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

• Applicant: Professorin Dr. Nina Henriette Uhlenhaut
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 243318943

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.

• DFG Programme: Independent Junior Research Groups