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Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037
Ag receptor loci poised for V(D)J rearrangement undergo germline transcription (GT) of unrearranged genes, and the accessible gene segments are associated with posttranslational modifications (PTM) on histones. In this study, we performed a comprehensive analysis of the dynamic changes of four PTM throughout B and T cell differentiation in freshly isolated ex vivo cells. Methylation of lysines 4 and 79 of histone H3, and acetylation of H3, demonstrated stage and lineage specificity, and were most pronounced at the J segments of loci poised for, or undergoing, rearrangement, except for dimethylation of H3K4, which was more equally distributed on V, D, and J genes. Focusing on the IgL loci, we demonstrated there are no active PTM in the absence of pre-BCR signaling. The 
locus GT and PTM on J genes are rapidly induced following pre-BCR signaling in large pre-B cells. In contrast, the 
locus shows greatly delayed onset of GT and PTM, which do not reach high levels until the immature B cell compartment, the stage at which receptor editing is initiated. Analysis of MiE–/– mice shows that this enhancer plays a key role in inducing not only GT, but PTM. Using an inducible pre-B cell line, we demonstrate that active PTM on J genes occur after GT is initiated, indicating that histone PTM do not make the J region accessible, but conversely, GT may play a role in adding PTM. Our data indicate that the epigenetic profile of IgL genes is dramatically modulated by pre-BCR signaling and B cell differentiation status.
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 Grants R01 A129672, R01 A152313, and R01 AI61167 (to A.J.F.).
2 Address correspondence and reprint requests to Dr. Ann J. Feeney, Department of Immunology and Microbial Science, IMM22, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: feeney{at}scripps.edu
3 Abbreviations used in this paper: GT, germline transcription; ChIP, chromatin immunoprecipitation; DP, double positive; PHD, plant homeodomain; PTM, posttranslational modification; WT, wild type; CAD, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase.
4 The online version of this article contains supplementary material.
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  K. Beck, M. M. Peak, T. Ota, D. Nemazee, and C. Murre Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci J. Exp. Med., September 28, 2009; 206(10): 2271 - 2284. [Abstract] [Full Text] [PDF]
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