Hormonal Regulation of Mammalian Gene Expression

我们的目标是定义氧化核受体(OX-NR)配体和辅因子复合体如何影响 通过控制基因表达模式来控制生理和疾病。这背后的假设是 有观点认为，OX-NR信号是通过配体引导的染色质修饰来介导的，而由此产生的 诱导表观基因组状态(表观状态)动员基因群或网络以产生独特的细胞功能 和生理学。为了做到这一点，在Aim I中，我们将使用蛋白质化学方法来定义动态 参与调控的核受体组装的表观基因组复合体的性质 氧化代谢(OX-NRS)从代谢活性物质分离的表观复合体的变化 组织，如肌肉和棕色脂肪组织，由环境调节器，包括运动，寒冷 暴露和禁食将确定特定背景基因调控所需的关键表观遗传调节因子。 特殊目标II将建立与以下因素相关的基因表达特征的比较变化 上述表观复合体的变化。此外，我们将监测关键代谢参数的变化 受代谢应激源的影响以及OX-NR配体和调节剂的治疗。在AIM III中，染色质 免疫沉淀与大规模平行测序(ChLP-SEQ)实验将确定 OX-NRs在代谢活跃组织中的特定基因组位置(序列)。刺激诱导 OX-NR周期的变化，结合AIM II中确定的基因表达的变化，将使 表观复合体和基因调控之间的因果联系。目标四将定义 通过定位关键的组蛋白乙酰化激活和甲基化标记获得OX-NRS的表观遗传学特征 在有和没有应激诱导的情况下代谢活跃的组织。我们认为核受体起到了 在推动表观基因组控制方面的关键作用。通过在表观基因组、新陈代谢和 正常生理学这一应用提供了一种独特的方法来将这种理解扩展到新陈代谢 并促进开发可通过以下方式治疗新陈代谢疾病的新型药物 处理基因组。 相关性(请参阅说明)： 这项建议旨在确定氧化核激素受体如何调节结构， 基因组的功能和可获得性，以控制基因表达和身体生理。受体 调节通路与肥胖症、糖尿病和心血管疾病的流行特别相关 这项工作有望为HEW诊断学的发展提供见解和 治疗学。

Our goal is to define how oxidative nuclear receptor (ox-NR) ligands and cofactor complexes influence physiology and disease by controlling patterns of gene expression. The underlying hypothesis of this proposal is that ox-NR signaling is mediated by ligand-directed chromatin modifications and that the resulting induced epigenomic state (epi-state) mobilizes groups or networks of genes to produce unique cell function and physiology. To do this, in Aim I we will use a protein chemistry approach to define the dynamic properties of epi-genomic complexes (epi-complexes) assembled by nuclear receptors involved in regulating oxidative metabolism (ox-NRs). Changes induced in epi-complexes isolated from metabolically active tissues, such as muscle and brown adipose tissue, by environmental modulators including exercise, cold exposure, and fasting, will identify key epigenetic regulators required for context-specific gene regulation. Specific Aim II will establish the comparative changes in gene expression signatures that correlate to changes in the above epi-complexes. In addition, we will monitor shifts In key metabolic parameters influenced by the metabolic stressors and treatment with ox-NR ligands and modulators. In Aim III, chromatin mmunoprecipitation coupled to massively parallel sequencing (ChlP-Seq) experiments will determine the specific genomic locations (cistromes) of ox-NRs in the metabolically active tissues. Stimuli-Induced alterations in ox-NR cistromes, combined with the changes in gene expression identified in Aim II, will allow causal associations to be drawn between epi-complexes and gene regulation. Aim IV will define the epigenetic signatures of ox-NRs by mapping key histone acetylation activation and methylation markers in metabolically active tissues with and without stress induction. We believe that nuclear receptors play a critical role in driving epigenomic control. By making key links between the epigenome, metabolism and normal physiology this application provides a unique means to extend this understanding to metabolic disease and facilitates the development of new classes of drugs that can treat diseases of metabolism by treating the genome. RELEVANCE (See instructions): This proposal is directed at identifying how oxidative nuclear hormone receptors modulate the structure, function and accessibility of the genome to control gene expression and body physiology. Receptor regulated pathways are particularly relevant to the epidemics of obesity, diabetes and cardiovascular disease and this work Is anticipated to provide insights for the development of hew diagnostics and therapeutics.