Institut de recherches cliniques de Montréal
Molecular Genetics and Development
Our laboratory studies the regulation of gene expression during development by using transgenic and knock-out approaches. We created several mouse models of human genetic diseases. Our research has two main focuses, the first consists in studying human globin regulation of hemoglobin switching during development and the role of transcriptional factors during differentiation, the second consists in understanding the genetic and molecular mechanisms of polycystic kidney disease.
The human globin gene family is tissue- and stage-specific. The sequential expression of different genes forming the loci of α- and β-globin at different stages of mammalian development is called hemoglobin switching. Presently, the molecular mechanisms underlying this switch still remain unknown. Our research thus focuses on the elucidation of this phenomenon in vivo through genetic approaches including epigenetic and epistasis factors.
We have generated a murine sickle cell model by the expression of a modified hemoglobin. Our results show that this transgenic mice displays the biochemical and structural characteristics of sickled red blood cells and reproduce an in vivo pathology similar to that observed in sickle cell patients. We are developing different innovative approaches in gene therapy that will be useful for treatment of this disease.
Polycystic kidney disease is the most frequent inherited genetic disorder in humans (1/500) and an atypical form of cancer. We have generated a unique genetic model by targeting expression of the proto-oncogene c-myc in transgenic mice. The phenotype of this disease is present in utero and leads to renal insufficiency in adulthood. This murine model is a unique and essential tool for understanding polycystic kidney disease pathogenesis and eventually for development of treatment. Our research also consists in determining the role of the Pkd1 gene in the human disease that we cloned in order to define its role in pathogenesis, cellular differentiation, and signaling pathway(s).
- Kurbegovic A*, Côté O*, Couillard M, Ward CJ, Harris PC, Trudel M. (* both authors contributed equally) Pkd1 transgenic mice: Adult model of polycystic kidney disease with extrarenal and renal phenotypes. Hum. Mol. Gen. 19, 1174-1189 (2010)
- Beauchemin H, Trudel M. Evidence for bigenic chromatin subdomain in fetal to adult hemoglobin switch regulation. Mol. Cell. Biol. 29, 1635-1648 (2009)
- Felfly H, Trudel M. Long Term Correction of β-Thalassemia with Minimal Cellular Requirement and Transplantation Modalities. Mol. Ther. 15, 1701-1709 (2007)
- Eiymo Mwa Mpollo M-S, Beaudoin M, Berg PE, Beauchemin H, D’Agati VD, Trudel M. BP1 is a negative modulator of definitive erythropoiesis. Nucleic Acids Res. 34, 5232-5237 (2006)