TY - JOUR
T1 - Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ
AU - Della Chiara, Giulia
AU - Gervasoni, Federica
AU - Fakiola, Michaela
AU - Godano, Chiara
AU - D’Oria, Claudia
AU - Azzolin, Luca
AU - Bonnal, Raoul Jean Pierre
AU - Moreni, Giulia
AU - Drufuca, Lorenzo
AU - Rossetti, Grazisa
AU - Ranzani, Valeria
AU - Bason, Ramona
AU - de Simone, Marco
AU - Panariello, Francesco
AU - Ferrari, Ivan
AU - Fabbris, Tanya
AU - Zanconato, Francesca
AU - Forcato, Mattia
AU - Romano, Oriana
AU - Caroli, Jimmy
AU - Gruarin, Paola
AU - Sarnicola, Maria Lucia
AU - Cordenonsi, Michelangelo
AU - Bardelli, Alberto
AU - Zucchini, Nicola
AU - Ceretti, Andrea Pisani
AU - Mariani, Nicolò Maria
AU - Cassingena, Andrea
AU - Sartore-Bianchi, Andrea
AU - Testa, Giuseppe
AU - Gianotti, Luca
AU - Opocher, Enrico
AU - Pisati, Federica
AU - Tripodo, Claudio
AU - Macino, Giuseppe
AU - Siena, Salvatore
AU - Bicciato, Silvio
AU - Piccolo, Stefano
AU - Pagani, Massimiliano
N1 - Funding Information: We would like to thank D. Parazzoli, M. Garrè, F. Casagrande, and E. Martini at IFOM imaging facility for technical assistance; D. Pasini and M. Zanotti for initial support with organoids; M. Miozzo for helping in clinical classification of primary tumor samples; M. Fassan, V. Guzzardo and D. Di Biagio for CRC samples and in situ hybridization. This work was supported by grants from the Italian Ministry of Education, University and Research (MIUR), and the National Council of Research of Italy (CNR) under the EPIGEN Flagship project to S.B., M.P., S.P., and G.T.; the Fondazione AIRC grant IG2016-ID. 18575 and European Research Council (ERC) CoG grant n° 617978 to M.P.; the Fondazione AIRC under 5 per Mille 2019-ID. 22759 program to S.B., M.P., and S.P.; the European Research Council (ERC) AdG grant n° 670126 to S.P. HOMIC - Human Organoid Models Integrative Center is supported by the “Fondazione Romeo ed Enrica Invernizzi” and University of Milan. M. Fakiola was supported by Fondazione Umberto Veronesi. Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85104785818&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-021-22544-y
DO - https://doi.org/10.1038/s41467-021-22544-y
M3 - Article
C2 - 33879786
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2340
ER -