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igh locus suicide recombination does not depend on NHEJ in contrast to CSR in B cells

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Cellular & Molecular Immunology 2019年第2期16卷 201-202页

作者： Hend Boutouil François Boyer Jeanne Cook-Moreau Michel Cogné Sophie Péron CRIBL UMR CNRS 7276 INSERM U126287000 LimogesFrance institut Universitaire de France 75000 ParisFrance

igh locus suicide recombination(LSR)occurs in activated Blymphocytes and may result in the death of the concerned B cell,justifying the name“locus suicide recombination”.1 LSR,as for immunoglobulin(Ig)class switch recombination(CSR),is an intrachromosomal recombination in the Ig heavy chain(igh)***,LSR somehow appears to be the detrimental counterpart of CSR in activated B cells,since CSR intends for cells to actively participate in immune responses while LSR eliminates B ***,an important question to address is the regulation and the exact molecular mechanism of LSR.

关键词： CSR eliminate concerned

A novel regulatory region controls igh locus transcription and switch recombination to a subset of isotypes

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Cellular & Molecular Immunology 2019年第11期16卷 887-889页

作者： Rocío Amoretti-Villa Mélanie Rogier Isabelle Robert Vincent Heyer Bernardo Reina-San-Martin institut de Génétique et de Biologie Moléculaire et Cellulaire(IGBMC) IllkirchFrance institut National de la Santéet de la Recherche Médicale(INSERM) U1258IllkirchFrance Centre National de la Recherche Scientifique(CNRS) UMR7104IllkirchFrance Universitéde Strasbourg IllkirchFrance

Class switch recombination(CSR)occurs at the igh locus and replaces the immunoglobulin(Ig)isotype expressed from IgM to IgG,IgE or IgA,endowing the B cell receptor with novel effector *** is triggered by activation-induced cytidine deaminase(AID),1 an enzyme that deaminates cytosines to uracils in single-stranded DNA exposed by *** distinct antibody isotypes are encoded in the igh locus in individual transcription units composed of a cytokine-inducible promoter,an intronic exon,and a switch region(Sx),followed by the exons encoding the constant region(Cx)(Fig.S1a).During CSR,the choice of recombination to a particular isotype is determined by the stimulation-dependent activation of specific promoters,triggering the generation of noncoding germline transcripts(GLTs).2 Thus far,the transcriptional regulation of the igh locus is known to be controlled by the Eμenhancer,located downstream of the variable region and upstream of the donor switch region(Sμ),and the 3′regulatory region(3′RR)super-enhancer located downstream of Cα.

关键词： igh stimulation replace

Mediator contributes to igh locus VDJ rearrangements by promoting usage of most distal V segments

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Cellular & Molecular Immunology 2020年第4期17卷 407-409页

作者： Iman Dalloul Zeinab Dalloul Sandrine Le Noir François Boyer Bernardo Reina-San-Martin Jeanne Cook-Moreau Michel Cogné UMR CNRS 7276 INSERM U1262Universite de LimogesLimoges 87025France INSERM U1258 UMR CNRS 7104Institut de Genetique et de Biologie Moleculaire et CellulaireUniversitéde StrasbourgIllkirch 67400France

INTRODUCTION The immunoglobulin heavy(igh)chain locus includes a large cluster of V,D and J segments spanning thousands of kilobases in mammals and its expression implies long-range 3D-regulation of various gene modifications.1 V(D)J recombination occurs during early B-cell ontogeny.2 It is regulated by multiple transcription factors and cis-regulatory elements,and most notably by the intronic 5′Eμelement located in the JH to Cμintron.3 The intergenic control region 1(IGCR1)located between the VH and D gene clusters inhibits rearrangement of the most DH-proximal VH gene segments,while promoting usage of distal VH gene segments.4 Other downstream elements of the locus,flanking its 3′end might have more subtle roles:while the large 3′regulatory region(3′RR)shows strong internal synergies2 and behaves as a superenhancer in mature B *** deletion showed no influence on the VDJ repertoire and rather increased transcription of unrearranged V segments.3–5 Insulators binding CTCF farther downstream of the 3′RR were shown,however,to promote usage of distal VH segments.6 Altogether,there are strong indications that elements involved in long-distance regulation of transcription might also influence VDJ ***-frame splicing of VDJ exons is also needed for full Ig expression.7 Given the functional importance of gene architecture and long-range interactions for the igh locus physiology,we explored the dependence of the VDJ repertoire on Med1,a known actor of long-range enhancer interactions.

关键词： B cells mediator VDJ repertoire

Deletion of the immunoglobulin heavy chain 3′ regulatory region super-enhancer affects somatic hypermutation in B1 B cells

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Cellular & Molecular Immunology 2019年第2期16卷 195-197页

作者： Issaoui Hussein Ghazzaui Nour Boyer François Denizot Yves Saintamand Alexis Centre National de la Recherche Scientifique UnitéMixte de Recherche 7276 Institut National de la Santéet de la Recherche Médicale U1262CBRSrue du Pr.Descottes87025 LimogesFrance INSERM U1236 UniversitéRennes 1RennesFrance

Mouse B1 B cells originate in the embryonic liver and are the major B-cell population in the peritoneal and pleural cavities.1–5 By contrast,mouse B2 B cells originate in the bone marrow and are the major B-cell population in the bone marrow,spleen,and blood.B1 and B2 B cells differ not only in their origin and locations,but also in their antigen specificity,cell surface markers,capacities for class-switch recombination(CSR)and somatic hypermutation(SHM).igh cis-regulatory regions and,particularly,transcriptional super-enhancers are major locus regulators under both normal and pathological conditions.6,7 Important differences have been found regarding the ability of the igh 3′regulatory region(3′RR)super-enhancer to control the B1 and B2 B-cell fate.

关键词： spleen specificity peritoneal

A dual function for the chromatin organizer Special A-T rich Binding Protein 1 in B-lineage cells

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Cellular & Molecular Immunology 2023年第10期20卷 1114-1126页

作者： Morgane Thomas Charlotte Bruzeau Ophélie Alyssa Martin Justine Pollet Sébastien Bender Claire Carrion Sandrine Le Noir Eric Pinaud Laboratoire Contrôle de la Réponse Immune B et des Lymphoproliférations(CRIBL) Universitéde LimogesCNRS UnitéMixte de Recherche 7276Inserm Unité1262LimogesFrance Centre Hospitalier Universitaire Dupuytren Service d’ImmunopathologieLimogesFrance Centre Hospitalier Universitaire de Limoges Centre National de l’Amylose AL et Autres Maladies par Dépôt d’Immunoglobulines MonoclonalesLimogesFrance Laboratoire Suivi des Therapies Innovantes Institut de Genetique HumaineUMR 9002 CNRS-UMMontpellierFrance

SATB1(Special A-T rich Binding protein 1)is a cell type-specific factor that regulates the genetic network in developing T cells and *** T cells,SATB1 is required for lineage commitment,VDJ recombination,development and *** that its expression varies during B-cell differentiation,the involvement of SATB1 needs to be clarified in this *** a KO mouse model in which SATB1 was deleted from the pro-B-cell stage,we examined the consequences of SATB1 deletion in naive and activated B-cell *** model indicates first,unlike its essential function in T cells,that SATB1 is dispensable for B-cell development and the establishment of a broad igh ***,we show that SATB1 exhibits an ambivalent function in mature B cells,acting sequentially as a positive and negative regulator of Ig gene transcription in naive and activated cells,***,our study indicates that the negative regulatory function of SATB1 in B cells extends to the germinal center response,in which this factor limits somatic hypermutation of Ig genes.

关键词： B cells Nuclear factor Ambivalent Somatic hypermutation

Physiological and druggable skipping of immunoglobulin variable exons in plasma cells

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Cellular & Molecular Immunology 2019年第10期16卷 810-819页

作者： Mohamad Omar Ashi Nivine Srour Jean-Marie Lambert Anne Marchalot Ophelie Martin Sandrine Le Noir Eric Pinaud Maria Victoria Ayala Christophe Sirac Jerome Sauliere Jerome Moreaux Michel Cogne Laurent Delpy Unite Mixte de Recherche Centre National de la Recherche Scientifique 7276 INSERM U1262-Controle de la Reponse Immune B et LymphoproliferationsUniversitede LimogesLimogesFrance institute of Human Genetics CNRS-UM UMR9002Department of Biological HaematologyCHU MontpellierUniversity of MontpellierUFR MedecineMontpellierFrance institut Universitaire de France Universitede LimogesLimogesFrance Present address:Lady Davis institute for Medical Research McGill University3755 Cote Ste-Catherine RoadMontrealQC H3T 1E2Canada

The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin(Ig)*** recently demonstrated that aberrant Ig chains lacking variable(V)domains can be produced after nonsense-associated altered splicing(NAS)***,the expression of these truncated Ig polypeptides heightens endoplasmic reticulum stress and shortens plasma cell(PC)*** questions remain regarding the molecular mechanisms underlying this new truncated Ig exclusion(TIE-)checkpoint and its restriction to the ultimate stage of B-cell *** address these issues,we evaluated the extent of NAS of Ig pre-mRNAs using an Ig heavy chain(igh)knock-in model that allows for uncoupling of V exon skipping from TIE-induced *** found high levels of V exon skipping in PCs compared with B cells,and this skipping was correlated with a biallelic boost in igh transcription during PC *** analysis further revealed that the skipped V exon turned into a ***,we showed that hypertranscription of Ig genes facilitated V exon skipping upon passive administration of splice-switching antisense oligonucleotides(ASOs).Thus,V exon skipping is coupled to transcription and increases as PC differentiation proceeds,likely explaining the late occurrence of the TIE-checkpoint and opening new avenues for ASO-mediated strategies in PC disorders.

关键词： Immunoglobulin Exon skipping Plasma cells Antisense Oligonucleotides Nonsense-associated altered splicing