Histone Reader BRWD1 Targets and Restricts Recombination to the Igk Locus

B lymphopoiesis requires that immunoglobulin genes be accessible to the RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin suggesting that additional mechanisms must restrict RAG-mediated DNA cleavage. Here, we demonstrate 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-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 provide a paradigm in which, at any particular antigen receptor locus, specialized mechanisms enforce lineage and stage specific recombination.