@article{1b3dc556d7614280bf533fcc87448511,
title = "RAG-Mediated DNA Breaks Attenuate PU.1 Activity in Early B Cells through Activation of a SPIC-BCLAF1 Complex",
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.",
keywords = "B cell development, BCLAF1 transcription factor, DNA damage response, PU.1 transcription factor, RAG, SPIC transcription factor, pre-B cells",
author = "Deepti Soodgupta and White, {Lynn S.} and Wei Yang and Rachel Johnston and Andrews, {Jared M.} and Masako Kohyama and Murphy, {Kenneth M.} and Nima Mosammaparast and Payton, {Jacqueline E.} and Bednarski, {Jeffrey J.}",
note = "Funding Information: This work was supported by NIH grants K08 AI102946 (J.J.B.), R01 CA193318 (N.M.), R01 CA227001 (N.M.), and R01 CA188286 (J.E.P.). J.J.B. is supported by the Alex's Lemonade Stand Foundation, the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, the Barnard Trust, and an American Society of Hematology Scholar Award. N.M. is an American Cancer Society Research Scholar and is supported by the Alvin J. Siteman Cancer Research Fund. We thank the Genome Technology Access Center (P30 CA91842 and UL1 TR000448) at Washington University School of Medicine for assistance with experiments. NIH grants to Regeneron (U01HG004085) and the CSD Consortium (U01HG004080) funded the KOMP Program. D.S. L.S.W. W.Y. J.M.A. and R.J. performed experiments and data analyses. N.M. and J.E.P. provided expertise and assisted with data analyses. M.K. and K.M.M. provided mice and expertise for the studies. J.J.B. supervised the project, interpreted experiments, wrote the manuscript, and secured funding. The authors declare no competing interests. Funding Information: This work was supported by NIH grants K08 AI102946 (J.J.B.), R01 CA193318 (N.M.), R01 CA227001 (N.M.), and R01 CA188286 (J.E.P.). J.J.B. is supported by the Alex{\textquoteright}s Lemonade Stand Foundation , the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund , the Barnard Trust , and an American Society of Hematology Scholar Award. N.M. is an American Cancer Society Research Scholar and is supported by the Alvin J. Siteman Cancer Research Fund . We thank the Genome Technology Access Center ( P30 CA91842 and UL1 TR000448 ) at Washington University School of Medicine for assistance with experiments. NIH grants to Regeneron ( U01HG004085 ) and the CSD Consortium ( U01HG004080 ) funded the KOMP Program. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = oct,
day = "22",
doi = "10.1016/j.celrep.2019.09.026",
language = "English",
volume = "29",
pages = "829--843.e5",
journal = "Cell Reports",
issn = "2211-1247",
number = "4",
}