Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ

• Published in: Nature communications Vol. 12; no. 1; pp. 2340 - 18
• Main Authors: Della Chiara, Giulia, Gervasoni, Federica, Fakiola, Michaela, Godano, Chiara, D’Oria, Claudia, Azzolin, Luca, Bonnal, Raoul Jean Pierre, Moreni, Giulia, Drufuca, Lorenzo, Rossetti, Grazisa, Ranzani, Valeria, Bason, Ramona, De Simone, Marco, Panariello, Francesco, Ferrari, Ivan, Fabbris, Tanya, Zanconato, Francesca, Forcato, Mattia, Romano, Oriana, Caroli, Jimmy, Gruarin, Paola, Sarnicola, Maria Lucia, Cordenonsi, Michelangelo, Bardelli, Alberto, Zucchini, Nicola, Ceretti, Andrea Pisani, Mariani, Nicolò Maria, Cassingena, Andrea, Sartore-Bianchi, Andrea, Testa, Giuseppe, Gianotti, Luca, Opocher, Enrico, Pisati, Federica, Tripodo, Claudio, Macino, Giuseppe, Siena, Salvatore, Bicciato, Silvio, Piccolo, Stefano, Pagani, Massimiliano
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-04-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38/39; 38/91; 45/15; 631/61/212/177; 631/67/1504/1885; 631/67/2329; 631/67/69; Adaptor Proteins, Signal Transducing - genetics; Cancer; Cell death; Chromatin; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Deregulation; Enhancer Elements, Genetic; Enhancers; Epigenesis, Genetic; Epigenetics; Gene Expression Regulation, Neoplastic; Heterogeneity; Histone Code; Humanities and Social Sciences; Humans; Models, Genetic; multidisciplinary; Organoids; Organoids - metabolism; Regulators; RNA-Seq; Science; Science (multidisciplinary); Single-Cell Analysis; Trans-Activators - genetics; Transcription; Transcription Factors - genetics; Tumor Cells, Cultured; Tumors; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22544-y

Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues.
The role of epigenetic deregulation in colorectal cancer (CRC) is not fully understood yet. Here the authors use patient-derived organoids, epigenomics and single-cell RNA-seq to reveal that YAP/TAZ are key regulators that bind to active enhancers in CRC and promote tumour survival.