The DOTOS project will study the role of DOT1L in synovial joint development, homeostasis and disease with specific attention towards osteoarthritis (OA), one of the most common chronic diseases.We identified an association between the DOT1L (DOT1-like histone H3 methyltransferase) gene and OA. Histone methylation is a regulator of gene transcription. Some histone methylations result in increased gene expression, e.g. lysine methylation at lysine 79 in histone 3 (H3K79). DOT1L is the only known H3K79 methyltransferase. We demonstrated that DOT1L plays an important role in the canonical Wnt signaling cascade in a molecular complex involving TCF transcription factors.These observations stimulated us to now investigate the role of DOT1l in joint development and disease, processes associated with Wnt signaling.The key hypothesis for this project states that DOT1L and Wnt signalling are required for joint development and homeostasis but that their increased activation in progressive OA is detrimental to the joint.This project will teach us how DOT1L interacts with Wnts and other signalling pathways in joint biology and disease. In addition, we aim to develop a basis for future therapeutic approaches.Dr. Monteagudo, the candidate for the fellowship, will be trained in animal models and in translational research hypotheses. She will benefit from complementary skills training and interactions with industry to gain further maturity and independence as a researcher. This additional training will be beneficial to her career as well as to the European Research Area as there is a great societal need for translational researcher in the field of chronic joint diseases able to make links between basic biology and clinical questions. The project pays specific attention to cross-sectorial interactions and communication with the scientific community as well as with the primary stakeholders for osteoarthritis: the patients and population at risk.