和Nurd的样子招募到心脏基因座。 3）确定人类CHD4错义突变如何导致心脏疾病。