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Locus Activation in Pre-B Cell Development1
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198
Previous studies have shown that B cell development is blocked at the pre-B cell stage in IFN regulatory factor (IRF)4 (pip) and IRF8 (IFN consensus sequence binding protein) double mutant mice (IRF4,8–/–). In this study, the molecular mechanism by which IRF4,8 regulate pre-B cell development was further investigated. We show that IRF4,8 function in a B cell intrinsic manner to control pre-B cell development. IRF4,8–/– mice expressing a Bcl-2 transgene fail to rescue pre-B cell development, suggesting that the defect in B cell development in IRF4,8–/– mice is not due to a lack of survival signal. IRF4,8–/– pre-B cells display a high proliferation index that may indirectly inhibit the L chain rearrangement. However, forced cell cycle exit induced by IL-7 withdrawal fails to rescue the development of IRF4,8–/– pre-B cells, suggesting that cell cycle exit by itself is not sufficient to rescue the development of IRF4,8–/– pre-B cells and that IRF4,8 may directly regulate the activation of L chain loci. Using retroviral mediated gene transduction, we show that IRF4 and IRF8 function redundantly to promote pre-B cell maturation and the generation of IgM+ B cells. Molecular analysis indicates that IRF4, when expressed in IRF4,8–/– pre-B cells, induces 
germline transcription, enhances V(D)J rearrangement activity at the locus, and promotes L chain rearrangement and transcription. Chromatin immunoprecipitation assay further reveals that IRF4 expression leads to histone modifications and enhanced chromatin accessibility at the locus. Thus, IRF4,8 control pre-B cell development, at least in part, by promoting the activation of the locus.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant AI67891 (to R. L.).
2 Address correspondence and reprint requests to Dr. Runqing Lu, Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198
3 Abbreviations used in this paper: IRF, IFN regulatory factor; wt, wild type; ChIP, chromatin immunoprecipitation; CML, chronic myelogenous leukemia.
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