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ERF deletion rescues RAS deficiency in mouse embryonic stem cells

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dc.contributor.authorMayor-Ruiz, Cristina
dc.contributor.authorOlbrich, Teresa
dc.contributor.authorDrosten, Matthias
dc.contributor.authorLecona, Emilio
dc.contributor.authorVega-Sendino, Maria
dc.contributor.authorOrtega Jimenez, Sagrario
dc.contributor.authorDominguez, Orlando
dc.contributor.authorBarbacid, Mariano
dc.contributor.authorRuiz, Sergio
dc.contributor.authorFernandez-Capetillo, Oscar
dc.contributor.funderFundación La Caixa
dc.contributor.funderBoehringer Ingelheim Fonds
dc.contributor.funderBotín Foundation
dc.contributor.funderBanco Santander
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
dc.contributor.funderFundación La Marató TV3
dc.contributor.funderHoward Hughes Medical Institute
dc.date.accessioned2019-09-20T12:10:49Z
dc.date.available2019-09-20T12:10:49Z
dc.date.issued2018-04-01
dc.description.abstractMEK inhibition in combination with a glycogen synthase kinase-3β (GSK3β) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon remain poorly understood. Here we show that RAS nullyzygosity reduces the growth of mouse ESCs (mESCs) and prohibits their differentiation. Upon RAS deficiency or MEK inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor), a transcriptional repressor from the ETS domain family, translocates to the nucleus, where it binds to the enhancers of pluripotency factors and key RAS targets. Remarkably, deletion of Erf rescues the proliferative defects of RAS-devoid mESCs and restores their capacity to differentiate. Furthermore, we show that Erf loss enables the development of RAS nullyzygous teratomas. In summary, this work reveals an essential role for RAS proteins in pluripotency and identifies ERF as a key mediator of the response to RAS/MEK/ERK inhibition in mESCs.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipWe thank Cian Lynch, Jorge Monsech, and Diego Megias for their help with microarray, ChIP-seq, and high-throughput microscopy analyses. We also thank Dr. Manuel Serrano and Dr. André Nussenzweig for their input on the manuscript, and Dr. Diego Sanz for his support throughout the project. C.M.-R. was funded by a PhD fellowship from La Caixa Foundation, T.O. was funded by a PhD fellowship from the Boehringer Ingelheim Fonds, and S.R. was funded by a Ramon y Cajal contract (RYC-2011-09242). Research was funded by Fundación Botín and Banco Santander through its Santander Universities Global Division; grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-23753 and SAF2014- 57791-REDC; these projects were cofinanced with European Fonds Européen de Développement Économique et Régional [FEDER] funds), Fundació La Marato de TV3, Howard Hughes Medical Institute, and the European Research Council (ERC- 617840) to O.F.-C.; and grants from the Spanish Ministryof Economy and Competitiveness (SAF2013-49147-P and SAF2016-80874-P; these projects were cofinanced with European FEDER funds) to S.R. Author contributions: C.M.-R. and S.R. conducted most of the experiments; T.O. helped with the characterization of RASlox/lox mESCs and with ERF localization studies; E.L. helped with ChIP-seq experiments; M.D., S.O., and M.B. contributed to the work on RAS-deficient cells; M.V.-S. provided technical help; O.D. helped with genomics experiments and bioinformatics analysis; and S.R. and O.F.-C. coordinated the study and wrote the manuscript.es_ES
dc.format.number7-8es_ES
dc.format.page568-576es_ES
dc.format.volume32es_ES
dc.identifier.citationGenes Dev. 2018;32(7-8):568-576es_ES
dc.identifier.doi10.1101/gad.310086.117es_ES
dc.identifier.e-issn1549-5477es_ES
dc.identifier.issn0890-9369es_ES
dc.identifier.journalGenes & developmentes_ES
dc.identifier.pubmedID29650524es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/8360
dc.language.isoenges_ES
dc.publisherCold Spring Harbor Laboratory Presses_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2014-57791-REDCes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2011-23753es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2013-49147-Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SAF2016-80874-Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/617840es_ES
dc.relation.publisherversionhttps://doi.org/10.1101/gad.310086.117.es_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Inestabilidad Genómicaes_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject2ies_ES
dc.subjectERFes_ES
dc.subjectRASes_ES
dc.subjectmESCses_ES
dc.subjectPluripotencyes_ES
dc.subject.meshAnimalses_ES
dc.subject.meshCell Differentiationes_ES
dc.subject.meshCell Linees_ES
dc.subject.meshEmbryonic Stem Cellses_ES
dc.subject.meshEnhancer Elements, Genetices_ES
dc.subject.meshGene Deletiones_ES
dc.subject.meshMicees_ES
dc.subject.meshMice, Nudees_ES
dc.subject.meshRepressor Proteinses_ES
dc.subject.meshTeratomaes_ES
dc.subject.meshGenes, rases_ES
dc.titleERF deletion rescues RAS deficiency in mouse embryonic stem cellses_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
dspace.entity.typePublication
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relation.isAuthorOfPublication63a98289-e19e-4206-a78f-e82e93209dd9
relation.isAuthorOfPublication728b1f96-276b-4ab5-8640-8964fb72939f
relation.isAuthorOfPublicationeb478d8c-dd11-4b47-8795-7ac57cb60b2d
relation.isAuthorOfPublication.latestForDiscovery63742a80-a417-45e8-85a6-6c116bab49bf
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