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The Autoimmune Regulator Directly Controls the Expression of Genes Critical for Thymic Epithelial Function

Qing-Guo Ruan^*, Kenneth Tung, Daniel Eisenman^*, Yulius Setiady, Sarah Eckenrode^*, Bing Yi^*, Sharad Purohit^*, Wei-Peng Zheng^*, Yan Zhang^*, Leena Peltonen and Jin-Xiong She^1,*,

^* Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta, GA 30912; Department of Pathology, University of Virginia, Charlottesville, VA 22908; Department of Medical Genetics, University of Helsinki, and Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland, and Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and Department of Pathology, Medical College of Georgia, Augusta, GA 30912

The autoimmune regulator (Aire) gene plays an essential role in negative selection of T cells and deletion of autoreactive T cells in the thymus. The defect in thymic selection in Aire^–/– mice was attributed to the repressed expression of tissue-specific Ags in the thymic epithelial cells and defective Ag presentation; however, the molecular mechanism underlying these functions has been elusive. Using the chromatin immunoprecipitation technique, we demonstrate here that Aire binds in vivo to specific DNA sequence motifs and directly regulates thymic expression of genes important for thymic functions including expression of autoantigens, cytokines, transcription factors, and posttranslational modifiers. These results unambiguously established Aire as a key transcriptional regulator of the immune system.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Jin-Xiong She, Center for Biotechnology and Genomic Medicine, Medical College of Georgia, 1120 15th Street, CA4098, Augusta, GA 30912. E-mail address: jshe{at}mail.mcg.edu

² Abbreviations used in this paper: Aire, autoimmune regulator; APS1, autoimmune polyglandular syndrome type 1; TSA, tissue-specific Ag; TEC, thymic epithelial cell; mTEC, medullary TEC; ChIP, chromatin immunoprecipitation; LM-PCR, ligation-mediated PCR; EAP, experimental autoimmune prostatitis; WT, wild type; KO, knockout; d3tx, day 3 thymectomized; BMP, bone morphogenetic protein.

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