Activity of Nuclear Receptor Coregulators with Chromatin

核受体共调节因子与染色质的活性

• 批准号: 8334694
• 负责人: WILLIAM Lee KRAUS
• 金额: $ 43.37万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334694
• 关键词: Address; Adipose tissue; Area; Binding; Bioinformatics; Biological; Biological Assay; Biology; Breast Cancer Cell; Cancerous; Cell Cycle; Cell Nucleus; Cell physiology; Cells; ChIP-seq; Chromatin; Chromatin Loop; Chromatin Structure; Code; DNA Polymerase I; Data Set; Development; Diagnosis; Disease; Distal; Enhancers; Estrogen Receptors; Estrogen receptor positive; Estrogens; Event; Functional RNA; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genomics; Heart; Hour; Ligands; Light; Liver; MCF7 cell; Mammary gland; Membrane; Molecular; Mus; Nature; Neuraxis; Nuclear; Nuclear Receptors; Organ; Outcome; Pathology; Physiology; Play; Positron-Emission Tomography; Production; Proteins; RNA Polymerase II; Regulation; Regulator Genes; Research; Role; Running; Sequence Analysis; Set protein; Signal Pathway; Signal Transduction; System; TNF gene; Tamoxifen; Testing; Tissues; Transcript; Withdrawal; attenuation; base; biological systems; bone; cell type; comparative; defined contribution; estrophilin; histone modification; in vivo; insight; prevent; promoter; receptor binding; receptor function; reproductive; reproductive function; response; transcription factor

DESCRIPTION (provided by applicant): Estrogens play key roles in the normal development and function of reproductive organs, mammary glands, bone, heart, vasculature, adipose, and central nervous system, as well as common dysfunctions of the same tissues. The long-term objective of these studies is to achieve a better understanding of the mechanisms by which liganded ERs control global patterns of gene expression to regulate cellular physiology. Our overall hypothesis is that biological context will play a key role in determining the nature and extent of estrogen-dependent transcriptional responses, and that estrogen responses will differ from the responses to other signaling pathways. In this proposal, we will use a unique, sensitive, powerful, and comprehensive new genomic approach for transcriptional profiling called Global nuclear Run-On and Sequencing (GRO-seq), which is superbly suited to the analysis of specific transcriptional mechanisms that cannot be addressed by other means. In the studies described herein, we will use GRO-seq in combination with other genomic, computational, and gene-specific assays, to elucidate the molecular and genomic mechanisms underlying the immediate and primary effects (i.e., minutes, not hours) of estrogen on the transcriptomes of normal and cancerous cells, including effects on non-coding transcripts. Specifically, we will: (1) determine the functional relationships between estrogen signaling pathways, ERa binding events, and estrogen-dependent transcriptional outcomes, (2) determine the mechanisms of regulation and functional roles of non-coding estrogen-regulated transcripts, with an emphasis on antisense transcripts, and (3) define and analyze the immediate/primary estrogen-regulated transcriptome in a variety of biological systems. These studies will exploit the power of GRO-seq to address fundamental molecular mechanisms and will reveal new mechanistic insights that will change the way we think about estrogen signaling. The increased understanding of estrogen signaling gained from these studies will aid in finding better ways to prevent, diagnose, and treat estrogen-related diseases. In addition, since ERs represent prototypical signal-regulated transcription factors, the study of ER function using GRO-seq will shed light on gene regulation by other transcription factors and suggest new ways to study their biology.

描述（由申请人提供）：雌激素在生殖器官、乳腺、骨骼、心脏、脉管系统、脂肪和中枢神经系统的正常发育和功能以及相同组织的常见功能障碍中发挥关键作用。这些研究的长期目标是更好地理解配体ER控制基因表达的全球模式以调节细胞生理学的机制。我们的总体假设是，生物环境将发挥关键作用，在确定雌激素依赖性转录反应的性质和程度，雌激素反应将不同于其他信号通路的反应。在这项提案中，我们将使用一种独特的，敏感的，强大的，全面的新基因组方法进行转录分析，称为全局核运行和测序（GRO-seq），它非常适合分析无法通过其他手段解决的特定转录机制。在本文所述的研究中，我们将使用GRO-seq与其他基因组、计算和基因特异性测定组合，以阐明直接和主要效应（即，几分钟，而不是几小时）的雌激素对正常和癌细胞的转录组，包括对非编码转录的影响。具体而言，我们将：（1）确定雌激素信号传导途径，雌激素受体结合事件和雌激素依赖性转录结果之间的功能关系，（2）确定非编码雌激素调节转录物的调节机制和功能作用，重点是反义转录物，（3）定义和分析各种生物系统中的直接/初级雌激素调节转录组。这些研究将利用GRO-seq的力量来解决基本的分子机制，并将揭示新的机制见解，这将改变我们对雌激素信号传导的看法。从这些研究中获得的对雌激素信号传导的更多理解将有助于找到更好的方法来预防，诊断和治疗雌激素相关疾病。此外，由于ER代表了典型的信号调节转录因子，因此使用GRO-seq研究ER功能将揭示其他转录因子的基因调控，并提出研究其生物学的新方法。