Regulation of Heart Function by a Gata4-Fog2 transcriptional complex

描述（由申请人提供）：病理性刺激改变心脏的转录程序，从而促进心脏肥厚和衰竭的发病机制。这种转录程序受到染色质结构的深刻影响，染色质结构在响应细胞外信号时动态变化。心脏基因的表达也受到一系列关键转录因子的控制，包括对心脏肥厚至关重要的GATA4。染色质结构调节转录因子与DNA的结合，反过来，转录因子招募修饰染色质结构的蛋白质复合物。然而，关于染色质结构和转录因子之间复杂的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辅助因子FOG2对成人心脏的正常功能至关重要，部分是通过维持冠状动脉血管。此外，我们证明了GATA4和多梳复合体PRC2之间的一种新的相互作用，它通过催化组蛋白甲基化来控制细胞分化和谱系承诺。在本研究中，我们验证了GATA4-染色质相互作用调节心脏肥厚和衰竭中GATA4靶基因转录的广泛假设，这些相互作用是由FOG2和PRC2调节的。我们提出以下具体目标：(1)。在新生儿心肌细胞肥厚模型中，我们验证了肥厚刺激改变GATA4染色质占用并诱导染色质结构中GATA4依赖性变化从而驱动心肌肥厚基因表达改变的假设。（2）. 我们确定了FOG2- gata4调控的基因，这些基因有助于FOG2缺陷小鼠的心力衰竭表型，并剖析了FOG2影响这些基因的gata4依赖性转录的分子机制。(3)。我们验证了PRC2对心脏肥厚和功能至关重要的假设，并研究了GATA4-PRC2相互作用在调节心脏生长和稳态中的功能意义。这些目标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性提供新的见解。这些知识可能会导致心力衰竭的新治疗方法。

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.