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

Cellular & Molecular Immunology volume 17, pages 407–409 (2020)Cite this article

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′ Eμ element located in the JH to Cµ intron.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 cells. Its deletion showed no influence on the VDJ repertoire and rather increased transcription of unrearranged V segments.3,4,5 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 recombination. In-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. By checking the repertoire using high-throughput sequencing, we now show that Med1 also has a role in early rearrangements and promotes expression of distal VH genes. Med1 deficiency resulted in a significant repertoire bias, with decreased usage of distal V segments, together with decreased usage of the upstream JH1 and JH2 segments.

Mediator is a four-module complex with several important functions in binding transcription factors to RNA polymerase II (Pol II). It regulates Pol II C-terminal domain phosphorylation and Pol II status regarding transcription initiation, pausing or elongation.9 While not mandatory for transcription and lacking in some Mediator complexes, the Med1 subunit is characterized by specific and direct interaction with several transcriptional activators binding enhancer elements. It is involved in functional and physical loops between promoter and enhancer elements that stimulate transcription in activated cells.10 A single report described Med1 influence on gene recombination in activated mature B cells, where it promoted the long-distance interactions of IgH enhancers with target switch-regions and globally enhanced CSR to all Ig classes by 2 to 3-fold.8 VDJ recombination also involves long-distance interactions promoted by enhancer elements which control locus contraction.11,12

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Acknowledgements

This work was supported by grants from Association pour la Recherche sur le Cancer (PGA120150202338), ANR grant Ig-MemImpact 16-CE15-0019-01) and ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. We thank Mehdi Alizadeh for his help with MiSeq sequencing.

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Authors and Affiliations

  1. UMR CNRS 7276, INSERM U1262, Universite de Limoges, Limoges, 87025, France

    Iman Dalloul, Zeinab Dalloul, Sandrine Le Noir, François Boyer, Jeanne Cook-Moreau & Michel Cogné

  2. INSERM U1258, UMR CNRS 7104, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Université de Strasbourg, Illkirch, 67400, France

    Bernardo Reina-San-Martin

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  1. Iman Dalloul
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Contributions

M.C., J.C-.M. designed the study. I.D., S.L.N. and Z.D. performed experiments. F.B. analysed Ig repertoire data. B.R-.S-.M. provided mice and participated in manuscript writing.

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Correspondence to Michel Cogné.

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Dalloul, I., Dalloul, Z., Le Noir, S. et al. Mediator contributes to IgH locus VDJ rearrangements by promoting usage of most distal V segments. Cell Mol Immunol 17, 407–409 (2020). https://doi.org/10.1038/s41423-018-0175-z

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