Function and regulation of chromatin remodeling complexes in cardiac development and disease

染色质重塑复合物在心脏发育和疾病中的功能和调节

• 批准号: 10849290
• 负责人: Frank Leo Conlon
• 金额: $ 1.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10849290
• 关键词: Adult; Atrial Heart Septal Defects; Biochemical; Biological; Cardiac; Cardiac Myocytes; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Complex; Congenital Abnormality; Congenital Disorders; Data; Disease; Echocardiography; Electrocardiogram; Enhancers; Epigenetic Process; Female; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic study; Goals; Heart; Heart Abnormalities; Heart Diseases; Histologic; Histones; Homeostasis; Human; Infant Mortality; Kabuki Make-Up Syndrome; Link; Morphology; Mus; Mutation; Nucleosomes; Pathway interactions; Patients; Physiological; Play; Post-Translational Protein Processing; Proteins; Proteomics; Regulation; Role; Skeletal Muscle; Structural Congenital Anomalies; System; Testing; Tissues; Ventricular; Ventricular Septal Defects; Woman; atrioventricular septal defect; cardiogenesis; chromatin remodeling; congenital heart disorder; embryonic stem cell; heart function; histone methyltransferase; histone modification; improved outcome; in vivo; male; mutant; novel; programs; protein complex; protein function; sex; stem cell differentiation; structural heart disease; transcriptome sequencing

Abstract Congenital heart disease (CHD) remains the most common congenital malformation. Therefore, attaining a mechanistic understanding of cardiomyocyte formation is crucial for improving outcomes to structural heart disease. Post-translational modifications of histones act to regulate cardiac chromatin structure and hence, the temporal and spatial program of gene regulation during cardiac development. We have found that SMYD1, a cardiomyocyte essential histone methyltransferase interacts with the chromatin remodeling MLL4 class of Complex of Proteins ASsociated with Set1 (COMPASS) complex. SMYD1 has been shown to be essential for cardiac development and as we show here, causes CHD. Like SMYD1, two of the core components of the MLL4-COMPASS complex, KMT2D/MLL4 and KDM6a are essential for cardiac development and cause CHD. The goal of the current application is to test the central hypothesis that SMYD1 acts within the MLL4-COMPASS complex to clear histones at cardiac enhancers prior to gene activation. This will be achieved by: 1) 2) Determining the function of SMYD1 in the assembly and function of the cardiac MLL4- COMPASS complex and, 2) Establishing the requirement for KDM6a in MLL4- COMPASS activity. Collectively, these studies will provide a detailed mechanistic understanding of the tissue specific role for SMYD1 and MLL4-COMPASS complex in cardiac development and heart disease.

摘要