1. Histone reader BRWD1 targets and restricts recombination to the Igk locus.
- Author
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Mandal, Malay, Hamel, Keith M, Maienschein-Cline, Mark, Tanaka, Azusa, Teng, Grace, Tuteja, Jigyasa H, Bunker, Jeffrey J, Bahroos, Neil, Eppig, John J, Schatz, David G, and Clark, Marcus R
- Subjects
HISTONES ,IMMUNOGLOBULINS ,RECOMBINASES ,INTERLEUKIN-7 ,B cell receptors ,GENE expression ,BROMODOMAIN-containing proteins - 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 J
κ 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. [ABSTRACT FROM AUTHOR]- Published
- 2015
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