Our work centers on the crosstalk between proteins and genes. We are studying how mechanisms that ensure protein quality regulate transcription and transcript stability. We are currently pursuing the following research projects:
Dynamic control of gene expression
Transcription factors are key determinants of cellular metabolism and developmental potential. Their short lifespan allows cells to react quickly to changes in environment and fate. However, it remains largely unexplored how the removal of these regulators affects gene expression and facilitates cellular adaption. Our research aims to define the degradation patterns of transcription factors in the context of aging, stem cell, and cancer biology. The goal of these studies is to change the turnover of select transcription factors and thereby alter distinct genetic programs.
Regulation of energy metabolism through protein degradation
Degradation of transcription factors at mitochondrial promoters ensures swift and decisive adaptation of cellular energetics. In particular, the removal of the co-repressor NCoR1 through the ubiquitin-proteasome system appears to be involved in retrograde signaling, which allows nuclear respiratory genes to respond to mitochondrial activity. Enzymes that control the turnover of NCoR1 are attractive targets for intervention as they regulate oxidative phosphorylation.
Protein folding and mRNA stability in hematopoietic stem and progenitor cells
Millions of new blood cells are formed every day. And yet, the stem cells that are responsible for the generation of platelets, red, and white cells are long lived. How do they maintain their activity? Which mechanisms safeguard the quality of their proteome? We have found high levels of chaperones expressed in blood-forming stem and progenitor cells. These enzymes assist proteins in correct folding and prevent protein aggregation. Interestingly, one such chaperone also controls the decay of mRNA, linking protein and transcript stability. Its loss accelerates aging of hematopoietic stem cells and we are currently investigating how this enzyme synchronizes the fates of mRNAs with the polypeptides they encode.