Hormonal and Developmental Regulation of Gene Expression

描述（由申请人提供）：了解调控和表观遗传策略的分子逻辑，这些策略控制对调控信号、发育和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，我们研究了辅激活子和辅阻遏子对转录程序的整合，建立了它们在DMA结合转录因子调节基因转录中的作用，还建立了特定辅阻遏子复合物组分在配体依赖性基因激活中辅因子交换中的关键作用。已经发现了辅阻遏物依赖的泛素化/19 S蛋白体机制在基因激活中的募集的意想不到的作用，以及PARP 1作为将特定信号传导途径与转录应答程序连接的传感器的作用。垂体发育作为一个模型的调查已经允许在体内表征这些原则，并证明细胞类型的规范是通过协同作用的特定相互作用的转录因子诱导的重叠模式，由相反的信号梯度。在这次竞争性更新中，我们将专注于使用新开发的全基因组定位分析方法来探索转录激活程序的基因调控和表观遗传控制的新方面。我们将探讨特定的表观遗传策略的基因调控在发展和边界元件功能的分子机制。特定的基因激活程序出乎意料地需要特定的组蛋白去甲基化酶的作用的假设将被测试，并将探讨潜在的分子机制。基于PARP 1的传感器功能的发现，我们将调查的假设，其中聚（ADP-核糖）聚合酶的功能在核受体依赖的基因激活的基本策略涉及拓扑异构酶依赖的DNA切口与PARP 1酶促作用的激活，以消除组蛋白H1从一个特定的核小体。一个新的方面LEF/TCF独立的B-连环蛋白功能的细胞谱系确定与增殖事件将探讨使用Pit 1基因调控作为一个模型。这些方法结合了联合收割机基因组学、遗传学和分子生物学方法，为调控基因表达和器官发生的分子机制方面提供了新的见解，并将为基因应答协调程序的分子策略提供具体的见解。

DESCRIPTION (provided by applicant): Understanding the molecular logic of regulatory and epigenetic strategies that control genome-wide patterns of transcriptional response to regulatory signals, development and disease remains a key, unresolved issue. Under this Grant, we have investigated the integration of transcriptional programs by coactivators and corepressors, establishing their role in regulated gene transcription by DMA binding transcription factors, and also established the critical role of specific corepressor complex components in cofactor exchange in ligand- dependent gene activation. An unexpected role of a corepressor dependent recruitment of ubiquitylation/19S proteosome machinery in gene activation, and PARP1 as a sensor for linking specific signaling pathway to programs of transcriptional response have been discovered. Investigation of pituitary gland development as a model has permitted the in vivo characterization of these principles, and the demonstration that cell-type specification is achieved by synergistic actions of specific interacting transcription factors induced in overlapping patterns by opposing signaling gradients. In this competitive renewal, we will focus on the use of a newly-developed genome-wide location analysis method to explore the novel aspects of gene regulation and epigenetic control of transcriptional activation programs. We will explore specific epigenetic strategies of gene regulation during development and the molecular mechanisms underlying boundary element function. The hypothesis that specific gene activation programs unexpectedly require the actions of specific histone demethylases will be tested, and the underlying molecular mechanisms will be explored. Based on the discovery of the sensor function of PARP1, we will investigate the hypothesis that the basic strategy by which poly (ADP-ribose) polymerase functions in nuclear receptor-dependent gene activation involves topoisomerase-dependent DNA nicking with activation of PARP1 enzymatic action to dismiss histone H1 from a specific nucleosome. A novel aspect of LEF/TCF independent B-catenin function in cell lineage determination versus proliferation events will be explored using Pit1 gene regulation as a model. These approaches combine genomics, genetic and molecular biological approaches, providing novel insights into aspects of molecular mechanisms of regulated gene expression and organogenesis, and will provide specific insights into the molecular strategies underlying coordinated programs of gene response.