Independent Young Investigator Group Molecular Endocrinology

Aim: To understand the molecular mechanisms underlying the regulation of metabolic homeostasis by nuclear receptors and their associated transcription factors.

Research Focus

Nuclear hormone receptors comprise a large family of ligand-gated transcription factors that act as important regulators of numerous physiological processes such as reproduction, metabolism, homeostasis, inflammation and development. To regulate gene expression, nuclear receptors bind to consensus DNA sequences known as hormone response elements. Their intrinsic ability to bind small molecules not only provides a direct link between cellular signaling processes and the resulting regulation of gene expression but also presents promising pharmacological targets for several human disorders. Nuclear receptors bind a wide range of lipophilic signaling molecules, including lipids and steroids. As sensors for these signals they control the complex physiological pathways and gene networks known to be important in the development of numerous diseases, i.e. inflammatory disorders and insulin resistance. 

Importantly, the gene networks that constitute the hormone response not only consist of activated transcripts, but gene silencing is equally critical for maintaining cellular function. Unraveling the processes that regulate the assembly of transcriptional complexes which ultimately lead to the activation or repression of nuclear receptor target genes is therefore key to understanding the nature of physiological responses in health and disease.



Source: Nina Henriette Uhlenhaut, IDO/HMGU

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. Upon ligand binding, GR translocates from the cytoplasm to the nucleus where it can both positively and negatively regulate gene expression. GR is known to bind to consensus DNA sequences known as glucocorticoid response elements (GREs), but the exact mechanisms leading to transcriptional activation versus repression are unclear.

Major goals of the lab are to elucidate the regulatory polarity of GR and its co-regulatory proteins in the innate immune system and in insulin target tissues, and to determine the importance of cell type specific pathways in the transcriptional regulation of systemic metabolism. We use a combination of mouse molecular genetics with cutting edge genomic approaches to study the function of nuclear receptors and associated transcription factors in glucose homeostasis. How the GR, other nuclear receptors or transcription factors in general can activate certain genes while at the same time repressing others is an unresolved molecular paradox. The aim of these studies is to gain a deeper understanding of the interplay between transcriptional coregulators and the mechanisms of tissue-specificity that make nuclear receptors such powerful metabolic and anti-inflammatory regulators.