Histone reader BRWD1 targets and restricts recombination to the Igk locus

Nat Immunol. 2015 Oct;16(10):1094-103. doi: 10.1038/ni.3249. Epub 2015 Aug 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Down-Regulation / immunology
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / immunology
  • Histone Acetyltransferases / metabolism*
  • Immunoglobulins / genetics*
  • Interleukin-7 / genetics
  • Interleukin-7 / immunology
  • Mice
  • Recombination, Genetic / immunology*
  • Signal Transduction / immunology
  • Up-Regulation / immunology

Substances

  • BRD1 protein, mouse
  • IgK
  • Immunoglobulins
  • Interleukin-7
  • Histone Acetyltransferases

Associated data

  • GEO/GSE63302