Functions of CHD7 in regulating cardiogenesis

摘要： CHARGE综合征（眼缺损、心脏缺陷、胆囊闭锁、 生长/发育、生殖器异常和耳部异常）是一种严重的发育障碍， 多个器官先天性心脏病是CHARGE中最常见的出生缺陷之一， 影响了75%以上的患者。超过70%的CHARGE综合征病例是由单倍不足引起的 CHD 7是一种编码ATP依赖性染色质重塑因子的基因。我们项目的主要目标 揭示CHD 7在心脏发育过程中的功能，从而为心脏发育的机制提供见解。 CHD 7基因突变导致的出生缺陷。 我们最近发现CHD 7是SMADs 1、5和8的胚胎心脏相互作用伴侣 （SMADs 1/5/8），其是BMP受体激活的SMADs。我们进一步表明，CHD 7是必需的， 正常表达Nkx2.5，一种BMP信号下游的核心心源性转录因子。所以我们 这项研究提供了第一个证据，表明CHD 7是心源性基因的直接调节因子。目前 CHD 7在器官发生，包括心脏发育过程中的功能和分子活性， 难以捉摸，提出了一个主要的障碍，了解发育基础的出生缺陷，在充电 患者我们假设CHD 7调节关键心源性基因的表观遗传结构， 促进哺乳动物心脏的正常发育。提出了三个具体目标来检验这一假设。在 第一个目标，我们将揭示CHD 7在心肌细胞中的调控靶点网络， 心脏领域（SHF）。在第二个目标中，我们将研究CHD 7调节其表达的分子机制。 SHF衍生的心肌细胞中的靶基因/增强子。在第三个目标中，我们将测试遗传相互作用 Chd 7和BMP信号之间的联系 完成这项研究不仅将大大提高我们对组织的认识， CHD 7在发育中心脏的细胞和分子活动，也将为我们提供关键线索， 表观遗传调节因子如何与其他转录因子协调作用以促进正常器官发生 在哺乳动物中。从我们的研究中获得的信息对于理解这些机制将是非常宝贵的。 在CHARGE综合征患者中观察到的出生缺陷的基础。

Abstract: CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities and Ear anomalies) is a severe developmental disorder affecting multiple organs. Congenital heart diseases are among the most often observed birth defects in CHARGE, affecting >75% of patients. More than 70% of all CHARGE syndrome cases are caused by haploinsufficiency of CHD7, a gene that encodes an ATP-dependent chromatin remodeling factor. The major goal of our project is to reveal the functions of CHD7 during heart development and therefore provide mechanistic insights into the birth defects caused by mutations in CHD7. We recently identified CHD7 as an embryonic heart interaction partner of SMADs1, 5, and 8 (SMADs1/5/8), which are BMP receptor-activated SMADs. We further showed that CHD7 is required for normal expression of Nkx2.5, a core cardiogenic transcription factor downstream of BMP signaling. Thus, our study provided the first evidence suggesting CHD7 as a direct regulator of cardiogenic genes. Currently, the functions and molecular activities of CHD7 during organogenesis, including heart development, remain largely elusive, presenting a major barrier for understanding the developmental basis for the birth defects in CHARGE patients. We hypothesize that CHD7 regulates the epigenetic architecture of crucial cardiogenic genes to promote normal heart development in mammals. Three specific aims are proposed to test this hypothesis. In the first aim, we will reveal the regulatory target network of CHD7 in cardiomyocytes derived from the second heart field (SHF). In the second aim, we will examine the molecular mechanism by which CHD7 regulates its target genes/enhancers in SHF-derived cardiomyocytes. In the third aim, we will test the genetic interaction between Chd7 and BMP signaling. Accomplishing the proposed studies will not only greatly advance our knowledge of the tissular-, cellular- and molecular- activities of CHD7 in developing hearts, but also will provide us crucial clues regarding how an epigenetic regulator acts coordinately with other transcription factors to promote normal organogenesis in mammals. Information obtained from our research will be invaluable for understanding the mechanisms underlying the birth defects observed in CHARGE syndrome patients.