Critical roles of CHD7 during mouse 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Charge综合征的主要临床特征，影响75% 病人的数量。超过70%的电荷病例是由CHD7单倍体不足引起的，CHD7是一种 编码一种依赖于ATP的染色质重塑因子。这个项目的主要目标是揭示 CHD7在心脏发育过程中的作用，因此提供了对出生缺陷的机械性见解 由CHD7基因突变引起。 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 这项研究首次证明CHD7是心脏基因的直接表观遗传调节因子。 目前，CHD7在心脏发育中的功能和分子活性在很大程度上仍然难以捉摸。 为理解心脏缺陷的发育基础提供了一个主要障碍 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，本文提出了两个具体目标。在 第一个目标，我们将揭示CHD7在第二心脏来源的心肌细胞中的调控靶点网络 FIELD(SHF)，并检查CHD7是如何具体加载到其目标站点的。在第二个目标中，我们将测试 CHD7在募集组蛋白甲基转移酶促进组蛋白H3赖氨酸4甲基化中的作用 相关的增强剂。 完成拟议的研究不仅将极大地提高我们对组织的认识-- CHD7在发育心脏中的细胞和分子活性，但也将为我们提供关键线索 关于表观遗传调节因子如何与其他遗传/表观遗传调节因子协调作用以促进 哺乳动物的正常心脏生成。从我们的研究中获得的信息将对理解 在Charge综合征患者中观察到的心脏缺陷的潜在机制。

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 major clinical features of CHARGE syndrome, affecting >75% of patients. More than 70% of all CHARGE cases are caused by the haploinsufficiency of CHD7, a gene that encodes an ATP-dependent chromatin remodeling factor. The major goal of this 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 implicating CHD7 as a direct epigenetic regulator of cardiogenic genes. Currently, the functions and molecular activities of CHD7 during heart development remain largely elusive, presenting a major barrier for understanding the developmental basis for the heart defects in CHARGE patients. We hypothesize that CHD7 regulates the epigenetic architecture of crucial cardiogenic genes to promote normal heart development in mammals. Two specific aims are proposed to test this hypothesis. In the 1st aim, we will reveal the regulatory target network of CHD7 in cardiomyocytes derived from the second heart field (SHF) and examine how CHD7 is specifically loaded onto its target sites. In the 2nd aim, we will test the role of CHD7 in recruiting histone methyltransferase to promote methylation of histone H3 lysine 4 at its associated enhancers. 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 with crucial clues regarding how an epigenetic regulator acts coordinately with other genetic/epigenetic regulators to promote normal cardiogenesis in mammals. Information obtained from our research will be invaluable for understanding the mechanisms underlying the heart defects observed in CHARGE syndrome patients.