Regulation of Heart Function by a Gata4-Fog2 transcriptional complex

描述（由申请人提供）：病理刺激改变心脏的转录程序，从而导致心脏肥大和衰竭的发病机制。这一转录程序受到染色质结构的深刻影响，染色质结构动态地响应细胞外信号而变化。心脏基因表达也受一组关键转录因子控制，包括GATA 4，这是心脏肥大所必需的。染色质结构调节转录因子与DNA的结合，相反地，转录因子募集蛋白质复合物来修饰染色质结构。然而，很少有关于这种复杂的染色质结构和转录因子之间的相互作用的信息，特别是在心脏基因表达和心力衰竭的发病机制的背景下。我们和其他人已经表明，GATA 4是成人心脏功能的重要调节因子。在我们的初步数据中，我们进一步表明GATA 4辅因子FOG 2对成人心脏的正常功能是必不可少的，部分是通过维持冠状动脉血管系统。此外，我们证明了GATA 4和多梳复合物PRC 2之间的一种新的相互作用，PRC 2通过催化组蛋白甲基化来控制细胞分化和谱系定型。在这项提议中，我们测试了广泛的假设，即GATA 4-染色质相互作用调节心肌肥厚和心力衰竭中GATA 4靶基因的转录，这些相互作用受到FOG 2和PRC 2的调节。我们提出以下具体目标：（1）。在新生儿心肌细胞肥大模型中，我们检验了肥大刺激改变GATA 4染色质占有率并诱导GATA 4依赖性染色质结构变化的假设，这些变化驱动心脏肥大中基因表达的改变。（二）、我们确定了FOG 2-GATA 4调控的基因，这些基因导致FOG 2缺陷小鼠的心力衰竭表型，并剖析了FOG 2影响这些基因的GATA 4依赖性转录的分子机制。（三）、我们测试的假设，PRC 2是必不可少的心脏肥大和功能，并研究GATA 4-PRC 2的相互作用在调节心脏生长和稳态的功能意义。这些目标将提供新的见解，细胞环境如何通过转录因子和染色质结构之间的相互作用调节转录活性。这些知识可能会导致新的治疗方法心力衰竭。 公共卫生相关性：心力衰竭是工业化国家发病率和死亡率的主要原因。目前的治疗方法可以减缓心力衰竭的进展并减轻症状，但不能逆转其进程。心力衰竭进展的主要原因之一是基因表达改变。虽然过去20年的研究已经确定了许多控制心脏衰竭基因表达的关键因素，但对它们如何工作知之甚少。研究也开始表明，细胞内遗传物质的包装深刻地影响基因表达。然而，对包装如何响应来自细胞外部的信号（例如增加的工作量）的理解还没有很好地理解。在这项提案中，我们研究了一个关键的调节因子GATA 4如何控制基因表达，以及它如何修改基因包装以响应细胞的环境。这些知识可能会导致改善治疗方法，可以逆转心脏病的基因表达变化和疾病进程。

DESCRIPTION (provided by applicant): Pathological stimuli alter the transcriptional program of the heart, thereby contributing to the pathogenesis of cardiac hypertrophy and failure. This transcriptional program is profoundly influenced by chromatin structure, which changes dynamically in response to extracellular cues. Cardiac gene expression is also controlled by a set of key transcription factors, including GATA4, which is essential for cardiac hypertrophy. Chromatin structure regulates transcription factor binding to DNA, and conversely transcription factors recruit protein complexes that modify chromatin structure. However, little information is available about this complex interplay between chromatin structure and transcription factors, particularly in the context of cardiac gene expression and the pathogenesis of heart failure. We and others have shown that GATA4 is an essential regulator of adult heart function. In our preliminary data, we further show that the GATA4 cofactor FOG2 is essential for normal function of the adult heart, in part by maintaining the coronary vasculature. In addition, we demonstrate a novel interaction between GATA4 and the polycomb complex PRC2, which governs cellular differentiation and lineage commitment by catalyzing histone methylation. In this proposal, we test the broad hypothesis that GATA4- chromatin interactions regulate the transcription of GATA4 target genes in cardiac hypertrophy and failure, and these interactions are modulated by FOG2 and PRC2. We propose the following specific aims: (1). In a neonatal cardiomyocyte hypertrophy model, we test the hypothesis that hypertrophic stimulation alters GATA4 chromatin occupancy and induces GATA4-dependent changes in chromatin structure that drive altered gene expression in cardiac hypertrophy. (2). We identify genes regulated by FOG2-GATA4 that contribute to the heart failure phenotype of FOG2-deficient mice, and dissect molecular mechanisms by which FOG2 influences GATA4-dependent transcriptional of these genes. (3). We test the hypothesis that PRC2 is essential for cardiac hypertrophy and function, and investigate the functional significance of GATA4-PRC2 interaction in regulating cardiac growth and homeostasis. These aims will provide novel insights into how cellular context regulates transcriptional activity through interactions between transcription factors and chromatin structure. This knowledge may lead to novel therapeutic approaches for heart failure. PUBLIC HEALTH RELEVANCE: Heart failure is the leading cause of morbidity and mortality in industrialized nations. Current treatments can slow the progression of heart failure and reduce the symptoms, but cannot reverse its course. One of the main contributors to the progression of heart failure is altered gene expression. While research in the last 20 years has identified many key factors that control gene expression in the failing heart, little is known about how they work. Research is also beginning to show that the packaging of genetic material inside the cell profoundly influences gene expression. However, understanding of how the packaging responds to signals from outside the cell, such as increased workload, are not well understood. In this proposal, we study how one key regulator factor, GATA4, controls gene expression and how it modifies genetic packaging in response to the cell's environment. This knowledge may lead to improved therapies that can reverse gene expression changes and disease course in heart disease.