On 30 January at 14:15 Julia Maslovskaja will defend her docoral thesis „The importance of DNA binding and DNA breaks for AIRE-mediated transcriptional activation“.
Senior Research Fellow Ana Rebane (PhD (Molecular Biology), Institute of Biomedicine and Translational Medicine, University of Tartu)
Professor Pärt Peterson (PhD (Molecular Immunology), Institute of Biomedicine and Translational Medicine, University of Tartu)
Professor Jorma J. Palvimo (Ph.D.), Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
Although the gene set is the same in almost all cells of an organism, the gene expression is tightly regulated according to the cell’s needs and environmental cues. One interesting exception is medullary thymic epithelial cells (mTECs), that express much more genes than their physiological program requires. Such unusual gene expression pattern was termed promiscuous gene expression, and the autoimmune regulator (AIRE) protein was demonstrated to be responsible for its induction.
The thymus is the primary lymphoid organ of the immune system, where T cells commit their maturation process before exit to the bloodstream. The vast spectrum of genes gets expressed in mTECs and their products are presented on the cell surface to the maturing T cells. If T cell recognizes any of these products representing its own body, it is directed to the programmed cell death, and in this way dangerous autoimmune reactions are avoided. Predictably, the defects in AIRE hinder promiscuous gene expression, enabling autoreactive T cells to escape to the bloodstream and attack its own tissues, consequently causing rare autoimmune disease.
In this thesis, we aimed to clarify the molecular mechanisms of AIRE regulates gene expression. We found that AIRE is able to activate transcription from plasmid reporters lacking essential gene regulatory elements (promoter, intron, polyadenylation signal). In addition, AIRE binds strongly to plasmid DNA and does not require additional proteins for this interaction. We identified that AIRE interacts with proteins involved in DNA reparation and showed that topoisomerase inhibitors that contribute to DNA break formation, enhance AIRE-mediated transcriptional activity notably. In summary, our results complement previous publications demonstrating that AIRE is gene expression regulator notably different from known transcription factors.