Project 4: The role of TET3 in ROS-dependent DNA damage responses in cardiac fibrosis

PI Göttingen: E.M. Zeisberg; PI London: K. Otsu; PhD student: Sabine Maamari

Scientific background and preliminiary results

Every form of chronic heart disease is associated with cardiac fibrosis, and the degree of cardiac fibrosis is an independent risk factor for cardiovascular mortality. While accumulation of reactive oxygen species (ROS) and ensuing oxidative damage have similarly been unequivocally established as causal contributors to cardiovascular morbidity and mortality, underlying mechanisms are diverse and in their complexity still incompletely understood. Cardiac fibrosis as well as fibrosis of other organs has been demonstrated to be associated with both aberrant DNA methylation patterns and accumulation of DNA damage. Recent data suggests that the epigenetic regulator ten eleven translocation-3 (Tet3) zinc finger protein (which mediates oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and also of thymidine to 5-hydroxymethyluracil) has an additional function in mediating chromatin relaxation in response to DNA double-strand breaks. ROS in turn mediates DNA double-strand breaks as well as leads to decreased expression of TET3. This project aims to gain mechanistic insights into the mechanisms underlying the accumulation of DNA damage in response to oxidative stress. Specifically, this project will explore how lack of TET3 interferes with the endogenous mechanisms of DNA repair upon oxidative stress, and how this contributes to endothelial-mesenchymal transition (EndMT) and ultimately to cardiac fibrosis by utilizing mice lacking TET3 in endothelial cells or fibroblasts respectively.

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