The Epigenetic Landscape of Heart Development

 描述（由申请人提供）：NHLBI心血管发育联盟（CvDC）旨在提供对心脏发育调节因子的综合功能理解，以便将这些知识应用于先天性心脏病（CHD），这是由转录途径失调引起的。需要一种全球性的方法来真正实现网络级的洞察力，将心脏发育中起作用的基因调控成分结合在一起。有了这些知识，就有可能发现CHD中基因调控被破坏的分子途径。编码转录调节因子和染色质调节因子的基因突变是CHD的基础，这一发现为理解这些因子控制心脏分化和形态发生的网络提供了重要的动力。我们的CvDC小组已经部署了一系列广泛的方法来机械地理解心脏基因调控的基础。我们特别有动力去了解动态染色质相互作用，使远端调控元件能够调控细胞类型特异性基因表达，以及这些机制如何在导致CHD的突变面前无法适当部署。为实现这些目标，需要采取协调一致的办法，开展重大协作。快速和免费的数据 资源共享将使其他团体能够立即从我们的努力中受益，使他们能够根据CvDC的努力开展补充调查。有了这一理念，CvDC与许多其他实验室一起，将产生对心脏基因调控的重要见解，因为它适用于CHD。我们提出了一个中心项目，一个合作项目，和必要的核心，以合作推动冠心病研究向前发展。 本中心的研究目标如下：目标1：明确调控心脏分化的转录因子网络。目的2：确定协调心脏基因表达的三维相互作用。目的3：明确调控元件在心脏发育中的功能意义。 对于该合作项目，我们提出了以下目标：目标1：表征编码表观遗传因子和转录因子的基因中CHD相关突变导致的转录变化。目的2：确定表观遗传和转录因子编码基因突变引起的表观基因组变化。 我们提出的两个项目，加上对协作和数据共享的关注，以及强调跨学科互动的培训计划理念，将推动CvDC走向下一阶段的发现。我们的研究将为CHD提供新的重要见解，为诊断和治疗方法的转化发展提供坚实而广阔的平台。

 DESCRIPTION (provided by applicant): The NHLBI Cardiovascular Development Consortium (CvDC) aims to provide an integrated functional understanding of regulators of heart development, in order to apply this knowledge to congenital heart disease (CHD), which results from dysregulation of transcriptional pathways. A global approach is required to truly achieve the network-level insight that will bring together the components of gene regulation that are operative in heart development. With this knowledge, it will be possible to discover the molecular pathways through which gene regulation is disrupted in CHD. The finding that mutations in genes encoding transcriptional regulators and chromatin modulators underlie CHD provides significant motivation to understand the networks in which such factors function to control cardiac differentiation and morphogenesis. Our CvDC group has deployed a broad set of approaches to mechanistically understand the basis of cardiac gene regulation. We are particularly motivated to understand the dynamic chromatin interactions that enable distal regulatory elements to regulate cell-type specific gene expression and how these mechanisms fail to be appropriately deployed in the face of mutations that cause CHD. A concerted approach involving significant collaborative efforts is required to achieve these goals. Rapid and free data and resource sharing will enable other groups to benefit instantly from our efforts, allowing them to launch complementary investigations based on CvDC efforts. With this philosophy in place the CvDC, together with many other labs, will yield significant insights into cardiac gene regulation as it applies to CHD. We propose a center project, a collaborative project, and essential cores, to collaboratively propel CHD research forward. For the center project, we propose the following aims: Aim 1: To define the transcription factor (TF) networks that regulate cardiac differentiation. Aim 2: To determine the three-dimensional interactions that coordinate cardiac gene expression. Aim 3: To define the functional significance of regulatory elements in heart development. For the collaborative project, we propose the following aims: Aim 1: To characterize the transcriptional changes that result from CHD-associated mutations in genes encoding epigenetic factors and transcription factors. Aim 2: To define the epigenomic changes that result from mutations in genes encoding epigenetic and transcription factors. The two projects we propose, together with a focus on collaboration and data sharing, and a training plan philosophy that emphasizes cross-disciplinary interactions, will propel the CvDC towards its next phase of discovery. Our investigations will provide new and important insights into CHD, providing a solid and broad platform for translational development of diagnostic and therapeutic approaches.