Dr. François Potus, 2018 PHA Canada Paroian Family PH Research Scholarship recipient
Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada; Department of Medicine & Department of Biomedical and Molecular Sciences, Queens University, Kingston, ON
To learn more about Dr. Potus, click here.
As a young investigator, my main research interests consist of characterizing novel genetic mutations, which are changes in the DNA sequence that make up a gene. In particular, I worked on identifying “epigenetic changes” – modifications that affect the way genes work without changes in DNA sequence – associated with PAH. This has been the focus throughout my Ph.D. and postdoctoral training, conducted at Laval University (supervisors Dr. Sébastien Bonnet and Dr. Steeve Provencher) and Queen’s University (supervisor Dr. Stephen L. Archer), respectively.
Recently we successfully identified a novel genetic mutation that suggests an increased risk of developing PAH from a cohort of nearly 3,000 PAH patients. This gene, called TET2, is critically involved in a specific type of epigenetic change called “DNA methylation”, where a chemical compound (methyl group) is added to the DNA sequence of the gene. Another important role of the TET2 gene is the regulation of inflammation, something which occurs in almost all PAH patients. Our work confirmed that TET2 mutation is associated with an elevation of “cytokines” in the blood of the PAH patients. Cytokines are inflammatory markers that are characteristic of the pro-inflammatory state described in PAH.
Based on these findings, we aimed to explore the effects of a lack of TET2 in animal models using TET2-mutated mice. Not only did the mice spontaneously develop PAH, but experimental depletion of TET2 also led to increased inflammation (cytokine such as interleukin-1 beta). To investigate the therapeutic potential of these findings, we administrated an anti-inflammatory therapy (monoclonal antibody targeted IL-1b) to these TET2 mutated mice and observed improvement of PAH previously induced by TET2 depletion.
Thus, our work led to important discoveries, with the identification of TET2 as a novel gene mutation leading to PAH and involved in the pro-inflammatory state often witnessed in this population. Beyond increasing our basic knowledge of this disease, these findings also propose TET2 as a potential novel biomarker of the disease. Importantly, it suggests PAH patients could benefit from anti-inflammatory therapy and thus represents a step toward personalized medicine in PAH, a disease in dire need of curative therapies. Such tremendous work, and its recent publication (1), would not have been possible without the support from the PHA Canada Paroian Family Research Scholarship.
My future interests are to investigate the relationship between TET2 mutations and epigenetic changes, namely DNA methylation, and their interplay in the development and progression of PAH.
- Potus F, Pauciulo MW, Cook EK, Zhu N, Hsieh A, Welch CL, Shen Y, Tian L, Lima P, Mewburn J, D'Arsigny CL, Lutz KA, Coleman AW, Damico R, Snetsinger B, Martin AY, Hassoun PM, Nichols WC, Chung WK, Rauh MJ and Archer SL. Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension. Circulation. 2020.