Hormonal and Developmental Regulation of Gene Expression

描述（由申请人提供）：了解调控策略的分子逻辑，控制对调控信号、发育和人类疾病的转录反应的全基因组模式，仍然是一个关键的、未解决的问题。在这项资助下，我们研究了共激活子和共阻遏子对转录程序的整合，并确定了它们在DNA结合转录因子调控基因转录中的作用。此外，我们已经建立了在配体依赖性基因激活的辅因子交换的特定辅阻遏物复合物组件的关键作用。我们研究了配体对正常细胞中长距离相互作用的影响，并作为肿瘤生物学的一个组成部分，包括易位事件。垂体发育作为一个模型的调查已经允许在体内表征的Notch途径的新方面和Wnt垂体/2-连环蛋白POU结构域的相互作用在细胞类型特异性基因激活事件的作用。在这次竞争性更新中，基于本基金获得的初步数据，我们将重点关注核受体介导的转录激活的作用，这些转录激活由大量DNA重复序列中的特定反应元件驱动，从而产生新的小调控RNA和配体调控的ncRNA。我们将开发和应用全基因组定位分析3-D相互作用的方法，以探索基因调控和转录激活程序控制的新方面，旨在确定特定的策略，增强子和亚核位置事件的调节在发展和增殖的控制。我们还提出了一种新的非组蛋白甲基化策略，这是至关重要的核结构区域之间的转录单位的运动，生长控制基因调控的基础。我们的研究将非组蛋白修饰，ncRNA和核结构作为一个整合策略，调节哺乳动物转录程序。

DESCRIPTION (provided by applicant): Understanding the molecular logic of regulatory strategies that control genome-wide patterns of transcriptional response to regulatory signals, development and human disease remains a key, unresolved issue. Under this Grant, we have investigated the integration of transcriptional programs by coactivators and corepressors and have established their role in regulated gene transcription by DNA binding transcription factors. Furthermore, we have established the critical role of specific corepressor complex components in cofactor exchange in ligand-dependent gene activation. We have investigated the effects of ligands on long-distance interactions in normal cells and as a component of tumor biology, including translocation events. Investigation of pituitary gland development as a model has permitted the in vivo characterization of new aspects of the Notch pathway and the role of Wnt pituitary/2-catenin POU domain interactions in cell type-specific gene activation events. In this competitive renewal, based on preliminary data obtained under this Grant, we will focus on the role of nuclear receptor-mediated transcriptional activation driven by specific response elements in a large number of DNA repeats resulting in novel small regulatory RNAs and ligand-regulated ncRNAs. We will develop and apply genome-wide location analysis 3-D interaction methods to explore new aspects of gene regulation and control of transcriptional activation programs aimed at identifying specific strategies of enhancers and regulation of subnuclear location events during development and in control of proliferation. We also propose a novel non-histone methylation strategy, which is critical for the movement of transcription units between the nuclear architecture regions that underlie growth control gene regulation. Our studies will link non-histone protein modifications, ncRNAs and nuclear architecture as an integrating strategy for regulated mammalian transcriptional programs.