STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells

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• dc.contributor.author Richart, Laia
• dc.contributor.author Lapi, Eleonora
• dc.contributor.author Pancaldi, Vera
• dc.contributor.author Cuenca-Ardura, Mirabai
• dc.contributor.author Carrillo-de-Santa Pau, Enrique
• dc.contributor.author Madrid-Mencía, Miguel
• dc.contributor.author Neyret-Kahn, Hélène
• dc.contributor.author Radvanyi, François
• dc.contributor.author Rodríguez, Juan Antonio
• dc.contributor.author Cuartero, Yasmina
• dc.contributor.author Serra, François
• dc.contributor.author Le Dily, François
• dc.contributor.author Valencia, Alfonso
• dc.contributor.author Martí Renom, Marc A.
• dc.contributor.author Real, Francisco X.
• dc.date.accessioned 2022-01-28T08:05:59Z
• dc.date.available 2022-01-28T08:05:59Z
• dc.date.issued 2021
• dc.description.abstract 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.
• dc.description.sponsorship 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Richart L, Lapi E, Pancaldi V, Cuenca-Ardura M, Pau EC, Madrid-Mencía M, Neyret-Kahn H, Radvanyi F, Rodríguez JA, Cuartero Y, Serra F, Le Dily F, Valencia A, Marti-Renom MA, Real FX. STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells. Nucleic Acids Res. 2021;49(19):11005-21. DOI: 10.1093/nar/gkab864
• dc.identifier.doi http://dx.doi.org/10.1093/nar/gkab864
• dc.identifier.issn 0305-1048
• dc.identifier.uri http://hdl.handle.net/10230/52354
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Nucleic Acids Res. 2021;49(19):11005-21
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/609989
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-85926-P
• dc.rights © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword Gene regulation
• dc.subject.keyword Chromatin and epigenetics
• dc.title STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion