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

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) transcripti...

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Autores principales:	Ralph Stadhouders, Marjolein J W de Bruijn, Magdalena B Rother, Saravanan Yuvaraj, Claudia Ribeiro de Almeida, Petros Kolovos, Menno C Van Zelm, Wilfred van Ijcken, Frank Grosveld, Eric Soler, Rudi W Hendriks
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/380d635fd7a8458da581a6733d653c20
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spelling	oai:doaj.org-article:380d635fd7a8458da581a6733d653c202021-11-18T05:37:35ZPre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.1544-91731545-788510.1371/journal.pbio.1001791https://doaj.org/article/380d635fd7a8458da581a6733d653c202014-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24558349/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885During 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.Ralph StadhoudersMarjolein J W de BruijnMagdalena B RotherSaravanan YuvarajClaudia Ribeiro de AlmeidaPetros KolovosMenno C Van ZelmWilfred van IjckenFrank GrosveldEric SolerRudi W HendriksPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 12, Iss 2, p e1001791 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Ralph Stadhouders Marjolein J W de Bruijn Magdalena B Rother Saravanan Yuvaraj Claudia Ribeiro de Almeida Petros Kolovos Menno C Van Zelm Wilfred van Ijcken Frank Grosveld Eric Soler Rudi W Hendriks Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.
description	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.
format	article
author	Ralph Stadhouders Marjolein J W de Bruijn Magdalena B Rother Saravanan Yuvaraj Claudia Ribeiro de Almeida Petros Kolovos Menno C Van Zelm Wilfred van Ijcken Frank Grosveld Eric Soler Rudi W Hendriks
author_facet	Ralph Stadhouders Marjolein J W de Bruijn Magdalena B Rother Saravanan Yuvaraj Claudia Ribeiro de Almeida Petros Kolovos Menno C Van Zelm Wilfred van Ijcken Frank Grosveld Eric Soler Rudi W Hendriks
author_sort	Ralph Stadhouders
title	Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.
title_short	Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.
title_full	Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.
title_fullStr	Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.
title_full_unstemmed	Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.
title_sort	pre-b cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/380d635fd7a8458da581a6733d653c20
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Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions.

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