Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats

Histone H1 has seven variants in human somatic cells and contributes to chromatin compaction and transcriptional regulation. Knock-down (KD) of each H1 variant in breast cancer cells results in altered gene expression and proliferation differently in a variant specific manner with H1.2 and H1.4 KDs...

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Autores: Izquierdo-Bouldstridge, Andrea, Bustillos, Alberto, Bonet-Costa, Carles, Aribau-Miralbés, Patricia, García-Gomis, Daniel, Dabad, Marc, Esteve-Codina, Anna, Pascual-Reguant, Laura, Peiró, Sandra, Esteller, Manel, Murtha, Matthew, Millán-Ariño, Lluis, Jordan, Albert
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/174077
Acesso em linha:http://hdl.handle.net/10261/174077
Access Level:acceso abierto
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spelling Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeatsIzquierdo-Bouldstridge, AndreaBustillos, AlbertoBonet-Costa, CarlesAribau-Miralbés, PatriciaGarcía-Gomis, DanielDabad, MarcEsteve-Codina, AnnaPascual-Reguant, LauraPeiró, SandraEsteller, ManelMurtha, MatthewMillán-Ariño, LluisJordan, AlbertHistone H1 has seven variants in human somatic cells and contributes to chromatin compaction and transcriptional regulation. Knock-down (KD) of each H1 variant in breast cancer cells results in altered gene expression and proliferation differently in a variant specific manner with H1.2 and H1.4 KDs being most deleterious. Here we show combined depletion of H1.2 and H1.4 has a strong deleterious effect resulting in a strong interferon (IFN) response, as evidenced by an up-regulation of many IFN-stimulated genes (ISGs) not seen in individual nor in other combinations of H1 variant KDs. Although H1 participates to repress ISG promoters, IFN activation upon H1.2 and H1.4 KD is mainly generated through the activation of the IFN response by cytosolic nucleic acid receptors and IFN synthesis, and without changes in histone modifications at induced ISG promoters. H1.2 and H1.4 co-KD also promotes the appearance of accessibility sites genome wide and, particularly, at satellites and other repeats. The IFN response may be triggered by the expression of noncoding RNA generated from heterochromatic repeats or endogenous retroviruses upon H1 KD. In conclusion, redundant H1-mediated silencing of heterochromatin is important to maintain cell homeostasis and to avoid an unspecific IFN response.Spanish Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund [BFU2014–52237-P]. A.B. received a predoctoral fellowship from SENESCYT from Ecuador. M.D. was recipient of a fellowship from MINECO [PTA2014– 09515-I]. A.E.-C. was funded by the RED-BIO project of the Spanish National Bioinformatics Institute (INB) [PT13/0001/0044]. The INB is funded by the Spanish National Health Institute Carlos III (ISCIII) and MINECO. Funding for open access charge: Spanish Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund [BFU2014-52237-P].Peer reviewedOxford University PressMinisterio de Economía y Competitividad (España)European CommissionSecretaría de Educación Superior, Ciencia, Tecnología e Innovación (Ecuador)Instituto Nacional de Bioinformática (España)Instituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192017info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/174077reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014–52237-Pinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/PTA2014–09515-Ihttps://doi.org/10.1093/nar/gkx746Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1740772026-05-22T06:33:51Z
dc.title.none.fl_str_mv Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats
title Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats
spellingShingle Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats
Izquierdo-Bouldstridge, Andrea
title_short Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats
title_full Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats
title_fullStr Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats
title_full_unstemmed Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats
title_sort Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats
dc.creator.none.fl_str_mv Izquierdo-Bouldstridge, Andrea
Bustillos, Alberto
Bonet-Costa, Carles
Aribau-Miralbés, Patricia
García-Gomis, Daniel
Dabad, Marc
Esteve-Codina, Anna
Pascual-Reguant, Laura
Peiró, Sandra
Esteller, Manel
Murtha, Matthew
Millán-Ariño, Lluis
Jordan, Albert
author Izquierdo-Bouldstridge, Andrea
author_facet Izquierdo-Bouldstridge, Andrea
Bustillos, Alberto
Bonet-Costa, Carles
Aribau-Miralbés, Patricia
García-Gomis, Daniel
Dabad, Marc
Esteve-Codina, Anna
Pascual-Reguant, Laura
Peiró, Sandra
Esteller, Manel
Murtha, Matthew
Millán-Ariño, Lluis
Jordan, Albert
author_role author
author2 Bustillos, Alberto
Bonet-Costa, Carles
Aribau-Miralbés, Patricia
García-Gomis, Daniel
Dabad, Marc
Esteve-Codina, Anna
Pascual-Reguant, Laura
Peiró, Sandra
Esteller, Manel
Murtha, Matthew
Millán-Ariño, Lluis
Jordan, Albert
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
European Commission
Secretaría de Educación Superior, Ciencia, Tecnología e Innovación (Ecuador)
Instituto Nacional de Bioinformática (España)
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Histone H1 has seven variants in human somatic cells and contributes to chromatin compaction and transcriptional regulation. Knock-down (KD) of each H1 variant in breast cancer cells results in altered gene expression and proliferation differently in a variant specific manner with H1.2 and H1.4 KDs being most deleterious. Here we show combined depletion of H1.2 and H1.4 has a strong deleterious effect resulting in a strong interferon (IFN) response, as evidenced by an up-regulation of many IFN-stimulated genes (ISGs) not seen in individual nor in other combinations of H1 variant KDs. Although H1 participates to repress ISG promoters, IFN activation upon H1.2 and H1.4 KD is mainly generated through the activation of the IFN response by cytosolic nucleic acid receptors and IFN synthesis, and without changes in histone modifications at induced ISG promoters. H1.2 and H1.4 co-KD also promotes the appearance of accessibility sites genome wide and, particularly, at satellites and other repeats. The IFN response may be triggered by the expression of noncoding RNA generated from heterochromatic repeats or endogenous retroviruses upon H1 KD. In conclusion, redundant H1-mediated silencing of heterochromatin is important to maintain cell homeostasis and to avoid an unspecific IFN response.
publishDate 2017
dc.date.none.fl_str_mv 2017
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/174077
url http://hdl.handle.net/10261/174077
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014–52237-P
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/PTA2014–09515-I
https://doi.org/10.1093/nar/gkx746
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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