Glucocorticoid receptors are present in nearly all human somatic cells. They present important regulators of human metabolism and widely used anti-inflammatory drug targets – e.g. for allergies, asthma, rheumatoid arthritis or autoimmune diseases. So far, the therapeutic use of these steroid hormones is limited by severe side effects. “These undesirable effects are due to the activation of metabolic target genes,” said Dr. Nina Henriette Uhlenhaut. With funding from the ERC Starting Grant she hopes to learn more about the mechanisms underlying these functions.
An unresolved molecular paradox
Her plan is to investigate the unresolved molecular paradox of positive versus negative gene regulation by the glucocorticoid receptor. “I want to understand how a transcription factor can at the same time have activating and deactivating effects,” said Uhlenhaut. “So far, the mechanism is unknown. I have already shown that classical models are not sufficient to explain how glucocorticoid receptors silence genes.” Dr. Uhlenhaut’s hypothesis is that unknown regulatory proteins, DNA sequences, noncoding RNAs or combinations thereof may play a role. SILENCE, as her project is named, utilizes state-of-the-art genome-wide approaches to elucidate how glucocorticoid receptors regulate their target genes. She is planning a large-scale, genome-wide screen and wants to use next-generation sequencing technologies to identify regulatory mechanisms.
Dr. Nina Henriette Uhlenhaut heads the Independent Young Investigator Group Molecular Endocrinology at the Institute for Diabetes and Obesity of Helmholtz Zentrum München. Prior to this position, she worked at the Max Delbrück Center for Molecular Medicine in Berlin and at the Salk Institute in La Jolla, California.