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，该调控策略控制全基因组对调控信号、发育和人类疾病的转录反应模式，仍然是一个关键的、尚未解决的问题。在这项授权下，我们研究了共激活因子和辅助抑制因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，我们已经确定了特定的辅阻遏子复合体成分在辅因子交换中的关键作用。我们已经研究了配体对正常细胞以及作为肿瘤生物学组成部分的长距离相互作用的影响，包括易位事件。以垂体腺发育为模型的研究使得在体内表征Notch通路的新方面以及Wnt垂体素/2-连环蛋白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成为可能。在这次竞争性更新中，我们将根据根据这项授权获得的初步数据，重点讨论核受体介导的转录激活在大量DNA重复中由特定反应元件驱动的作用，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的三维交互方法，以探索转录激活程序的基因调控的新方面，旨在确定增强子的特定策略，以及在发育和控制增殖过程中对亚核定位事件的调控。我们还提出了一种新的非组蛋白甲基化策略，该策略对于转录单位在作为生长控制基因调控基础的核结构区域之间的移动至关重要。我们的研究将把非组蛋白蛋白修饰、ncRNAs和核结构作为受调控的哺乳动物转录程序的整合策略。 公共卫生相关性：本次竞争性更新中提出的实验将为基因转录的调控模式提供新的见解，重点是新技术，以研究配体依赖的DNA重复诱导和基因增强剂在基因表达计划以及对整合基因转录计划至关重要的ncRNAs和核架构策略中的作用。拟议的研究在揭示正常细胞和癌细胞中生长控制和核受体作用的分子基础方面具有特别的相关性。了解这些潜在的基因表达调控的新策略可能会转化为新型的治疗方式。

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.