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

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 los...

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Autores: Richart, Laia, Lapi, Eleonora, Pancaldi, Vera, Cuenca-Ardura, Mirabai, Carrillo-de-Santa Pau, Enrique, Madrid-Mencía, Miguel, Neyret-Kahn, Hélène, Radvanyi, François, Rodríguez, Juan Antonio, Cuartero, Yasmina, Serra, François, Le Dily, François, Valencia, Alfonso, Marti-Renom, Marc A., Real, Francisco X.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/52354
Acesso em linha:http://hdl.handle.net/10230/52354
http://dx.doi.org/10.1093/nar/gkab864
Access Level:acceso abierto
Palavra-chave:Gene regulation
Chromatin and epigenetics
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network_acronym_str ES
network_name_str España
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dc.title.none.fl_str_mv STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
title STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
spellingShingle STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
Richart, Laia
Gene regulation
Chromatin and epigenetics
title_short STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
title_full STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
title_fullStr STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
title_full_unstemmed STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
title_sort STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells
dc.creator.none.fl_str_mv Richart, Laia
Lapi, Eleonora
Pancaldi, Vera
Cuenca-Ardura, Mirabai
Carrillo-de-Santa Pau, Enrique
Madrid-Mencía, Miguel
Neyret-Kahn, Hélène
Radvanyi, François
Rodríguez, Juan Antonio
Cuartero, Yasmina
Serra, François
Le Dily, François
Valencia, Alfonso
Marti-Renom, Marc A.
Real, Francisco X.
author Richart, Laia
author_facet Richart, Laia
Lapi, Eleonora
Pancaldi, Vera
Cuenca-Ardura, Mirabai
Carrillo-de-Santa Pau, Enrique
Madrid-Mencía, Miguel
Neyret-Kahn, Hélène
Radvanyi, François
Rodríguez, Juan Antonio
Cuartero, Yasmina
Serra, François
Le Dily, François
Valencia, Alfonso
Marti-Renom, Marc A.
Real, Francisco X.
author_role author
author2 Lapi, Eleonora
Pancaldi, Vera
Cuenca-Ardura, Mirabai
Carrillo-de-Santa Pau, Enrique
Madrid-Mencía, Miguel
Neyret-Kahn, Hélène
Radvanyi, François
Rodríguez, Juan Antonio
Cuartero, Yasmina
Serra, François
Le Dily, François
Valencia, Alfonso
Marti-Renom, Marc A.
Real, Francisco X.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Gene regulation
Chromatin and epigenetics
topic Gene regulation
Chromatin and epigenetics
description 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.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/52354
http://dx.doi.org/10.1093/nar/gkab864
url http://hdl.handle.net/10230/52354
http://dx.doi.org/10.1093/nar/gkab864
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nucleic Acids Res. 2021;49(19):11005-21
info:eu-repo/grantAgreement/EC/FP7/609989
info:eu-repo/grantAgreement/ES/2PE/BFU2017-85926-P
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cellsRichart, LaiaLapi, EleonoraPancaldi, VeraCuenca-Ardura, MirabaiCarrillo-de-Santa Pau, EnriqueMadrid-Mencía, MiguelNeyret-Kahn, HélèneRadvanyi, FrançoisRodríguez, Juan AntonioCuartero, YasminaSerra, FrançoisLe Dily, FrançoisValencia, AlfonsoMarti-Renom, Marc A.Real, Francisco X.Gene regulationChromatin and epigeneticsCohesin 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.Oxford University Press202220222021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/52354http://dx.doi.org/10.1093/nar/gkab864reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésNucleic Acids Res. 2021;49(19):11005-21info:eu-repo/grantAgreement/EC/FP7/609989info:eu-repo/grantAgreement/ES/2PE/BFU2017-85926-P© 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.comhttps://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/523542026-06-12T07:21:37Z
score 15.811543

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