Transcriptional Control of Metabolic Homeostasis by Nuclear Hormone Receptors and Associated Coregulators

核激素受体和相关共调节因子对代谢稳态的转录控制

• 批准号: 243318943
• 负责人: Professorin Dr. Nina Henriette Uhlenhaut
• 金额: --
• 依托单位: Professur für Metabolic Programming
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/243318943?language=en
• 关键词: Transcriptional; Control; Metabolic; Homeostasis; Nuclear

Worldwide, the rise in obesity rates and associated metabolic disorders such as diabetes and cardiovascular disease present a major threat to human health. Obesity induces an insulinresistant state in liver, muscle and adipose tissue, resulting from a combination of altered functions of insulin target cells and the accumulation of macrophages that secrete proinflammatory mediators. The glucocorticoid receptor (GR) is one of the most potent anti-inflammatory drug targets in clinical use today and one of the most powerful metabolic regulators. It belongs to the nuclear hormone receptor family of ligand-gated transcription factors that act as important physiological regulators. Their intrinsic ability to bind small molecules not only presents a direct link between cellular signaling processes and the resultant regulation of gene expression but also provides ideal therapeutic targets.GR’s immunosuppressant and metabolic actions are the result of both positive and negative transcriptional regulation. How the GR, other nuclear receptors or transcription factors in general activate certain genes while at the same time repressing others remains an unresolved molecular paradox. By cistromic analyses in macrophages, we have found that classical models are insufficient to explain GR’s regulatory polarity. I therefore aim to further characterize negative and positive cis-regulatory elements occupied by GR during the regulation of inflammatory genes: Global chromosome conformation capture assays will be used to study three-dimensional chromatin interactions conferred by GR. We will also undertake a quantitative proteomics approach to analyze transcriptional complexes assembled on inflammatory enhancers and to identify novel interaction partners of GR. The aim of these studies is to investigate the function of distant enhancers and to improve our understanding of transcriptional repression. In parallel, a proteinprotein interaction screen to specifically elucidate the regulatory relationships between the entire nuclear receptor and the forkhead transcription factor families will be performed to determine their potential impact on the regulation of energy homeostasis. In addition, I propose exploring the role of E47, a potential GR coregulator that we identified and that is linked to transcriptional activation, in vivo using loss of function mouse models.These studies will provide a deeper understanding of the crosstalk between transcriptional coregulators and the mechanisms of tissue-specificity that make nuclear receptors such effective metabolic and anti-inflammatory regulators. My major goals are to elucidate the regulatory polarity of GR and its associated proteins in the innate immune system and in insulin target tissues. Understanding how the assembly of cis-regulatory complexes is mediated by combinatorial codes of coregulators and pioneering factors will ultimately open up new avenues for the treatment of metabolic and inflammatory disorders.

在世界范围内，肥胖率的上升以及糖尿病和心血管疾病等相关代谢紊乱对人类健康构成了重大威胁。肥胖会导致肝脏、肌肉和脂肪组织出现胰岛素抵抗状态，这是胰岛素靶细胞功能改变和分泌促炎介质的巨噬细胞积聚共同作用的结果。糖皮质激素受体（GR）是当今临床使用的最有效的抗炎药物靶点之一，也是最强大的代谢调节剂之一。它属于配体门控转录因子的核激素受体家族，作为重要的生理调节因子。它们结合小分子的内在能力不仅代表了细胞信号传导过程和由此产生的基因表达调节之间的直接联系，而且还提供了理想的治疗靶点。GR的免疫抑制剂和代谢作用是正转录调节和负转录调节的结果。 GR、其他核受体或转录因子如何激活某些基因，同时抑制其他基因，仍然是一个尚未解决的分子悖论。通过巨噬细胞的顺反体分析，我们发现经典模型不足以解释GR的调控极性。因此，我的目标是进一步表征 GR 在炎症基因调节过程中占据的负顺式和正顺式调节元件：全局染色体构象捕获分析将用于研究 GR 赋予的三维染色质相互作用。我们还将采用定量蛋白质组学方法来分析炎症增强子上组装的转录复合物，并鉴定 GR 的新相互作用伙伴。这些研究的目的是研究远端增强子的功能并提高我们对转录抑制的理解。与此同时，将进行蛋白质相互作用筛选，以具体阐明整个核受体和叉头转录因子家族之间的调节关系，以确定它们对能量稳态调节的潜在影响。此外，我建议利用功能丧失小鼠模型在体内探索 E47 的作用，E47 是我们发现的一种潜在的 GR 共调节因子，与转录激活相关。这些研究将更深入地了解转录共调节因子之间的串扰以及使核受体成为有效代谢和抗炎调节剂的组织特异性机制。我的主要目标是阐明 GR 及其相关蛋白在先天免疫系统和胰岛素靶组织中的调节极性。了解顺式调节复合物的组装如何通过共调节因子和先锋因子的组合编码介导，最终将为治疗代谢和炎症性疾病开辟新途径。