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

Author:

Harris Miera B.1,Chang Chih-Chao2,Berton Michael T.3,Danial Nika N.1,Zhang Jandong2,Kuehner Denise4,Ye Bihui H.2,Kvatyuk Marina4,Pandolfi Pier Paolo5,Cattoretti Giorgio2,Dalla-Favera Riccardo2,Rothman Paul B.4

Affiliation:

1. Integrated Program in Cellular, Molecular and Biophysical Sciences,1

2. Departments of Pathology and Genetics & Development, 2 and

3. Department of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio, 3 Texas

4. Departments of Medicine and Microbiology, 4 Columbia University College of Physicians and Surgeons, and

5. Department of Human Genetics and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 5 New York, New York, and

Abstract

ABSTRACT 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 ɛ 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 ɛ 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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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