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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Authors: Richart, Laia, Lapi, Eleonora, Pancaldi, Vera|||0000-0002-7433-624X, Cuenca Ardura, Mirabai, Carrillo de Santa Pau, Enrique, Madrid, Miguel|||0000-0002-3998-5316, Serra, François, Valencia, Alfonso|||0000-0002-8937-6789
Format: article
Publication Date:2021
Country:España
Institution:Universitat Politècnica de Catalunya (UPC)
Repository:UPCommons. Portal del coneixement obert de la UPC
Language:English
OAI Identifier:oai:upcommons.upc.edu:2117/354735
Online Access:https://hdl.handle.net/2117/354735
https://dx.doi.org/10.1093/nar/gkab864
Access Level:Open access
Keyword:Epigenetics
Chromatin
Bladder--Cancer--Genetic aspects
Bladder cancer cells
STAG2
STAG1
Genomic distribution
Gene regulation
Càncer -- Aspectes genètics
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
id ES_8a07f58ba6427e796c8fce76c57de2f9
oai_identifier_str oai:upcommons.upc.edu:2117/354735
network_acronym_str ES
network_name_str España
repository_id_str
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
Epigenetics
Chromatin
Bladder--Cancer--Genetic aspects
Bladder cancer cells
STAG2
STAG1
Genomic distribution
Gene regulation
Càncer -- Aspectes genètics
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
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|||0000-0002-7433-624X
Cuenca Ardura, Mirabai
Carrillo de Santa Pau, Enrique
Madrid, Miguel|||0000-0002-3998-5316
Serra, François
Valencia, Alfonso|||0000-0002-8937-6789
author Richart, Laia
author_facet Richart, Laia
Lapi, Eleonora
Pancaldi, Vera|||0000-0002-7433-624X
Cuenca Ardura, Mirabai
Carrillo de Santa Pau, Enrique
Madrid, Miguel|||0000-0002-3998-5316
Serra, François
Valencia, Alfonso|||0000-0002-8937-6789
author_role author
author2 Lapi, Eleonora
Pancaldi, Vera|||0000-0002-7433-624X
Cuenca Ardura, Mirabai
Carrillo de Santa Pau, Enrique
Madrid, Miguel|||0000-0002-3998-5316
Serra, François
Valencia, Alfonso|||0000-0002-8937-6789
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Epigenetics
Chromatin
Bladder--Cancer--Genetic aspects
Bladder cancer cells
STAG2
STAG1
Genomic distribution
Gene regulation
Càncer -- Aspectes genètics
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
topic Epigenetics
Chromatin
Bladder--Cancer--Genetic aspects
Bladder cancer cells
STAG2
STAG1
Genomic distribution
Gene regulation
Càncer -- Aspectes genètics
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
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
2021-10-14
2021
2021-10-27
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/354735
https://dx.doi.org/10.1093/nar/gkab864
url https://hdl.handle.net/2117/354735
https://dx.doi.org/10.1093/nar/gkab864
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 3.0 Spain
http://creativecommons.org/licenses/by-nc/3.0/es/
Attribution-NonCommercial 3.0 Spain
https://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 3.0 Spain
http://creativecommons.org/licenses/by-nc/3.0/es/
https://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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:UPCommons. Portal del coneixement obert de la UPC
instname:Universitat Politècnica de Catalunya (UPC)
instname_str Universitat Politècnica de Catalunya (UPC)
reponame_str UPCommons. Portal del coneixement obert de la UPC
collection UPCommons. Portal del coneixement obert de la UPC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869412670913904641
spelling STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cellsRichart, LaiaLapi, EleonoraPancaldi, Vera|||0000-0002-7433-624XCuenca Ardura, MirabaiCarrillo de Santa Pau, EnriqueMadrid, Miguel|||0000-0002-3998-5316Serra, FrançoisValencia, Alfonso|||0000-0002-8937-6789EpigeneticsChromatinBladder--Cancer--Genetic aspectsBladder cancer cellsSTAG2STAG1Genomic distributionGene regulationCàncer -- Aspectes genèticsÀrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::BioinformàticaCohesin 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 "Oxford University Press20212021-10-1420212021-10-27journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/354735https://dx.doi.org/10.1093/nar/gkab864reponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial 3.0 Spainhttp://creativecommons.org/licenses/by-nc/3.0/es/Attribution-NonCommercial 3.0 Spainhttps://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/3547352026-05-27T15:37:01Z
score 15,300724

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