Pre-B Cell Receptor Signaling Induces Immunoglobulin κ Locus Accessibility by Functional Redistribution of Enhancer-Mediated Chromatin Interactions

Abstract : During B cell development, the precursor B cell receptor (pre-BCR) checkpoint is thought to increase immunoglobulin κ light chain (Igκ) locus accessibility to the V(D)J recombinase. Accordingly, pre-B cells lacking the pre-BCR signaling molecules Btk or Slp65 showed reduced germline V(κ) transcription. To investigate whether pre-BCR signaling modulates V(κ) accessibility through enhancer-mediated Igκ locus topology, we performed chromosome conformation capture and sequencing analyses. These revealed that already in pro-B cells the κ enhancers robustly interact with the ∼3.2 Mb V(κ) region and its flanking sequences. Analyses in wild-type, Btk, and Slp65 single- and double-deficient pre-B cells demonstrated that pre-BCR signaling reduces interactions of both enhancers with Igκ locus flanking sequences and increases interactions of the 3'κ enhancer with V(κ) genes. Remarkably, pre-BCR signaling does not significantly affect interactions between the intronic enhancer and V(κ) genes, which are already robust in pro-B cells. Both enhancers interact most frequently with highly used V(κ) genes, which are often marked by transcription factor E2a. We conclude that the κ enhancers interact with the V(κ) region already in pro-B cells and that pre-BCR signaling induces accessibility through a functional redistribution of long-range chromatin interactions within the V(κ) region, whereby the two enhancers play distinct roles.
Document type :
Journal articles
Complete list of metadatas

Cited literature [79 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02131771
Contributor : Myriam Bodescot <>
Submitted on : Thursday, May 16, 2019 - 3:45:42 PM
Last modification on : Saturday, May 18, 2019 - 1:17:35 AM

File

journal.pbio.1001791.PDF
Publication funded by an institution

Identifiers

Collections

Citation

Ralph Stadhouders, Marjolein de Bruijn, Magdalena Rother, Saravanan Yuvaraj, Claudia Ribeiro de Almeida, et al.. Pre-B Cell Receptor Signaling Induces Immunoglobulin κ Locus Accessibility by Functional Redistribution of Enhancer-Mediated Chromatin Interactions. PLoS Biology, Public Library of Science, 2014, 12 (2), pp.e1001791. ⟨10.1371/journal.pbio.1001791⟩. ⟨inserm-02131771⟩

Share

Metrics

Record views

68

Files downloads

73