Differential regulation of mouse germline Ig gamma 1 and epsilon promoters by IL-4 and CD40.
Before Ig class switching, RNA transcription through the specific S regions undergoing recombination is induced by cytokines and other activators that induce and direct switching. The resulting germline (GL) transcripts are essential for switch recombination. To understand the differential regulation of mouse IgG1 and IgE, we compared the promoters for GL gamma1 and epsilon transcripts. We addressed the question of why the promoter that regulates GL epsilon transcription is more responsive to IL-4 than the gamma1 promoter and also why GL epsilon transcription is more dependent on IL-4 than is gamma1 transcription. We found that the IL-4-responsive region of the GL epsilon promoter is more inducible than that of the gamma1 promoter, although each promoter contains a binding site for the IL-4-inducible transcription factor Stat6, located immediately adjacent to a binding site for a basic region leucine zipper (bZip) family protein. However, the arrangement and sequences of the sites differ between the epsilon and gamma1 promoters. The GL epsilon promoter binds Stat6 with a 10-fold higher affinity than does the gamma1 promoter. Furthermore, the bZip elements of the two promoters bind different transcription factors, as the GL epsilon promoter binds and is activated by AP-1, whereas the gamma1 promoter binds and is activated by activating transcription factor 2. C/EBPbeta and C/EBPgamma also bind the gamma1 bZip element, although they inhibit rather than activate transcription. However, inhibition of promoter activity by C/EBPbeta does not require the bZip element and may instead occur via inhibiting the activity of NF-kappaB.
Mao
C S
CS
Department of Molecular Genetics, Program in Immunology and Virology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester MA 01655, USA.
Stavnezer
J
J
D051698:Activating Transcription Factor 2; D051696:Activating Transcription Factors; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D001798:Blood Proteins / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019013:CD40 Antigens / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D051790:G-Box Binding Factors; D005786:Gene Expression Regulation / Q000276:immunology; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics* / Q000378:metabolism; D007142:Immunoglobulin gamma-Chains / Q000235:genetics* / Q000378:metabolism; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology*; D020218:Response Elements / Q000276:immunology; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation / Q000276:immunology; D014407:Tumor Cells, Cultured
D051698:Activating Transcription Factor 2; D051696:Activating Transcription Factors; C497106:Atf2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D001798:Blood Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D019013:CD40 Antigens; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D051790:G-Box Binding Factors; D007139:Immunoglobulin epsilon-Chains; D007142:Immunoglobulin gamma-Chains; D016328:NF-kappa B; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D015847:Interleukin-4