Mechanism and Function of Cardiac Transcriptional Repression Networks

摘要 先天性心脏病（CHD）仍然是最常见的先天性畸形。因此，我们认为， 了解心肌细胞形成的机制对于改善 结构性心脏病的后果。尽管在过去的几年里， 将这些研究放在控制心肌细胞分化的转录因子网络上， 主要集中在转录激活上。然而，人们越来越认识到， 转录抑制的改变也导致CHD。转录抑制涉及 不仅心脏转录因子，而且广泛表达的多蛋白机器， 修饰和重塑染色质。其中突出的是核小体重塑， 脱乙酰酶（NuRD）复合物。在这个建议中，我们解决了染色体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。临界 CHD4的性质通过导致CHD的Chd4中的突变而突出。的目标 目前的应用是检验CHD4与NuRD复合物一起起作用的中心假设 来调节心脏染色质结构。这将通过以下方式实现：1）确定CHD 4是否 既抑制又激活心脏基因表达。2)描述CHD4和NuRD是如何 被招募到心脏部位。3)确定人类Chd4错义突变如何导致心脏病 疾病

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.