STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
| Autor: | Yasmina Cuartero, Alfonso Valencia, F. Radvanyi, Vera Pancaldi, Marc A. Marti-Renom, Miguel Madrid-Mencía, Enrique Carrillo-de-Santa Pau, Francisco X. Real, François Serra, Juan Antonio Rodríguez, Eleonora Lapi, Hélène Neyret-Kahn, François Le Dily, Mirabai Cuenca-Ardura, Laia Richart |
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| Přispěvatelé: | Asociación Española Contra el Cáncer, Institut National de la Santé et de la Recherche Médicale (Francia), Fondation Toulouse Cancer Sante, Ministerio de Ciencia, Innovación y Universidades (España), Institució Catalana de Recerca i Estudis Avançats, Government of Catalonia (España), Unión Europea. Comisión Europea, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Barcelona Supercomputing Center, Spanish National Cancer Research Center (CNIO), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Barcelona Institute of Science and Technology (BIST), Institució Catalana de Recerca i Estudis Avançats (ICREA), Universitat Pompeu Fabra [Barcelona] (UPF), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Transcription
Genetic AcademicSubjects/SCI00010 STAG2 Chromosomal Proteins Non-Histone [SDV]Life Sciences [q-bio] STAG1 Cell Cycle Proteins medicine.disease_cause Genomic distribution Histones 0302 clinical medicine DOMAIN Loss of Function Mutation ELEMENTS RNA Small Interfering Càncer -- Aspectes genètics Regulation of gene expression 0303 health sciences Gene knockdown Nuclear Proteins DNA Neoplasm Chromatin 3. Good health Cell biology Gene Expression Regulation Neoplastic Bladder cancer cells 030220 oncology & carcinogenesis Epigenetics INACTIVATION Signal Transduction Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC] GENES Biology 03 medical and health sciences Cell Line Tumor REVEALS Genetics medicine Humans Urothelium Gene Loss function 030304 developmental biology Cohesin Base Sequence MUTATIONS ANEUPLOIDY COHESIN COMPLEX Gene Expression Profiling Gene regulation Chromatin and Epigenetics COMPONENTS Molecular Sequence Annotation Gene regulation Gene Ontology HEK293 Cells Urinary Bladder Neoplasms Chromatin and epigenetics PRINCIPLES Bladder--Cancer--Genetic aspects Carcinogenesis |
| Zdroj: | Repisalud Instituto de Salud Carlos III (ISCIII) Nucleic Acids Research Nucleic Acids Research, Oxford University Press, 2021, ⟨10.1093/nar/gkab864⟩ UPCommons. Portal del coneixement obert de la UPC Universitat Politècnica de Catalunya (UPC) |
| ISSN: | 0305-1048 1362-4962 |
| DOI: | 10.1093/nar/gkab864⟩ |
| Popis: | Cohesin exists in two variants containing STAG1 or STAG2. STAG2 is one of the most mutated genes in cancer and a major bladder tumor suppressor. Little is known about how its inactivation contributes to tumorigenesis. Here, we analyze the genomic distribution of STAG1 and STAG2 and perform STAG2 loss-of-function experiments using RT112 bladder cancer cells; we then analyze the genomic effects by integrating gene expression and chromatin interaction data. Functional compartmentalization exists between the cohesin complexes: cohesin-STAG2 displays a distinctive genomic distribution and mediates short and mid-ranged interactions that engage genes at higher frequency than those established by cohesin-STAG1. STAG2 knockdown results in down-regulation of the luminal urothelial signature and up-regulation of the basal transcriptional program, mirroring differences between STAG2-high and STAG2-low human bladder tumors. This is accompanied by rewiring of DNA contacts within topological domains, while compartments and domain boundaries remain refractive. Contacts lost upon depletion of STAG2 are assortative, preferentially occur within silent chromatin domains, and are associated with de-repression of lineage-specifying genes. Our findings indicate that STAG2 participates in the DNA looping that keeps the basal transcriptional program silent and thus sustains the luminal program. This mechanism may contribute to the tumor suppressor function of STAG2 in the urothelium. Fundación Científica de la Asociación Española Contra el Cáncer (to F.X.R., E.L., in part); V.P. is supported by INSERM, the Fondation Toulouse Cancer Santé and Pierre Fabre Research Institute as part of the Chair of Bioinformatics in Oncology of the CRCT; Bioinfo4women programme at the Barcelona Supercomputing Center; European Union's H2020 Framework Programme through the ERC [609989 to M.A.M.-R., in part]; Spanish Ministerio de Ciencia, Innovación y Universidades [BFU2017-85926-P to M.A.M.-R.]; C.N.I.O. is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa [SEV-2015-0510]; C.R.G. acknowledges support from ‘Centro de Excelencia Severo Ochoa 2013–2017’ [SEV-2012-0208]; Spanish ministry of Science and Innovation to the EMBL partnership and the CERCA Programme/Generalitat de Catalunya (to C.R.G.); C.R.G. also acknowledges support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement; Spanish Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014–2020 Smart Growth Operating Program (to C.N.A.G.). Funding for open access charge: Own funds. Peer Reviewed "Article signat per 15 autors/es: Laia Richart, Eleonora Lapi, Vera Pancaldi, Mirabai Cuenca-Ardura, Enrique Carrillo-de-Santa Pau, Miguel Madrid-Mencía, Hélène Neyret-Kahn, François Radvanyi, Juan Antonio Rodríguez, Yasmina Cuartero, François Serra, François Le Dily, Alfonso Valencia, Marc A Marti-Renom, Francisco X Real " |
| Databáze: | OpenAIRE |
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