Regulation of metabolism and stress response by the Mediator complex in C. elegans and in the mouse pancreas

Stefan Taubert, Ph.D.
University of British Columbia, CA

Individual gene programs must be expressed at the right time and in the right place (cell or tissue type), and dysregulated gene expression can cause or exacerbate numerous diseases, such as diabetes and cancer. Our research focuses on Mediator, an evolutionarily conserved multi-protein complex that is vital for eukaryotic transcription. Individual Mediator subunits interact physically and functionally with specific transcription factors and thus implement specific gene programs and biological processes such as stress responses, metabolic re-programming, and lineage-specific developmental programs. Using C. elegans, we have shown that Mediator subunit MDT-15/MED15 integrates the regulation of fatty acid metabolism, oxidative stress responses, starvation adaptation, prevention of endoplasmic reticulum (ER) stress, xenobiotic/drug detoxification, and trace metal homeostasis. Molecularly, MDT-15 partners with the nuclear hormone receptor NHR-49/HNF4, the master redox regulator SKN-1/Nrf, and other conserved transcription factors to implement these specific regulatory pathways. Our recent work suggests that MDT-15 and NHR-49 corporately control a metabolic adaptation response that is activated in multiple distinct stresses. Moreover, we have begun to explore the function of MED15 in mammalian models. In the mouse model, we find that MED15 is required for the development and specification of the pancreatic b-cells by interacting with a Homeobox transcription factor, such that loss of MED15 results in immature b-cells and diabetes-like phenotypes. In sum, MDT-15/MED15 plays important roles in the lineage-specific development and in stress adaptation programs

Department of Nutritional Sciences
Interdepartmental Graduate Program in Nutritional Sciences
http://www.nutrisci.wisc.edu