Developmental Switch in the Transcriptional Activity of a Long-Range Regulatory Element

Abstract

Eukaryotic gene expression is often controlled by distant regulatory elements. In developing B lymphocytes, transcription is associated with V(D)J recombination at immunoglobulin loci. This process is regulated by remote cis-acting elements. At the immunoglobulin heavy chain (IgH) locus, the 3′ regulatory region (3′RR) promotes transcription in mature B cells. This led to the notion that the 3′RR orchestrates the IgH locus activity at late stages of B cell maturation only. However, long-range interactions involving the 3′RR were detected in early B cells, but the functional consequences of these interactions were unknown. Here we show that not only does the 3′RR affect transcription at distant sites within the IgH variable region but also it conveys a transcriptional silencing activity on both sense and antisense transcription. The 3′RR-mediated silencing activity is switched off upon completion of V_H-DJ_H recombination. Our findings reveal a developmentally controlled, stage-dependent shift in the transcriptional activity of a master regulatory element.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00509-15.

ACKNOWLEDGMENTS

We thank F. W. Alt for providing genomic DNA from IGCR1-deficient mice and for advice. We also thank the animal facility staff at the IPBS and F. L'Faqihi, V. Duplan-Eche, and A.-L. Iscache at the Purpan CPTP platform for their excellent assistance.

This work was supported by the Fondation ARC (grant PJA 20141201647), Agence Nationale de la Recherche, Institut National du Cancer (PLBIO15-134), Ligue Contre le Cancer-Comité de Haute-Garonne, and Cancéropôle Grand-Sud-Ouest.

F.-Z.B. and C.C. performed research and analyzed data; M.M., Y.D., and M.C. contributed new reagents or analytic tools; and A.A.K. designed research, analyzed data, and wrote the paper.

We declare that we have no conflicts of interest.