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: 10162637
• 负责人: KAI JIAO
• 金额: $ 25.32万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162637
• 关键词: ATAC-seq; Address; Affect; Affinity; Architecture; Area; Binding; Biochemical; CHARGE syndrome; CHD7 gene; CRISPR/Cas technology; Cardiac Myocytes; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Clinical; Coloboma; Complex; Congenital Abnormality; Data; Development; Ear; Elements; Embryo; Embryonic Heart; Enhancers; Epigenetic Process; Eye; GATA4 gene; Gene Expression; Genes; Genetic; Genital; Genitalia; Goals; Growth and Development function; Heart; Heart Abnormalities; Histone H3; Human; Impairment; In Vitro; Knowledge; Literature; Lysine; Mammalian Cell; Mammals; Methylation; Molecular; Molecular Genetics; Mus; Mutation; Newborn Infant; Organ; Other Genetics; Patients; Reader; Reporter; Reporting; Research; Role; Signal Transduction; Site; Structure; Techniques; Testing; Transgenic Organisms; Translating; Transposase; bone morphogenetic protein receptors; cardiogenesis; clinical application; congenital heart disorder; deep sequencing; developmental disease; epigenetic regulation; genetic approach; histone methylation; histone methyltransferase; improved; in vivo; insight; mouse model; novel; recruit; transcription factor; transcriptome sequencing

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.

摘要： CHARGE综合征（眼睛缺损、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综合征的主要临床特征，影响>75% 病人。超过70%的CHARGE病例是由CHD 7的单倍不足引起的，该基因 编码ATP依赖性染色质重塑因子。这个项目的主要目标是揭示 CHD 7在心脏发育过程中的功能，因此提供了对出生缺陷的机制见解 是由CHD 7基因突变引起的 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表观遗传调节因子。 目前，CHD 7在心脏发育过程中的功能和分子活性在很大程度上仍然是难以捉摸的， 为理解CHARGE中心脏缺陷的发育基础提供了主要障碍 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。提出了两个具体目标来检验这一假设。在 第一个目标是揭示CHD 7在第二心脏心肌细胞中的调控靶点网络 字段（SHF），并检查CHD 7是如何专门加载到其目标网站。在第二个目标中，我们将测试 CHD 7在募集组蛋白甲基转移酶以促进组蛋白H3赖氨酸4在其 相关增强剂。 完成这项研究不仅将大大提高我们对组织的认识， CHD 7在心脏发育中的细胞和分子活动，也将为我们提供关键线索， 关于表观遗传调节剂如何与其他遗传/表观遗传调节剂协调作用以促进 正常的心脏发生。从我们的研究中获得的信息对理解 在CHARGE综合征患者中观察到的心脏缺陷的潜在机制。