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Two Different Transcription Factors Discriminate the –315C>T Polymorphism of the FcRI Gene: Binding of Sp1 to –315C and of a High Mobility Group-Related Molecule to –315T¹

Shunsuke Kanada^2,*,, Nobuhiro Nakano^2,*, Daniel P. Potaczek^2,*,, Keiko Maeda^*, Naomi Shimokawa^*, Yusuke Niwa^*, Tatsuo Fukai^*, Marek Sanak, Andrew Szczeklik, Hideo Yagita, Ko Okumura^*,, Hideoki Ogawa^* and Chiharu Nishiyama^3,*

^* Atopy (Allergy) Research Center and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland

The -chain is a specific component of FcRI, which is essential for the cell surface expression of FcRI and the binding of IgE. Recently, two single nucleotide polymorphisms (SNPs) in the -chain promoter, –315C>T and –66T>C, have been shown by statistic studies to associate with allergic diseases. The effect of –66 SNP on GATA-1-mediated promoter activity has been already indicated. In the present study, to investigate roles of the –315 SNP on the -chain promoter functions, the transcription activity was evaluated by reporter assay. The -chain promoter carrying –315T (minor allele) possessed significantly higher transcriptional activity than that of –315C (major allele). EMSA indicated that the transcription factor Sp1, but not Myc-associated zinc finger protein (MAZ), was bound to the –315C allele probe and that a transcription factor belonging to a high mobility group-family bound to the –315T allele probe. The chromatin immunoprecipitation assay suggested that high mobility group 1, 2, and Sp1 bound around –315 of FcRI genomic DNA in vivo in the human basophil cell line KU812 with –315C/T and in human peripheral blood basophils with –315C/C, respectively. When cell surface expression level of FcRI on basophils was analyzed by flow cytometry, basophils from individuals carrying –315T allele expressed significantly higher amount of FcRI compared with those of –315C/C. The findings demonstrate that a –315 SNP significantly affects human FcRI -chain promoter activity and expression level of FcRI on basophils by binding different transcription factors to the SNP site.

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¹ This work was supported by a Grant-in-Aid for Young Scientists (B) (to N.N.), and a Grant-in-Aid for Scientific Research (C) (to C.N.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant from the 2007 WAO fellowship (to D.P.P.). D.P.P. is supported by Foundation for Polish Science START Stipend 2007 and Japan Society for the Promotion of Science Postdoctoral Fellowship FY 2007–2008.

² S.K., N.N., and D.P.P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Chiharu Nishiyama, Atopy (Allergy) Research Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. E-mail address: chinishi{at}med.juntendo.ac.jp

⁴ Abbreviations used in this paper: SNP, single nucleotide polymorphism; HMG, high mobility group; ChIP, chromatin immunoprecipitation; MFI, mean fluorescence intensity; LD, linkage disequilibrium.