Cancer is one of the leading causes of death worldwide and its management remains challenging. Tumor evolution, the process of genetic and epigenetic divergence and selection of cancer cell clones in a heterogeneous tumor, is a key aspect of disease progression and therapy resistance. The main goal of this proposal is to expand our understanding of the biological mechanisms involved in these processes. So far, the role of chromatin regulation and epigenetics in tumor evolution remains poorly characterized and understood. This is particularly relevant in bladder cancer where mutations in chromatin regulation are very frequent and are associated with advanced and therapy resistant disease. Epi-BCE will advance the state-of-the-art through the discovery of epigenetic mechanisms that drive bladder cancer progression and chemoresistance in cell subpopulations, and tumors with chromatin deregulation. Specifically, I will utilize a carcinogen-based mouse model of bladder cancer that recapitulates human cancer stages from early to advanced and therapy resistant disease. I will perform transcriptomics and epigenomics at bulk and single-cell level at stages of disease progression. In addition, I will employ genetically engineered mice with ablation of chromatin regulation proteins, integrative computational analysis and functional genetic experiments to identify key mechanisms. Epi-BCE will be a platform for professional growth. I will receive technical training in experimental mouse models, bioinformatics, and 3D genomics through a secondment. I will engage in new professional networks and acquire transferable skills. Grantsmanship activities will support the fellow towards a path to independence. Overall, the proposed experiments will yield scientific knowledge and reusable datasets on cancer biology. These outcomes will promote and accelerate future research on cancer management and therapeutics.