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Molecular and Cellular Biology, February 2006, p. 810-821, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.810-821.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

E2A and IRF-4/Pip Promote Chromatin Modification and Transcription of the Immunoglobulin {kappa} Locus in Pre-B Cells

Adam S. Lazorchak,1 Mark S. Schlissel,2 and Yuan Zhuang1*

Department of Immunology, Duke University Medical Center, Box 3010, 328 Jones Building, Research Drive, Durham, North Carolina 27710,1 Department of Molecular and Cell Biology, University of California, 439 Life Sciences Addition, Berkeley, California 947202

Received 18 July 2005/ Returned for modification 15 September 2005/ Accepted 11 November 2005

The immunoglobulin kappa light chain (Ig{kappa}) locus is regulated in a lineage- and stage-specific manner during B-cell development. The highly restricted timing of V to J gene recombination at the pre-B-cell stage is under the control of two enhancers, the intronic enhancer ({kappa}Ei) and the 3' enhancer ({kappa}E3'), flanking the constant exon. E2A transcription factors have been indicated to be directly involved in the regulation of Ig{kappa} locus activation. In this study, we utilize E2A-deficient pre-B cells to directly investigate the mechanism of E2A-mediated Ig{kappa} activation. We demonstrate that Ig{kappa} germ line transcription is severely impaired and recombination is blocked in the absence of E2A. Reconstitution of E2A–/– pre-B cells with inducible human E2A (E47R) is sufficient to promote chromatin modification of Ig{kappa} and rescue Ig{kappa} germ line transcription and J{kappa} gene recombinase accessibility. Furthermore, we show that increased E2A recruitment to {kappa}Ei and {kappa}E3' correlates with activation of Ig{kappa} in pre-B cells and that recruitment of E2A to {kappa}E3' is in part dependent on the transcription factor IRF-4. Inhibition of IRF-4 expression in pre-B cells leads to a significant reduction of Ig{kappa} germ line transcription and enhancer acetylation. In the absence of E2A, increased IRF-4 expression is not sufficient to promote Ig{kappa} enhancer chromatin modification or transcription, suggesting that the sequential involvement of IRF-4 and E2A is necessary for the activation of the Ig{kappa} locus. Finally, we provide genetic evidence in the mouse that E2A gene dosage can influence the development of pre-B cells during the phase of Ig{kappa} gene activation.

* Corresponding author. Mailing address: Department of Immunology, Duke University Medical Center, Box 3010, 328 Jones Building, Research Drive, Durham, NC 27710. Phone: (919) 613-7824. Fax: (919) 613-7853. E-mail: yzhuang{at}duke.edu.

Molecular and Cellular Biology, February 2006, p. 810-821, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.810-821.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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