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

基本信息

批准号：
10540020
负责人：
Frank Leo Conlon
金额：
$ 56.65万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10540020
关键词：
Address Adult Antibodies Biochemical Cardiac Cardiac Myocytes Cardiac development ChIP-seq Chromatin Chromatin Remodeling Factor Chromatin Structure Complex Congenital Abnormality Core Protein Data Set Development Disease Embryo Embryonic Heart Enhancers Epigenetic Process Gene Activation Gene Expression Gene Expression Regulation Genetic Genetic Transcription Genetic study Goals Health Heart Heart Diseases Histone H3 Histones Homeostasis Human Infant Mortality Lead MLL gene Malignant Neoplasms Methylation Mutation Nucleosomes Patients Pharmaceutical Preparations Post-Translational Protein Processing Proteins Proteomics Regulation Role Skeletal Muscle Structural Congenital Anomalies System Testing Time Tissues Transposase base cardiogenesis chromatin remodeling congenital heart disorder heart function histone methyltransferase histone modification improved outcome in vivo insight member mutant programs promoter protein complex protein function protein protein interaction structural heart disease success

项目摘要

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.

抽象的先天性心脏病（CHD）仍然是最常见的先天畸形。因此，了解心肌细胞形成的机制至关重要改善结构性心脏病的结果。翻译后修饰组蛋白的作用是调节心脏染色质结构，从而调节颞叶和心脏发育过程中基因调控的空间程序。我们发现 SMYD1，一种心肌细胞必需的组蛋白甲基转移酶，与染色质重塑 MLL4 类与 Set1 相关的蛋白质复合物（指南针）复杂。 SMYD1 已被证明对于心脏功能至关重要正如我们在此所示，发育会导致冠心病。和SMYD1一样，两个核心 MLL4-COMPASS 复合体、KMT2D/MLL4 和 KDM6a 的组件是必不可少的影响心脏发育并导致冠心病。当前应用程序的目标是测试中心假设是 SMYD1 在 MLL4-COMPASS 复合体中发挥作用，以清除在基因激活之前，组蛋白位于心脏增强子处。这将通过以下方式实现：1) 2) 确定 SMYD1 在心脏 MLL4- 的组装和功能中的功能 COMPASS 复合体，2) 在 MLL4 中建立 KDM6a 的要求 - 指南针活动。总的来说，这些研究将提供详细的机制了解 SMYD1 和 MLL4-COMPASS 复合物的组织特异性作用心脏发育和心脏病。