RAG-Mediated DNA Breaks Attenuate PU.1 Activity in Early B Cells through Activation of a SPIC-BCLAF1 Complex

Deepti Soodgupta, Lynn S. White, Wei Yang, Rachel Johnston, Jared M. Andrews, Masako Kohyama, Kenneth M. Murphy, Nima Mosammaparast, Jacqueline E. Payton, Jeffrey J. Bednarski

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Early B cell development is regulated by stage-specific transcription factors. PU.1, an ETS-family transcription factor, is essential for coordination of early B cell maturation and immunoglobulin gene (Ig) rearrangement. Here we show that RAG DNA double-strand breaks (DSBs) generated during Ig light chain gene (Igl) rearrangement in pre-B cells induce global changes in PU.1 chromatin binding. RAG DSBs activate a SPIC/BCLAF1 transcription factor complex that displaces PU.1 throughout the genome and regulates broad transcriptional changes. SPIC recruits BCLAF1 to gene-regulatory elements that control expression of key B cell developmental genes. The SPIC/BCLAF1 complex suppresses expression of the SYK tyrosine kinase and enforces the transition from large to small pre-B cells. These studies reveal that RAG DSBs direct genome-wide changes in ETS transcription factor activity to promote early B cell development.

Original languageEnglish
Pages (from-to)829-843.e5
JournalCell Reports
Volume29
Issue number4
DOIs
StatePublished - Oct 22 2019

Keywords

  • B cell development
  • BCLAF1 transcription factor
  • DNA damage response
  • PU.1 transcription factor
  • RAG
  • SPIC transcription factor
  • pre-B cells

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