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Molecular and Cellular Biology, October 1999, p. 7264-7275, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Transcriptional Repression of Stat6-Dependent Interleukin-4-Induced Genes by BCL-6: Specific Regulation of Iepsilon Transcription and Immunoglobulin E Switching

Miera B. Harris,1 Chih-Chao Chang,2 Michael T. Berton,3 Nika N. Danial,1 Jandong Zhang,2 Denise Kuehner,4 Bihui H. Ye,2 Marina Kvatyuk,4 Pier Paolo Pandolfi,5 Giorgio Cattoretti,2 Riccardo Dalla-Favera,2 and Paul B. Rothman4,*

Integrated Program in Cellular, Molecular and Biophysical Sciences,1 Departments of Pathology and Genetics & Development,2 and Departments of Medicine and Microbiology,4 Columbia University College of Physicians and Surgeons, and Department of Human Genetics and Molecular Biology Program, Memorial Sloan Kettering Cancer Center,5 New York, New York, and Department of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio,3 Texas

Received 28 December 1998/Returned for modification 19 February 1999/Accepted 20 July 1999

The BCL-6 proto-oncogene encodes a POZ/zinc-finger transcription factor that is expressed in B cells and a subset of CD4+ T cells within germinal centers. Recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription, but the target genes for this activity have not yet been identified. The binding site for BCL-6 shares striking homology to the sites that are the target sequence for the interleukin-4 (IL-4)-induced Stat6 (signal transducers and activators of transcription) signaling molecule. Electrophoretic mobility shift assays demonstrate that BCL-6 can bind, with different affinities, to several DNA elements recognized by Stat6. Expression of BCL-6 can repress the IL-4-dependent induction of immunoglobulin (Ig) germ line varepsilon  transcripts, but does not repress the IL-4 induction of CD23 transcripts. Consistent with the role of BCL-6 in modulating transcription from the germ line varepsilon  promoter, BCL-6-/- mice display an increased ability to class switch to IgE in response to IL-4 in vitro. These animals also exhibit a multiorgan inflammatory disease characterized by the presence of a large number of IgE+ B cells. The apparent dysregulation of IgE production is abolished in BCL-6-/- Stat6-/- mice, indicating that BCL-6 regulation of Ig class switching is dependent upon Stat6 signaling. Thus, BCL-6 can modulate the transcription of selective Stat6-dependent IL-4 responses, including IgE class switching in B cells.

* Corresponding author. Mailing address: Department of Medicine/Microbiology, Columbia University, 630 W. 168th St., New York, NY 10032-3702. Phone: (212) 305-6982. Fax: (212) 305-1870. E-mail: pbr3{at}columbia.edu.

Molecular and Cellular Biology, October 1999, p. 7264-7275, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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