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

Abstract

Summary: 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. : ETS-family transcription factors are key regulators of early B cell development. Soodgupta et al. show that RAG-induced DNA breaks generated during antigen receptor gene recombination activate a SPIC/BCLAF1 transcription factor complex that counters PU.1 activity and regulates gene expression changes to promote transition from large to small pre-B cells. Keywords: pre-B cells, DNA damage response, B cell development, RAG, PU.1 transcription factor, SPIC transcription factor, BCLAF1 transcription factor