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，获得心肌细胞形成的机制的理解是至关重要的 来改善结构性心脏病的预后。的翻译后修饰 组蛋白起调节心脏染色质结构的作用，因此， 心脏发育过程中基因调控空间程序。我们发现 SMYD 1是一种心肌细胞必需的组蛋白甲基转移酶， 染色质重塑MLL 4类与Set 1相关的蛋白质复合物 （COMPASS）complex. SMYD 1已被证明是心脏所必需的。 正如我们在这里所展示的，它会导致冠心病。与SMYD 1一样， MLL 4-COMPASS复合物的组分KMT 2D/MLL 4和KDM 6a是必不可少的 心脏发育和导致冠心病。当前应用程序的目标是测试 SMYD 1在MLL 4-COMPASS复合物中起作用以清除 基因激活前心脏增强子处的组蛋白。这将通过以下方式实现：1）2） 确定SMYD 1在心脏MLL 4 - 1的组装和功能中的功能 COMPASS复合物，2）在MLL 4中确定KDM 6a的要求- COMPASS活动。总的来说，这些研究将提供一个详细的机制， 了解SMYD 1和MLL 4-COMPASS复合物在 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.