Critical roles of CHD7 during mouse cardiogenesis

CHD7 在小鼠心脏发生过程中的关键作用

• 批准号: 10625572
• 负责人: KAI JIAO
• 金额: $ 14.82万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-23 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625572
• 关键词: Critical; roles; CHD7; during; mouse

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.

抽象的： CHARGE 综合征（眼睛缺损、心脏缺陷、后鼻孔闭锁、视力发育迟缓） 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% 的患者。超过 70% 的 CHARGE 病例是由 CHD7 的单倍体不足引起的，该基因 编码 ATP 依赖性染色质重塑因子。该项目的主要目标是揭示 CHD7 在心脏发育过程中的功能，因此提供了出生缺陷的机制见解 由CHD7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 SMADs。我们进一步表明 CHD7 是 Nkx2.5 的正常表达，Nkx2.5 是 BMP 信号下游的核心心原性转录因子。因此，我们的 研究提供了第一个证据表明 CHD7 作为心源性基因的直接表观遗传调节因子。 目前，CHD7 在心脏发育过程中的功能和分子活性仍然很大程度上难以捉摸， 为理解 CHARGE 心脏缺陷的发育基础带来了主要障碍 患者。我们假设 CHD7 调节关键心原性基因的表观遗传结构 促进哺乳动物心脏的正常发育。提出了两个具体目标来检验这一假设。在 第一个目标，我们将揭示第二心脏来源的心肌细胞中CHD7的调控靶点网络 场（SHF）并检查 CHD7 如何特异性加载到其目标位点上。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 相关的增强子。 完成拟议的研究不仅将极大地增进我们对组织的了解， CHD7 在发育中的心脏中的细胞和分子活性，而且也将为我们提供重要的线索 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发生。从我们的研究中获得的信息对于理解非常宝贵 在 CHARGE 综合征患者中观察到的心脏缺陷的潜在机制。

项目成果

Myocardial Mycn is essential for mouse ventricular wall morphogenesis.

• DOI: 10.1016/j.ydbio.2012.10.005
• 发表时间: 2013-01-01
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Harmelink C;Peng Y;DeBenedittis P;Chen H;Shou W;Jiao K
• 通讯作者: Jiao K

Functions of miRNAs during Mammalian Heart Development.

• DOI: 10.3390/ijms17050789
• 发表时间: 2016-05-21
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Yan S;Jiao K
• 通讯作者: Jiao K

Cell autonomous requirement of endocardial Smad4 during atrioventricular cushion development in mouse embryos.

• DOI: 10.1002/dvdy.22493
• 发表时间: 2011-01
• 期刊: DEVELOPMENTAL DYNAMICS
• 影响因子: 2.5
• 作者: Song, Langying;Zhao, Mei;Wu, Bingruo;Zhou, Bin;Wang, Qin;Jiao, Kai
• 通讯作者: Jiao, Kai

CHD7 regulates cardiovascular development through ATP-dependent and -independent activities.

CHD7 通过 ATP 依赖性和非依赖性活动调节心血管发育。

• DOI: 10.1073/pnas.2005222117
• 发表时间: 2020
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Yan,Shun;Thienthanasit,Rassarin;Chen,Dongquan;Engelen,Erik;Brühl,Joanna;Crossman,DavidK;Kesterson,Robert;Wang,Qin;Bouazoune,Karim;Jiao,Kai
• 通讯作者: Jiao,Kai

Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B.

• DOI: 10.1093/hmg/ddq462
• 发表时间: 2011-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Bing Wang;Tanvi Sinha;K. Jiao;R. Serra;Jianbo Wang