DEVELOPMENT OF BIOINFORMATIC METHODS FOR THE INTEGRATION OF TRANSCRIPTOMIC AND EPIGENOMIC ANALYSIS OF COLORECTAL CANCER DERIVED ORGANOIDS.

Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction as a key driver of tumor transcriptional deregulation and dependencies. In this work, we seek to unravel the chromatin landscape of human colorectal cancer (CRC) by exploiting the organoid model in order to identify a common epigenetic blueprint and investigate its relevance in other types of cancers. To this extent, we generated a library of patient-derived organoids (PDOs) from different subtypes of CRC representing the heterogeneity of this type of tumor. We reconstructed the epigenetic landscape of CRC and retrieved a catalog of regulatory elements using a complete panel of the most common histone modifications. Next, we identified a conserved and tumor-specific enhancerome that is cancer cell-intrinsic and independent of interpatient tumor heterogeneity. Interestingly, we also identified the transcriptional co-activator YAP and TAZ as key regulators of the conserved CRC gained enhancerome. Reaching beyond CRC, we took advantage of ATAC-seq data of diverse tumor malignancies to demonstrate that our CRC enhancer blueprint was a conserved feature of epigenetic deregulation in human cancer pathology. We next sought to depict the cancer epigenetic deregulation at single-cell resolution demonstrating the specificity of our cancer regulatory blueprint for malignant cells in different types of cancer, suggesting a key role of the cancer regulatory blueprint in tumorigenesis and maintenance of the cancer cell state. Despite the considerable genetic and clinical heterogeneity of CRC, our work suggests a common layer of YAP/TAZ-mediated epigenetic deregulation in cancer and provides a detailed epigenetic resource of critical importance for identifying therapeutic targets with enhanced precision.