Uncovering regulators of H3K79 methylation in cartilage to identify targets for osteoarthritis therapy

Osteoarthritis (OA), the most common chronic joint disease, is characterized by progressive damage to the articular cartilage, remodelling of the joint-associated bone, and inflammation. Current OA treatments are limited to pain relief, physiotherapy, or joint replacement surgery in severe cases, yet drugs that stop the disease progression are lacking. DOT1L is an enzyme that chemically modifies an amino-acid (Lysine at position 79) in the Histone-3 protein (H3K79) by adding a methyl group. We identified DOT1L as key protector of cartilage health and reported that DOT1L activity, indicated by the levels of H3K79 methylation (H3K79me), is reduced in OA compared to non-OA cartilage. Thus, maintaining H3K79me seems to be critical to preserve joint health and prevent the development or progression of OA. Here, we aim to uncover regulators of H3K79me using a dual strategy. First, we will identify which histone demethylase enzymes are responsible for the removal of methyl groups of H3K79 using a combination of in vitro, ex vivo, and in vivo techniques. Second, we will use a discovery approach based on a large-scale siRNA screening in a human articular chondrocyte cell line. We will investigate the therapeutic impact of targeting regulators identified using both approaches for OA in chondrocytes and explants from OA-patients and in well-established OA mouse models. This project could therefore identify new targets for therapy of a disease with an enormous medical need.