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

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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 I $epsilon$ 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 thatBCL-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 sitesthat are the target sequence for the interleukin-4 (IL-4)-inducedStat6 (signal transducers and activators of transcription) signalingmolecule. Electrophoretic mobility shift assays demonstrate thatBCL-6 can bind, with different affinities, to several DNA elementsrecognized by Stat6. Expression of BCL-6 can repress the IL-4-dependentinduction of immunoglobulin (Ig) germ line $varepsilon$ transcripts, butdoes not repress the IL-4 induction of CD23 transcripts. Consistentwith the role of BCL-6 in modulating transcription from the germline $varepsilon$ promoter, BCL-6^/ mice display an increased ability to class switch to IgE in responseto IL-4 in vitro. These animals also exhibit a multiorgan inflammatorydisease characterized by the presence of a large number of IgE⁺ B cells. The apparent dysregulation of IgE production is abolishedin BCL-6^/ Stat6^/ mice, indicating that BCL-6 regulation of Ig class switchingis dependent upon Stat6 signaling. Thus, BCL-6 can modulate thetranscription of selective Stat6-dependent IL-4 responses, includingIgE class switching in Bcells.

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

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