Chromatin remodeling complexes in heart development

心脏发育中的染色质重塑复合物

• 批准号: 7128851
• 负责人: Benoit Gaetan Bruneau
• 金额: $ 48万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128851
• 关键词: adenosinetriphosphatase; cardiogenesis; cell differentiation; chromatin; congenital heart disorder; developmental genetics; enzyme activity; genetic regulation; genetically modified animals; heart cell; laboratory mouse; mammalian embryology; molecular genetics; nucleosomes; protein protein interaction; protein structure function; transcription factor

DESCRIPTION (provided by applicant): Congenital heart defects (CHDs) occur in about 1% of live births, and result in significant mortality and morbidity. We currently have very little understanding of the basis of CHDs. Transcription factors are key regulators of heart formation, and mutations in cardiac transcription factor genes can cause CHDs in humans. These findings have underscored the need for precise dosage of transcription factor proteins in the developing heart. It is of paramount importance to understand the molecular basis of decreased transcription factor dosage in disease, in order to be able to rationally design non-surgical therapies for CHDs. The function of transcription factors is intimately related to and regulated by the structure of chromatin at their target sites in the genome. Chromatin remodeling affects the accessibility and activity of transcription factors; this occurs largely via ATP-dependent chromatin remodeling complexes, which loosen nucleosomes to allow access to the transcriptional machinery. We have recently identified a component of the mammalian Swi/Snf (BAF) chromatin complex, called Baf60c, which is expressed primarily in the developing heart and has key roles in regulating several aspects of cardiac morphogenesis. This has established a new paradigm in transcriptional regulation, by adding an additional layer of regulation in the form of tissue-specific chromatin remodeling complexes. We hypothesize that Baf60c and BAF chromatin remodeling complexes play critical dose-dependent roles to integrate cardiac transcription factors in active regulation of crucial aspects of cardiac morphogenesis and lineage decisions The aims of the current proposal are: 1. To functionally define the tissue-specific and dosage-sensitive roles played by the cardiac-restricted BAF complex subunit Baf60c and the BAF complex in heart morphogenesis. This will be accomplished by cardiac-specific deletion of Baf60c and Brg1, the BAF complex ATPase. 2. To uncover the role of the BAF complex in lineage decisions in the anterior (secondary) heart field. This will be accomplished by anterior heart field-specific deletion of Baf60c and Brg1, along with genetic lineage tracing. 3. To identify the molecular basis of interactions between Baf60c and cardiac transcription factors. The knowledge generated by the results of each aim will be crucial to our understanding of heart patterning and the mechanisms underlying CHDs. The results obtained in this project will provide new and important insights into the causes of CHDs. We will discover new and important gene regulation pathways that form the heart, and importantly we will understand how these pathways are dysfunctional in human disease.

描述（由申请人提供）：约 1% 的活产婴儿患有先天性心脏病 (CHD)，并导致显着的死亡率和发病率。目前我们对先心病的基础了解甚少。转录因子是心脏形成的关键调节因子，心脏转录因子基因的突变可导致人类患冠心病。这些发现强调了发育中的心脏需要精确剂量的转录因子蛋白。了解疾病中转录因子剂量减少的分子基础至关重要，以便能够合理设计先心病的非手术疗法。转录因子的功能与其基因组靶位点的染色质结构密切相关并受其调节。染色质重塑影响转录因子的可及性和活性；这主要是通过 ATP 依赖性染色质重塑复合物发生的，该复合物松开核小体以允许进入转录机制。我们最近鉴定了哺乳动物 Swi/Snf (BAF) 染色质复合物的一个成分，称为 Baf60c，它主要在发育中的心脏中表达，在调节心脏形态发生的多个方面发挥关键作用。通过以组织特异性染色质重塑复合物的形式添加额外的调控层，这建立了转录调控的新范例。我们假设 Baf60c 和 BAF 染色质重塑复合物在整合心脏转录因子以主动调节心脏形态发生和谱系决定的关键方面方面发挥关键的剂量依赖性作用。当前提案的目的是： 1. 在功能上定义组织特异性和心脏限制性 BAF 复合物亚基 Baf60c 和 BAF 复合物在心脏形态发生中发挥的剂量敏感作用。这将通过心脏特异性删除 Baf60c 和 Brg1（BAF 复合物 ATP 酶）来实现。 2. 揭示 BAF 复合体在前（次级）心区谱系决策中的作用。这将通过前心区特异性删除 Baf60c 和 Brg1 以及遗传谱系追踪来实现。 3. 确定Baf60c与心脏转录因子相互作用的分子基础。每个目标的结果产生的知识对于我们理解心脏模式和先心病的机制至关重要。该项目获得的结果将为先心病的病因提供新的重要见解。我们将发现形成心脏的新的重要基因调控途径，更重要的是，我们将了解这些途径在人类疾病中如何发挥功能障碍。