RAG-Mediated DNA Breaks Attenuate PU.1 Activity in Early B Cells Through Activation of a SPIC-BCLAF1 Complex
63 Pages Posted: 1 Apr 2019 Sneak Peek Status: Review CompleteMore...
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 uniquely 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.
Keywords: Pre-B cells, DNA damage response, B cell development, RAG, PU.1 transcription factor, SPIC transcription factor, BCLAF1 transcription factor
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