Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

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

Cellular & Molecular Immunology volume 16, pages 887–889 (2019)Cite this article

Subjects

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 functions. CSR is triggered by activation-induced cytidine deaminase (AID),1 an enzyme that deaminates cytosines to uracils in single-stranded DNA exposed by transcription. The 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 Eµ enhancer, 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.3

To determine whether deletion of the γ1E region has an impact on S region transcription, we measured the levels of Iμ-Cμ and Iα-Cα GLTs by RT-qPCR (Fig. 1d). Surprisingly, deletion of the γ1E region had no negative effect on S region transcription, and both transcripts appeared to accumulate in the γ1E−/− clones (Fig. 1d). Hence, the reduced CSR efficiency observed in γ1E−/− clones cannot be explained by defects in transcription. A possible explanation is that the γ1E region participates in the 3D conformational changes occurring at the IgH locus during CSR.4,5 Alternatively, the Sα region may be insensitive to a putative transcriptional effect of the γ1E region due to its close proximity to the 3′RR super-enhancer (2 kb).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    Article  CAS  Google Scholar 

  2. Yewdell, W. T. & Chaudhuri, J. A transcriptional serenAID: the role of noncoding RNAs in class switch recombination. Int. Immunol. 29, 183–196 (2017).

    Article  CAS  Google Scholar 

  3. Chaudhuri, J. et al. Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Adv. Immunol. 94, 157–214 (2007).

    Article  CAS  Google Scholar 

  4. Wuerffel, R. et al. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity 27, 711–722 (2007).

    Article  CAS  Google Scholar 

  5. Thomas-Claudepierre, A. S. et al. Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination. J. Exp. Med. 213, 303–312 (2016).

    Article  CAS  Google Scholar 

  6. Medvedovic, J. et al. Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire. Immunity 39, 229–244 (2013).

    Article  CAS  Google Scholar 

  7. Predeus, A. V. et al. Targeted chromatin profiling reveals novel enhancers in Ig H and Ig L chain Loci. J. Immunol. 192, 1064–1070 (2014).

    Article  CAS  Google Scholar 

  8. Li, W., Notani, D. & Rosenfeld, M. G. Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat. Rev. Genet. 17, 207–223 (2016).

    Article  CAS  Google Scholar 

  9. Nakamura, M. et al. High frequency class switching of an IgM+ B lymphoma clone CH12F3 to IgA+ cells. Int. Immunol. 8, 193–201 (1996).

    Article  CAS  Google Scholar 

  10. Arnold, L. W., Grdina, T. A., Whitmore, A. C. & Haughton, G. Ig isotype switching in B lymphocytes. Isolation and characterization of clonal variants of the murine Ly-1+ B cell lymphoma, CH12, expressing isotypes other than IgM. J. Immunol. 140, 4355–4363 (1988).

    CAS  PubMed  Google Scholar 

  11. Ono, S. J. et al. Identification of a stimulus-dependent DNase I hypersensitive site between the Ialpha and Calpha exons during immunoglobulin heavy chain class switch recombination. FEBS Lett. 467, 268–272 (2000).

    Article  CAS  Google Scholar 

  12. Kaminski, D. A. & Stavnezer, J. Enhanced IgA class switching in marginal zone and B1 B cells relative to follicular/B2 B cells. J. Immunol. 177, 6025–6029 (2006).

    Article  CAS  Google Scholar 

  13. Issaoui, H. et al. The IgH 3’ regulatory region super-enhancer does not control IgA class switch recombination in the B1 lineage. Cell. Mol. Immunol. 15, 289–291 (2018).

    Article  Google Scholar 

  14. Braikia, F. Z. et al. Inducible CTCF insulator delays the IgH 3’ regulatory region-mediated activation of germline promoters and alters class switching. Proc. Natl Acad. Sci. USA 114, 6092–6097 (2017).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank members of the Reina-San-Martin laboratory for discussions, A. Khamlichi for comments on the manuscript, C. Ebel for assistance with cell sorting, M. Gendron for animal care, and Marie-Christine Birling for help with the generation of the γ1E−/− mouse model. R.A.-V. was supported by the IGBMC’s International PhD Program LABEX fellowship and by the Fondation Recherche Médicale. This study was supported by the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the program Investissements d’Avenir labeled ANR-10-IDEX-0002-02.

Author information

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France

    Rocío Amoretti-Villa, Mélanie Rogier, Isabelle Robert, Vincent Heyer & Bernardo Reina-San-Martin

  2. Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France

    Rocío Amoretti-Villa, Mélanie Rogier, Isabelle Robert, Vincent Heyer & Bernardo Reina-San-Martin

  3. Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France

    Rocío Amoretti-Villa, Mélanie Rogier, Isabelle Robert, Vincent Heyer & Bernardo Reina-San-Martin

  4. Université de Strasbourg, Illkirch, France

    Rocío Amoretti-Villa, Mélanie Rogier, Isabelle Robert, Vincent Heyer & Bernardo Reina-San-Martin

Authors
  1. Rocío Amoretti-Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mélanie Rogier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabelle Robert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vincent Heyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernardo Reina-San-Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, B.R.-S.-M., R.A.-V., M.R., and I.R. Methodology, B.R.-S.-M., R.A.-V., and I.R. Investigation, R.A.-V., M.R., I.R., and V.H. Writing—original draft, R.A.-V. Writing—review and editing, B.R.-S.-M. and I.R. Supervision, B.R.-S.-M. and I.R. Funding Acquisition, B.R.-S.-M.

Corresponding author

Correspondence to Bernardo Reina-San-Martin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amoretti-Villa, R., Rogier, M., Robert, I. et al. A novel regulatory region controls IgH locus transcription and switch recombination to a subset of isotypes. Cell Mol Immunol 16, 887–889 (2019). https://doi.org/10.1038/s41423-019-0267-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0267-4

This article is cited by

Search

Advanced search

Quick links