Transcriptomics

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3

Pre-BCR Signaling induce IgK 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 k light chain (Igk) locus accessibility to the V(D)J recombinase. Accordingly, pre-B cells lacking the pre-BCR signaling molecules Btk or Slp65 showed reduced germline Vk transcription. To investigate whether pre-BCR signaling modulates Vk accessibility through enhancer-mediated Igk locus topology, we performed chromosome conformation capture and sequencing analyses. These revealed that already in pro-B cells the k enhancers robustly interact with the ~3.2 Mb Vk 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 Igk locus flanking sequences and increases interactions of the 3’k enhancer with Vk genes. Remarkably, pre-BCR signaling does not significantly affect interactions between the intronic enhancer and Vk genes, which are already robust in pro-B cells. Both enhancers interact most frequently with highly used Vk genes, which are often marked by transcription factor E2a. We conclude that the k enhancers interact with the Vk region already in pro-B cells and that pre-BCR signaling induces accessibility through a functional redistribution of long-range chromatin interactions within the Vk region, whereby the two enhancers play distinct roles. We performed genome-wide expression profiling of FACS-purified B220+CD19+ pre-B cell fractions from wild-type (WT), Btk and Slp65 single and double deficient VH81x transgenic Rag1-/- mice (n=4 of each genotype). In these experiments non-VH81x transgenic Rag1-/- pro-B cells served as controls (n=3).

REANALYSIS of: E-GEOD-53896

ORGANISM(S): Mus musculus  

PROVIDER: E-GEOD-53896 | ExpressionAtlas | 2015-07-31

REPOSITORIES: ExpressionAtlas

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Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.

Stadhouders Ralph R   de Bruijn Marjolein J W MJ   Rother Magdalena B MB   Yuvaraj Saravanan S   Ribeiro de Almeida Claudia C   Kolovos Petros P   Van Zelm Menno C MC   van Ijcken Wilfred W   Grosveld Frank F   Soler Eric E   Hendriks Rudi W RW  

PLoS biology 20140218 2


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 reve  ...[more]

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