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dc.contributor.authorMarina-Zarate, Ester 
dc.contributor.authorPerez-Garcia, Arantxa 
dc.contributor.authorRamiro, Almudena R 
dc.date.accessioned2017-10-20T14:56:03Z
dc.date.available2017-10-20T14:56:03Z
dc.date.issued2017
dc.identifierISI:000409061900002
dc.identifier.citationFront Immunol. 2017; 8:1076
dc.identifier.issn1664-3224
dc.identifier.urihttp://hdl.handle.net/20.500.12105/5186
dc.description.abstractIn response to antigenic stimulation B cells undergo class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) to replace the primary IgM/IgD isotypes by IgG, IgE, or IgA. CSR is initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues at the switch (S) regions of IgH. B cell stimulation promotes germline transcription (GLT) of specific S regions, a necessary event prior to CSR because it facilitates AID access to S regions. Here, we show that CCCTC-binding factor (CTCF)-deficient mice are severely impaired in the generation of germinal center B cells and plasma cells after immunization in vivo, most likely due to impaired cell survival. Importantly, we find that CTCF-deficient B cells have an increased rate of CSR under various stimulation conditions in vitro. This effect is not secondary to altered cell proliferation or AID expression in CTCF-deficient cells. Instead, we find that CTCF-deficient B cells harbor an increased mutation frequency at switch regions, probably reflecting an increased accessibility of AID to IgH in the absence of CTCF. Moreover, CTCF deficiency triggers premature GLT of S regions in naive B cells. Our results indicate that CTCF restricts CSR by enforcing GLT silencing and limiting AID access to IgH.
dc.description.sponsorshipThe authors thank all members of the B Cell Biology Laboratory, J Mendez and VG de Yebenes for critical reading of the manuscript, F Alvarez-Prado for help with sequence analysis, F Sanchez-Cabo for advise on statistics analysis, and N Galjart and K Rajewsky for kindly providing the CTCF<SUP>fl/+</SUP> and the CD19-Cre<SUP>ki/+</SUP> mice, respectively. AP-G was a fellow of the research training program (FPU-AP2009-1732) funded by the Ministerio de Educacion, Cultura y Deporte; EM-Z is a fellow of the research training program (FPI) funded by the Ministerio de Economia y Competitividad (BES-2014-069525); AR is supported by Centro Nacional de Investigaciones Cardiovaculares (CNIC). This work was funded with the following grants to AR: SAF2013-42767-R and SAF2016-75511-R (Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016 Programa Estatal de I+D+i Orientada a los Retos de la Sociedad Retos Investigacion: Proyectos I+D+i 2016, Ministerio de Economia, Industria y Competitividad) and co-funding by Fondo Europeo de Desarrollo Regional (FEDER) and the European Research Council Starting Grant program (BCLYM-207844). The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation and is a Severo Ochoa Centre of Excellence (MEIC award SEV-2015-0505).
dc.language.isoeng
dc.publisherFrontiers Media 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectClass switch recombination
dc.subjectCCCTC-binding factor
dc.subjectGermline transcription
dc.subjectActivation-induced deaminase
dc.subjectSomatic hypermutation
dc.subjectACTIVATION-INDUCED DEAMINASE
dc.subjectS-MU REGION
dc.subjectSOMATIC HYPERMUTATION
dc.subjectV(D)J RECOMBINATION
dc.subjectFACTOR CTCF
dc.subjectB-CELLS
dc.subjectLOCUS
dc.subjectELEMENTS
dc.subjectAID
dc.subjectGENES
dc.titleCCCTC-Binding Factor Locks Premature IgH Germline Transcription and Restrains Class Switch Recombination
dc.typejournal article
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID28928744
dc.format.volume8
dc.identifier.doi10.3389/fimmu.2017.01076
dc.contributor.funderMinisterio de Educación, Cultura y Deporte (España) 
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderFundación ProCNIC 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) 
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España) 
dc.description.peerreviewed
dc.relation.publisherversionhttps://doi.org/10.3389/fimmu.2017.01076
dc.identifier.journalFrontiers in immunology
dc.repisalud.orgCNICCNIC::Grupos de investigación::Biología de linfocitos B
dc.repisalud.institucionCNIC
dc.relation.projectIDMINECO/ICTI2013-2016/SEV-2015-0505es_ES
dc.relation.projectIDMINECO/ICTI2013-2016/BES-2014-069525es_ES
dc.relation.projectIDMINECO/ICTI2013-2016/SAF2016-75511-Res_ES
dc.relation.projectIDMINECO/ICTI2013-2016/SAF2013-42767-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/207844es_ES
dc.rights.accessRightsopen accesses_ES


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