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.

文摘: