Hormonal and Developmental Regulation of Gene Expression

基因表达的激素和发育调节

基本信息

批准号：
7616447
负责人：
MICHAEL G ROSENFELD
金额：
$ 49.01万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-10-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7616447
关键词：
Architecture Area Binding Biological Boundary Elements Cell Lineage Chromatin Structure Code Complex DNA Development Developmental Gene Expression Regulation Disease Epigenetic Process Event Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomics Goals Grant Histone H1 Histone H1(s)Histones Hormonal Investigation Ligands Link Location Logic Lysine Mediating Methods Modeling Molecular Molecular Genetics Mus Nuclear Nuclear Receptors Nucleosomes Organogenesis Pathway interactions Pattern Poly(ADP-ribose) Polymerases Program Development Regulation Role Signal Pathway Signal Transduction Technology Testing Topoisomerase Transcriptional Activation base cell type chromatin remodeling cofactor derepression genome-wide in vivo insight model development multicatalytic endopeptidase complex novel pituitary gland development programs receptor response sensor transcription factor

项目摘要

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.

描述（由申请人提供）：了解控制整个基因组对调节信号，发育和疾病的转录响应的分子逻辑，这些策略的转录响应模式仍然是一个关键，尚未解决的问题。根据这项赠款，我们研究了共激活因子和核压子的转录程序的整合，从而确定了它们在DMA结合转录因子通过DMA结合转录因子调节基因转录中的作用，并确定了在辅助基因激活中，在辅因子交换中特定核心压剂复合物成分的关键作用。在基因激活中依赖泛素化/19S蛋白体机械的核心依赖性募集以及PARP1作为将特定信号传导途径与转录响应程序联系起来的传感器的意外作用。对垂体发育作为模型的研究允许对这些原理的体内表征进行体内表征，并且证明了通过相反的信号传导梯度通过相反的信号传导梯度引起的特定相互作用转录因子的协同作用来实现细胞类型的规范。在这种竞争性更新中，我们将重点介绍使用新开发的全基因组位置分析方法来探索基因调控的新方面和转录激活程序的表观遗传控制。我们将探索开发过程中基因调节的特定表观遗传策略以及边界元素函数的分子机制。将测试特定基因激活程序意外需要特定组蛋白脱甲基酶的作用的假设，并将探讨潜在的分子机制。根据PARP1的传感器函数的发现，我们将研究以下假设：在核受体依赖性基因激活中，聚（ADP-核糖）聚合酶在核受体依赖性基因激活中起作用的基本策略涉及拓扑异构酶依赖性DNA依赖性DNA脱离toposomerase的DNA，并激活PARP1的激活PARP1酶促作用从特定的核心组中解散组酮H1。 LEF/TCF独立B-catenin功能在细胞谱系测定中与增殖事件中的一个新方面将使用PIT1基因调节作为模型探索。这些方法结合了基因组学，遗传和分子生物学方法，为受调节的基因表达和器官发生的分子机制方面提供了新的见解，并将为基因反应协调方案的分子策略提供特定的见解。