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，调控信号、发育和人类疾病的全基因组转录反应模式仍然是一个关键的、未解决的问题。在此资助下，我们研究了协同激活因子和协同抑制因子转录程序的整合，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，我们已经确定了特定的辅抑制因子复合物组分在配体依赖性基因激活的辅因子交换中的关键作用。我们研究了配体对正常细胞长距离相互作用的影响，以及作为肿瘤生物学的一个组成部分，包括易位事件。将垂体发育作为一个模型进行研究，可以在体内表征Notch通路的新方面，以及Wnt垂体/2-catenin POU结构域相互作用在细胞类型特异性基因激活事件中的作用。在这一竞争性更新中，基于该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重复中的特定应答元件驱动，从而产生新的小调节rna和配体调节的ncRNAs。我们将开发和应用全基因组定位分析3-D相互作用方法来探索基因调控和转录激活程序控制的新方面，旨在确定增强子的具体策略和亚核定位事件在发育和增殖控制中的调控。我们还提出了一种新的非组蛋白甲基化策略，这对于生长控制基因调控的核结构区域之间转录单位的运动至关重要。我们的研究将把非组蛋白修饰、ncrna和核结构作为调控哺乳动物转录程序的整合策略联系起来。

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. PUBLIC HEALTH RELEVANCE: The experiments proposed in this competitive renewal will provide novel insights into regulated patterns of gene transcription, focusing on new technologies to investigate the role of ligand-dependent induction of DNA repeats and gene enhancers in gene expression programs and in ncRNAs and nuclear architecture strategies critical for integrating gene transcriptional programs. The proposed studies have particular relevance in uncovering the molecular basis of growth control and nuclear receptor actions in normal and cancer cells. Understanding these new strategies underlying regulation of gene expression is likely to translate into new types of therapeutic modalities.