Functions of CHD7 in regulating cardiogenesis

摘要： Charge综合征(眼缺损、心脏缺陷、后鼻孔闭锁、发育迟缓 生长/发育、生殖器异常和耳朵异常)是一种严重的发育障碍，影响 多个器官。先天性心脏病是最常见的出生缺陷之一， 影响了75%的患者。超过70%的充电综合征病例是由单倍体功能不全引起的 CHD7基因，编码一种依赖于ATP的染色质重塑因子。我们项目的主要目标是 揭示CHD7在心脏发育过程中的作用，从而提供对CHD7在心脏发育过程中 CHD7基因突变导致的出生缺陷。 我们最近确定CHD7是SMADs1、5和8的胚胎心脏相互作用伙伴 (SMADs1/5/8)，它们是BMP受体激活的Smad。我们进一步表明，CHD7是 BMP信号下游的核心生心转录因子NKX2.5的正常表达。因此，我们的 研究提供了第一个证据，表明CHD7是心脏基因的直接调节者。目前， CHD7在器官发生过程中的功能和分子活性，包括心脏发育，在很大程度上仍然存在 难以捉摸，这是理解主管出生缺陷的发育基础的主要障碍 病人。我们假设CHD7调节关键致心基因的表观遗传结构，以 促进哺乳动物心脏的正常发育。为了检验这一假说，本文提出了三个具体目标。在……里面 第一个目标，我们将揭示CHD7在心肌细胞中的调控靶点网络，第二个目标是 心场(SHF)。在第二个目标中，我们将研究CHD7调节其 SHF来源的心肌细胞的靶基因/增强子。在第三个目标中，我们将测试遗传交互作用 CHD7和BMP信号之间。 完成拟议的研究不仅将极大地提高我们对组织的认识-- CHD7在心脏发育过程中的细胞和分子活性，也将为我们提供关于 表观遗传调控因子如何与其他转录因子协同作用促进正常器官发生 在哺乳动物身上。从我们的研究中获得的信息对于理解这些机制将是无价的。 在Charge综合征患者中观察到的出生缺陷的潜在原因。

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.