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dc.contributor.author | Marina-Zarate, Ester | |
dc.contributor.author | Perez-Garcia, Arantxa | |
dc.contributor.author | Ramiro, Almudena R | |
dc.date.accessioned | 2017-10-20T14:56:03Z | |
dc.date.available | 2017-10-20T14:56:03Z | |
dc.date.issued | 2017 | |
dc.identifier | ISI:000409061900002 | |
dc.identifier.citation | Front Immunol. 2017; 8:1076 | |
dc.identifier.issn | 1664-3224 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/5186 | |
dc.description.abstract | In 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.sponsorship | The 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.iso | eng | |
dc.publisher | Frontiers Media | |
dc.type.hasVersion | VoR | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Class switch recombination | |
dc.subject | CCCTC-binding factor | |
dc.subject | Germline transcription | |
dc.subject | Activation-induced deaminase | |
dc.subject | Somatic hypermutation | |
dc.subject | ACTIVATION-INDUCED DEAMINASE | |
dc.subject | S-MU REGION | |
dc.subject | SOMATIC HYPERMUTATION | |
dc.subject | V(D)J RECOMBINATION | |
dc.subject | FACTOR CTCF | |
dc.subject | B-CELLS | |
dc.subject | LOCUS | |
dc.subject | ELEMENTS | |
dc.subject | AID | |
dc.subject | GENES | |
dc.title | CCCTC-Binding Factor Locks Premature IgH Germline Transcription and Restrains Class Switch Recombination | |
dc.type | journal article | |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 28928744 | |
dc.format.volume | 8 | |
dc.identifier.doi | 10.3389/fimmu.2017.01076 | |
dc.contributor.funder | Ministerio de Educación, Cultura y Deporte (España) | |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.contributor.funder | Fundación ProCNIC | |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | |
dc.contributor.funder | Ministerio de Economía, Industria y Competitividad (España) | |
dc.description.peerreviewed | Sí | |
dc.relation.publisherversion | https://doi.org/10.3389/fimmu.2017.01076 | |
dc.identifier.journal | Frontiers in immunology | |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Biología de linfocitos B | |
dc.repisalud.institucion | CNIC | |
dc.relation.projectID | MINECO/ICTI2013-2016/SEV-2015-0505 | es_ES |
dc.relation.projectID | MINECO/ICTI2013-2016/BES-2014-069525 | es_ES |
dc.relation.projectID | MINECO/ICTI2013-2016/SAF2016-75511-R | es_ES |
dc.relation.projectID | MINECO/ICTI2013-2016/SAF2013-42767-R | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/207844 | es_ES |
dc.rights.accessRights | open access | es_ES |