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RETRACTED ARTICLE: Trans-silencing effect of the 3′RR immunoglobulin heavy chain enhancer on Igκ transcription at the pro-B cell stage

Cellular & Molecular Immunology volume 16, pages 668–670 (2019)Cite this article

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A Retraction to this article was published on 10 June 2021

This article has been updated

Due to their impact on nuclear organization, enhancers are master regulators of cell fate.1,2 The immunoglobulin heavy chain (IgH) locus undergoes numerous changes (such as transcription, accessibility, DNA breaks, and mutations) throughout B-cell differentiation. Several of these events are controlled by the IgH 3′ regulatory region (3′RR). The 3′RR is the master control element of mature B-cell IgH transcription,3 somatic hypermutation (SHM),4,5 conventional class switch recombination (CSR),4,6,7,8,9,10 and locus suicide recombination (LSR).11 In contrast, the 3′RR is expected to be dispensable for V(D)J recombination.12,13 During B-cell development, the heavy and light chain loci are poised for their VDJ and VJ rearrangements, respectively. The IgH locus rearranges first, with D-J joining at the pro-B-cell stages, followed by V-DJ joining at the pre-B-cell stage. The Igk locus is poised for VJ rearrangements at the pre-B cell stage. A transient association (trans-mediated by Igκ enhancer elements) between IgH and Igk loci has been demonstrated at the pre-B cell stage.14,15 Recently, unexpected and novel findings have shown that the 3′RR acts as a cis transcriptional silencer of sense and antisense germinal V, D, and J transcription at the pro-B cell stage.16,17 In light of these intriguing 3′RR features, we undertook the current study to determine if such a trans silencing effect could also be found for Igk transcription.

Our research has been approved by our local ethics committee review board (Comité Régional d’Ethique sur l’Expérimentation Animale du Limousin, Limoges, France) and carried out according to the European guidelines for animal experimentation. Pro-B cell experiments were performed with RAG-deficient (RAG−/−) and double 3′RR6-RAG-deficient (Δ3′RR–RAG−/−) mice developed in our animal facility. Femoral pro-B cells were recovered with the EasySepTM Mouse B-cell Isolation Kit (STEMCELL Technologies, France). RNA was extracted using TRIzol reagent (Thermo Fisher Scientific) according to manufacturer’s instructions. Two pooled RNA samples (from four to six mice) were obtained for each genotype. RNA libraries were obtained using TruSeq stranded total RNA with Ribo-Zero Gold (Illumina) according to the manufacturer’s instructions. RNAseq experiments were performed using the Nice Sophia Antipolis genomics platform as previously reported.7,8,17 Data were deposited in Gene Expression Omnibus under the accession number GSE117449. Mature B-cells (CD43− splenocytes) were obtained from four 129 wt mice (Charles Rivers Laboratories, France) and four Δ3′RR mice (in a 129 background) before and 48 h after in vitro stimulation (1 × 106 cells per ml in RPMI 1640 with 10% fetal calf serum) with 5 μg/ml LPS. Two pooled RNA samples (from two mice each) were obtained for each genotype. RNAseq experiments were performed as above and RNAseq data were deposited under the accession number GSE90760.

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Acknowledgements

This work was supported by grants from Ligue Contre le Cancer (Equipe labellisée LIGUE 2018) and Agence Nationale de la Recherche (ANR: projet EpiSwitch-3′RR 2016). N.G. was supported by a grant from the Association de Spécialisation et d’Orientation Scientifique (Lebanon), the municipality of Khiam (Lebanon), and the Société Française d’Hématologie. H.I. is supported by a fellowship of the University of Limoges. F.B. is supported by the Fondation Partenariale de l’Université de Limoges and ALURAD. We thank the Nice Sophia Antipolis genomic platform for the RNAseq experiments.

Author contributions

H.I., N.G., A.S., F.B., O.A.M., J.C.M., and Y.D. designed and performed the experiments and wrote the manuscript. Y.D. obtained the financial grants.

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  1. Alexis Saintamand

    Present address: Inserm U1236, Université Rennes 1, Rennes, France

  2. These authors contributed equally: Nour Ghazzaui, Hussein Issaoui.

Authors and Affiliations

  1. CNRS UMR 7276, Inserm U1262, Université de Limoges, Limoges, France

    Nour Ghazzaui, Hussein Issaoui, Ophélie Alyssa Martin, Alexis Saintamand, Jeanne Cook-Moreau, Yves Denizot & François Boyer

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Correspondence to Yves Denizot.

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Ghazzaui, N., Issaoui, H., Martin, O.A. et al. RETRACTED ARTICLE: Trans-silencing effect of the 3′RR immunoglobulin heavy chain enhancer on Igκ transcription at the pro-B cell stage. Cell Mol Immunol 16, 668–670 (2019). https://doi.org/10.1038/s41423-018-0189-6

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