Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination

Anne Sophie Thomas-Claudepierre, Isabelle Robert, Pedro P. Rocha, Ramya Raviram, Ebe Schiavo, Vincent Heyer, Richard Bonneau, Vincent M. Luo, Janardan K. Reddy, Tilman Borggrefe, Jane A. Skok, Bernardo Reina-San-Martin

Research output: Contribution to journalArticle

Abstract

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by the transcription-coupled recruitment of activation-induced cytidine deaminase (AID) to Ig switch regions (S regions). During CSR, the IgH locus undergoes dynamic three-dimensional structural changes in which promoters, enhancers, and S regions are brought to close proximity. Nevertheless, little is known about the underlying mechanisms. In this study, we show that Med1 and Med12, two subunits of the mediator complex implicated in transcription initiation and long-range enhancer/promoter loop formation, are dynamically recruited to the IgH locus enhancers and the acceptor regions during CSR and that their knockdown in CH12 cells results in impaired CSR. Furthermore, we show that conditional inactivation of Med1 in B cells results in defective CSR and reduced acceptor S region transcription. Finally, we show that in B cells undergoing CSR, the dynamic long-range contacts between the IgH enhancers and the acceptor regions correlate with Med1 and Med12 binding and that they happen at a reduced frequency in Med1-deficient B cells. Our results implicate the mediator complex in the mechanism of CSR and are consistent with a model in which mediator facilitates the long-range contacts between S regions and the IgH locus enhancers during CSR and their transcriptional activation.

Original languageEnglish (US)
Pages (from-to)303-312
Number of pages10
JournalJournal of Experimental Medicine
Volume213
Issue number3
DOIs
StatePublished - Jan 1 2016

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Thomas-Claudepierre, A. S., Robert, I., Rocha, P. P., Raviram, R., Schiavo, E., Heyer, V., Bonneau, R., Luo, V. M., Reddy, J. K., Borggrefe, T., Skok, J. A., & Reina-San-Martin, B. (2016). Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination. Journal of Experimental Medicine, 213(3), 303-312. https://doi.org/10.1084/jem.20141967