Inhibition of histone demethylases as an approach to restore deficient DOT1L activity in osteoarthritis

DOT1L is a histone methyltransferase involved in epigenetic regulation of the Wnt signaling cascade. The host lab identified a key role for DOT1L as master regulator of cartilage health and disease, with the enzyme specifically regulating the activation of Wnt signaling. Loss of DOT1L activity contributes to hyper-activation of Wnt signalling and this leads to cartilage destruction. DOT1L activity is reduced in patients with osteoarthritis. Therefore, increasing DOT1L levels and activity may protect against disease development. In this new PhD project, we aim to further evaluate how DOT1L levels and activity are regulated to identify those new targets for the treatment of this chronic joint disease.