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Association between the Igk and Igh immunoglobulin loci mediated by the 3′ Igk enhancer induces 'decontraction' of the Igh locus in pre–B cells

Nature Immunology volume 9, pages 396–404 (2008)Cite this article

Abstract

Variable-(diversity)-joining (V(D)J) recombination at loci encoding the immunoglobulin heavy chain (Igh) and immunoglobulin light chain (Igk) takes place sequentially during successive stages in B cell development. Using three-dimensional DNA fluorescence in situ hybridization, here we identify a lineage-specific and stage-specific interchromosomal association between these two loci that marks the transition between Igh and Igk recombination. Colocalization occurred between pericentromerically located alleles in pre–B cells and was mediated by the 3′ Igk enhancer. Deletion of this regulatory element prevented association of the Igh and Igk loci, inhibited pericentromeric recruitment and locus 'decontraction' of an Igh allele, and resulted in greater distal rearrangement of the gene encoding the variable heavy-chain region. Our data indicate involvement of the Igk locus and its 3′ enhancer in directing the Igh locus to a repressive nuclear subcompartment and inducing the Igh locus to decontract.

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Figure 1: Interchromosomal association between one Igh allele and one Igk allele coincides with pericentromeric recruitment of the two loci.
Figure 2: The association between Igh and Igk occurs on the pericentromerically recruited allele.
Figure 3: Increased pericentromeric recruitment of Igk promotes a higher frequency of interchromosomal association between Igh and Igk and more pericentromeric recruitment of Igh dependent on 3′Eκ.
Figure 4: Association of Igh and Igk increases with increasing recruitment of Igk to pericentromeric regions.
Figure 5: The association of Igh and Igk and the pericentromeric recruitment of Igh at the pre–B cell stage in development are mediated by 3′Eκ.
Figure 6: The association of Igh and Igk mediates decontraction of the Igh locus.
Figure 7: Deletion of the VHJ558 CT7-526A1 probe occurs more frequently in 3′Eκ-knockout pre–B cells than in wild-type or MiEκ-knockout pre–B cells.
Figure 8: Altered spectrum of proximal versus distal VH gene segment rearrangements in 3′Eκ-knockout splenic B cells.

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Acknowledgements

We thank P. Lopez for expertise and contribution to flow cytometry. F. Alt (Harvard University) provided 3′Eκ-knockout mice. Supported by the Wellcome Trust, New York University School of Medicine and the National Institutes of Health (RO1 HL48702 and RO1 AI40227 to M.S.S.).

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  1. Hong-Erh Liang

    Present address: Present address: University of California, San Francisco, San Francisco, California 94143, USA.,

Authors and Affiliations

  1. Department of Pathology, New York University School of Medicine, New York, 10016, New York, USA

    Susannah L Hewitt, Katarzyna Marszalek & Jane A Skok

  2. The Department of Immunology and Molecular Pathology, Division of Infection and Immunity, University College London, London, W1T 4JF, UK

    Deborah Farmer & Jane A Skok

  3. Department of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USA

    Emily Cadera, Hong-Erh Liang & Mark S Schlissel

  4. Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, 92093, California, USA

    Yang Xu

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Contributions

S.L.H., bone marrow preparation, FISH experiments and V(D)J analysis; D.F., FISH experiments; K.M., bone marrow preparation and flow cytometry staining; E.C. and M.S.S., V(D)J analysis and breeding of 3′Eκ-knockout mice and MiEκ-knockout mice; H.-E.L., V(D)J analysis; Y.X., analysis of MiEκ-knockout mice; and J.A.S., FISH experiments and confocal analysis.

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Correspondence to Jane A Skok.

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Hewitt, S., Farmer, D., Marszalek, K. et al. Association between the Igk and Igh immunoglobulin loci mediated by the 3′ Igk enhancer induces 'decontraction' of the Igh locus in pre–B cells. Nat Immunol 9, 396–404 (2008). https://doi.org/10.1038/ni1567

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