title: Histone reader BRWD1 targets and restricts recombination to the Igk locus.
abstract: B lymphopoiesis requires that immunoglobulin genes be accessible to RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin, which suggests that additional mechanisms must restrict RAG-mediated DNA cleavage. Here we show that developmental downregulation of interleukin 7 (IL-7)-receptor signaling in small pre-B cells induced expression of the bromodomain-family member BRWD1, which was recruited to a specific epigenetic landscape at Igk dictated by pre-B cell receptor (pre-BCR)-dependent Erk activation. BRWD1 enhanced RAG recruitment, increased gene accessibility and positioned nucleosomes 5' to each Jκ recombination signal sequence. BRWD1 thus targets recombination to Igk and places recombination within the context of signaling cascades that control B cell development. Our findings represent a paradigm in which, at any particular antigen-receptor locus, specialized mechanisms enforce lineage- and stage-specific recombination.
authors: Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.
authors: Malay
authors: M
authors: Mandal
authors: Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.
authors: Keith M
authors: KM
authors: Hamel
authors: Center for Research Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Mark
authors: M
authors: Maienschein-Cline
authors: Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.
authors: Azusa
authors: A
authors: Tanaka
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Grace
authors: G
authors: Teng
authors: Department of Human Genetics, Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA.
authors: Jigyasa H
authors: JH
authors: Tuteja
authors: Department of Pathology, University of Chicago, Chicago, Illinois, USA.
authors: Jeffrey J
authors: http://orcid.org/0000-0002-9351-7003
authors: JJ
authors: Bunker
authors: Center for Research Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Neil
authors: N
authors: Bahroos
authors: Reproductive Biology, The Jackson Laboratory, Bar Harbor, Maine, USA.
authors: John J
authors: JJ
authors: Eppig
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: David G
authors: DG
authors: Schatz
authors: Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.
authors: Marcus R
authors: MR
authors: Clark
mesh_terms: D000818:Animals; D017209:Apoptosis; D015536:Down-Regulation / Q000276:immunology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007136:Immunoglobulins / Q000235:genetics*; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology; D051379:Mice; D011995:Recombination, Genetic / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D000092468:Bromodomain Containing Proteins
chemical_list: D051548:Histone Acetyltransferases; D007136:Immunoglobulins; D015851:Interleukin-7; C562256:BRD1 protein, mouse; D000092468:Bromodomain Containing Proteins; C014609:IgK