Moving upstream of DOT1L activity and H3K79 methylation to safeguard the articular cartilage

Osteoarthritis is the most common chronic joint disease with enormous societal costs. In osteoarthritis, structure and function of the joints are gradually affected leading to pain and disability. Current treatment options remain limited and no drug strategies are available that can stop the progression disease. We have contributed to the discovery that DOT1L, an enzyme that modulates gene expression in the cell nucleus, plays a role in this disease. We have learned that DOT1L safeguards the cartilage by limiting the activation of a specific molecular pathway, called Wnt signaling. Hyper-activation of this pathway leads to joint disease. In this project, we aim to further study the role of DOT1L in joint health and disease and more in particular the factors that control DOT1L’s activity. We will use a translational research approach using state-of-the art technologies in the analysis of patient derived cells and samples combined with innovative in vitro set-ups and with mouse models of disease. Our research plan aims to integrate these human and animal model data and to precisely define the regulation of DOT1L’s activity and the opportunities it offers to develop new therapeutic strategies by enhancing DOT1L activity when osteoarthritis develops.