The Gustafsson group studies the molecular mechanisms of transcription regulation in mammalian cells. The work can be divided into two different subareas:
The laboratory investigates the mechanisms of mammalian mitochondrial transcription. The levels of mitochondrial transcription are regulated in response to the overall respiratory needs of the eukaryotic cell, but the molecular mechanisms behind this regulation are poorly understood. Much of the work is performed using in vitro biochemistry and a reconstituted system for mammalian mtDNA transcription, containing only a promoter containing DNA fragment, and recombinant proteins. One of our areas of interest is the MTERF family of proteins. These proteins regulate mitochondrial gene expression at many different levels, including transcription initiation, transcription termination, and during protein translation. We are also studying DNA sequence dependent transcription termination in mitochondria. In our work, we have seen that a G-quadruplex structure formed in nascent RNA during transcription can stimulate termination. The mechanism is reminiscent of Rho-independent transcription termination in prokaryotes, with the exception that a G-quadruplex structure replaces the hairpin loop formed in bacterial mRNA during transcription of terminator sequences.
We have ongoing collaboration with the Maria Falkenberg group at the University of Gothenburg. This work intends to analyze the link between mitochondrial transcription and DNA replication. We have also a long-standing collaboration with the Nils-Göran Larsson laboratory at the Max Planck Institute for the Biology of Ageing in Köln, which has world-leading expertise in mouse genetics and cell biology.
Signal transduction pathways trigger a wide variety of physiological responses, including changes in Pol II activity via the multiprotein Mediator complex. Mediator is essential for basal and regulated expression of nearly all Pol II dependent genes and depletion of human Mediator from nuclear extracts abolishes Pol II transcription. Gene specific activator proteins stimulate transcription by recruitment of general transcription factors (GTFs) to promoters. In this process, Mediator supposedly functions as a bridge between the regulatory proteins and the basal pol II transcription machinery. Direct interactions have been demonstrated between many activators and specific Mediator subunits, e.g. β-catenin, p53, Gli3, and nuclear hormone receptors.
In the group, we are trying to establish the molecular mechanisms of Mediator-dependent regulation of transcription. To this end we use a combination of biochemistry and molecular biology techniques. A major goal during the last couple of years has been to characterize cyclin dependent kinase 8 (Cdk8), a conserved component of the Mediator complex. Another development and area of interest in the laboratory is the realization that Mediator may influence transcription and chromatin structure at centromeres and telomeres.