GATA-3-dependent enhancer activity in IL-4 gene regulation.
Previously, we analyzed the proximal IL-4 promoter in directing Th2-specific activity. An 800-base pair proximal promoter conferred some Th2-selective expression in transgenic mice. However, this region directed extremely low reporter mRNA levels relative to endogenous IL-4 mRNA, suggesting that full gene activity requires additional enhancer elements. Here, we analyzed large genomic IL-4 regions for enhancer activity and interaction with transcription factors. The proximal IL-4 promoter is only moderately augmented by GATA-3, but certain genomic regions significantly enhanced GATA-3 promoter transactivation. Some enhancing regions contained consensus, GATA sites that bound Th2-specific complexes. However, retroviral transduction of GATA-3 into developing T cells induced IL-5 to full Th2 levels, but only partially restored IL-4 production. Thus, we propose that GATA-3 is permissive, but not sufficient, for full IL-4 enhancement and may act through GATA elements surrounding the IL-13/IL-4 gene locus.
Department of Pathology and Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Ranganath
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Ouyang
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Bhattarcharya
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Grupe
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Peltz
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Murphy
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology; D019169:Jurkat Cells; D051379:Mice; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics* / Q000276:immunology
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4