Regulation of Heart Function by a Gata4-Fog2 transcriptional complex

描述(申请人提供)：病理刺激改变心脏的转录程序，从而导致心肌肥大和衰竭的发病机制。这一转录程序深受染色质结构的影响，染色质结构会随着细胞外信号的变化而动态变化。心脏基因的表达还受一系列关键转录因子的控制，包括对心肌肥大至关重要的GATA4。染色质结构调节转录因子与DNA的结合，反过来，转录因子招募改变染色质结构的蛋白质复合体。然而，关于染色质结构和转录因子之间的这种复杂相互作用的信息很少，特别是在心脏基因表达和心力衰竭发病机制的背景下。我们和其他人已经证明，GATA4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GATA4辅因子FOG2对于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，我们还证明了GATA4和多梳复合体PRC2之间的一种新的相互作用，该复合体通过催化组蛋白甲基化来控制细胞分化和谱系承诺。在这个提议中，我们检验了广泛的假设，即GATA4-染色质相互作用调节心肌肥厚和衰竭中GATA4靶基因的转录，这些相互作用受FOG2和PRC2的调节。我们提出了以下具体目标：(1)。在新生心肌细胞肥大模型中，我们验证了肥大刺激改变GATA4染色质占有率并诱导依赖于GATA4的染色质结构改变的假说，从而驱动心肌肥厚中基因表达的改变。(2)。我们确定了FOG2-GATA4调控的导致FOG2基因缺陷小鼠心力衰竭表型的基因，并剖析了FOG2影响这些基因依赖于GATA4转录的分子机制。(3)。我们验证了PRC2对心肌肥大和功能至关重要的假设，并探讨了GATA4-PRC2相互作用在调节心脏生长和内稳态中的功能意义。这些目的将为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动提供新的见解。这一知识可能会导致心力衰竭的新治疗方法。 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，减轻症状，但不能逆转其进程。心力衰竭进展的主要因素之一是基因表达的改变。尽管过去20年的研究已经确定了许多控制衰竭心脏基因表达的关键因素，但人们对它们是如何发挥作用的知之甚少。研究也开始表明，细胞内遗传物质的包装深刻地影响着基因的表达。然而，对包装如何响应来自细胞外的信号，如增加的工作负荷，还没有很好的理解。在这项提议中，我们研究了一个关键的调节因子GATA4是如何控制基因表达的，以及它是如何根据细胞的环境修改遗传包装的。这些知识可能会导致改进的治疗方法，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.