Functions of CHD7 in regulating cardiogenesis

CHD7 调节心脏发生的功能

• 批准号: 9336477
• 负责人: KAI JIAO
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336477
• 关键词: Address; Affect; Affinity; Alleles; Architecture; Bioinformatics; CHARGE syndrome; CHD7 gene; Cardiac Myocytes; Cell Culture Techniques; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Coloboma; Complex; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Development; Ear; Embryo; Embryonic Heart; Enhancers; Epigenetic Process; Eye; GATA4 gene; Gene Dosage; Gene Expression; Gene Targeting; Genes; Genetic; Genetic screening method; Genital system; Goals; Growth and Development function; Heart; Heart Abnormalities; Heterozygote; Human; Knowledge; Ligands; Light; Lysine; Mammals; Methylation; Molecular; Mus; Mutation; Newborn Infant; Nucleosomes; Organ; Organogenesis; Patients; Penetrance; Phenotype; RNA Sequences; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Structure; Testing; Translating; abstracting; base; bone morphogenetic protein receptors; cardiogenesis; cell type; clinical application; congenital heart disorder; developmental disease; disease-causing mutation; dosage; embryo tissue; embryonic stem cell; epigenetic regulation; extracellular; field study; histone methyltransferase; insight; mouse model; transcription factor

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.

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