Grant: Foundation Grant

The gene expression program of a cell defines its identity, i.e. it tells us, and the cell itself, who it is, what is its role and how to play it in complex organisms like ours. We study mechanisms for the control of gene expression and their misregulation in disease. The blueprint for this control is in our DNA and changes in this blueprint result in mutations. In addition to studying this genetic level of gene regulation, we also investigate epigenetic mechanisms, ie mechanisms that govern the wrapping of genetic material (DNA) into chromosomes. Both genetic and epigenetic mechanisms orchestrate the complex development of a functional human and their deregulation cause diseases. We use a hormone-coding gene of the pituitary gland as our model system and throughout the years we have discovered new regulators and new mechanisms that account for normal processes but also disease states. We have thus predicted a form of hormone deficiency that is lethal to neonates, explained it and provided a treatment that fully recovers the lethal outcome of this condition. The new frontier in the field is the epigenetic level of regulation and we are exploring this with state-of-the-art high-throughput massive DNA sequencing technologies. We also identified mechanisms involved in development of the pituitary tumors that cause Cushing disease. This disease is particularly deleterious because of excessive uncontrolled hormone production leading to hypertension, diabetes, osteoporosis, and metabolic disruption. We have partly explained the resistance to hormone feedback that characterises these tumors and we now seek to determine how cell growth is deregulated in order to develop novel treatment approaches.