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

摘要 先天性心脏病(CHD)仍然是最常见的先天性畸形。 因此，从机理上理解心肌细胞的形成是至关重要的。 用于改善结构性心脏病的预后。翻译后的修改 组蛋白起到调节心脏染色质结构的作用，因此，临时和 心脏发育过程中基因调控的空间程序。我们发现， SMYD1是一种心肌细胞必需的组蛋白甲基转移酶，它与 染色质重塑与Set1相关的MLL4类蛋白复合体 (指南针)情结。SMYD1已被证明是心脏疾病所必需的 正如我们在这里展示的那样，发展会导致CHD。像SMYD1一样，有两个核心 MLL4-COMPASS复合体、KMT2D/MLL4和KDM6a的组件是必不可少的 导致心脏发育和导致冠心病。当前应用程序的目标是测试 SMYD1在MLL4-COMPASS复合体中作用的中心假设是清除 在基因激活之前，心脏增强剂中的组蛋白。这将通过以下方式实现：1)2) 确定SMYD1在心脏MLL4组装和功能中的功能- Compass Complex和，2)确定MLL4中对KDM6a的要求- 指南针活动。总的来说，这些研究将提供一个详细的机制 SMYD1和MLL4-COMPASS复合体的组织特异性作用 心脏发育和心脏病。

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.