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

在世界范围内，肥胖率的上升以及相关的代谢紊乱，如糖尿病和心血管疾病，对人类健康构成了重大威胁。肥胖诱导肝脏、肌肉和脂肪组织中的胰岛素抵抗状态，这是由胰岛素靶细胞的功能改变和分泌促炎介质的巨噬细胞的积累的组合引起的。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标之一，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。GR与小分子结合的内在能力不仅在细胞信号传导过程和基因表达调控之间存在直接联系，而且还提供了理想的治疗靶点。GR的免疫抑制和代谢作用是正转录和负转录调控的结果。GR、其他核受体或转录因子如何在激活某些基因的同时抑制其他基因仍然是一个尚未解决的分子悖论。通过巨噬细胞顺反分析，我们发现经典模型不足以解释GR的调节极性。因此，我的目标是进一步表征在炎症基因调节过程中GR所占据的阴性和阳性顺式调节元件：全球染色体构象捕获分析将用于研究三个-我们还将采用定量蛋白质组学方法来分析组装在炎症增强子上的转录复合物，并鉴定GR的新相互作用伙伴。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，一个蛋白质-蛋白质相互作用的屏幕，以具体阐明整个核受体和叉头转录因子家族之间的调控关系，将进行，以确定其对能量稳态的调节的潜在影响。此外，我建议探索E47的作用，一个潜在的GR coregulator，我们确定，并与转录激活，在体内使用功能丧失的小鼠models.These研究将提供更深入的理解之间的串扰转录coregulators和组织特异性的机制，使核受体等有效的代谢和抗炎调节。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是如何通过辅助调节因子和先锋因子的组合编码介导的，最终将为代谢和炎症疾病的治疗开辟新的途径。

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.