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：
10688188
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/10688188
关键词：
Address Adult Architecture Atrial Heart Septal Defects Binding Binding Sites Biochemical Bioinformatics Biological Assay CHD4 gene Cardiac Cardiac Myocytes 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 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 Repression Role Structural Congenital Anomalies System Testing Tissues Transcription Repressor Transcriptional Activation Ventricular Ventricular Septal Defects 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畸形。所以，获得对心肌细胞形成机制的理解对于改善心肌细胞形成至关重要结构性心脏病的结果。尽管过去几年人们非常重视这些研究放在控制心肌细胞分化的转录因子网络上主要关注转录激活。然而，人们越来越认识到转录抑制的改变也会导致冠心病。转录抑制涉及不仅是心脏转录因子，而且还广泛表达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酶 (NuRD) 复合物。在这个提案中，我们讨论了染色质结构域解旋酶的作用 DNA 结合蛋白 4 (CHD4)，NuRD 复合物的催化核心成分。关键的 Chd4 突变导致 CHD，凸显了 CHD4 的本质。的目标目前的应用是测试 CHD4 与 NuRD 复合体一起发挥作用的中心假设调节心脏染色质结构。这将通过以下方式实现： 1) 确定 CHD4 是否既抑制又激活心脏基因表达。 2) 描述CHD4和NuRD如何招募到心脏基因座。 3) 确定人类 Chd4 错义突变如何导致心脏病疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CHD4 is recruited by GATA4 and NKX2-5 to repress noncardiac gene programs in the developing heart.

CHD4 被 GATA4 和 NKX2-5 招募来抑制发育中的心脏中的非心脏基因程序。

DOI：
发表时间：
2022-04-01
期刊：
影响因子：
10.5
作者：
Robbe, Zachary L;Shi, Wei;Wasson, Lauren K;Scialdone, Angel P;Wilczewski, Caralynn M;Sheng, Xinlei;Hepperla, Austin J;Akerberg, Brynn N;Pu, William T;Cristea, Ileana M;Davis, Ian J;Conlon, Frank L
通讯作者：
Conlon, Frank L

Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1.

人类 CHD4 的错义突变通过抑制 ADAMTS1 导致心室致密化不全。

DOI：
发表时间：
2023-06-23
期刊：
影响因子：
20.1
作者：
Shi, Wei;Scialdone, Angel P;Emerson, James I;Mei, Liu;Wasson, Lauren K;Davies, Haley A;Seidman, Christine E;Seidman, Jonathan G;Cook, Jeanette G;Conlon, Frank L
通讯作者：
Conlon, Frank L

Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation.

心脏蛋白质组学揭示了男性和女性之间在性腺形成之前出现的性染色体依赖性差异。

DOI：
10.1016/j.devcel.2021.09.022
发表时间：
2021-11-08
期刊：
Developmental cell
影响因子：
11.8
作者：
Shi, Wei;Sheng, Xinlei;Dorr, Kerry M.;Hutton, Josiah E.;Emerson, James, I;Davies, Haley A.;Andrade, Tia D.;Wasson, Lauren K.;Greco, Todd M.;Hashimoto, Yutaka;Federspiel, Joel D.;Robbe, Zachary L.;Chen, Xuqi;Arnold, Arthur P.;Cristea, Ileana M.;Conlon, Frank L.
通讯作者：
Conlon, Frank L.