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Transcription Factor-Dependent Chromatin Remodeling of Il18r1 during Th1 and Th2 Differentiation¹

Departments of Pediatrics, Herman B. Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202

The IL-18R-chain is expressed on Th1 but not Th2 cells. We have recently shown that Stat4 is an important component of programming the Il18r1 locus (encoding IL-18R) for maximal expression in Th1 cells. Il18r1 is reciprocally repressed during Th2 development. In this report, we demonstrate the establishment of DH patterns that are distinct among undifferentiated CD4 T, Th1, and Th2 cells. Stat6 is required for the repression of Il18r1 expression and in Stat6-deficient Th2 cultures, mRNA levels, histone acetylation, and H3K4 methylation levels are intermediate between levels observed in Th1 and Th2 cells. Despite the repressive effects of IL-4 during Th2 differentiation, we observed only modest binding of Stat6 to the Il18r1 locus. In contrast, we observed robust GATA-3 binding to a central region of the locus where DNase hypersensitivity sites overlapped with conserved non-coding sequences in Il18r1 introns. Ectopic expression of GATA-3 in differentiated Th1 cells repressed Il18r1 mRNA and surface expression of IL-18R. These data provide further mechanistic insight into transcription factor-dependent establishment of Th subset-specific patterns of gene expression.

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 This work was supported by U.S. Public Health Service Award AI45515 (to M.H.K.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Mark H. Kaplan, Department of Pediatrics, and Microbiology and Immunology, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, 702 Barnhill Drive, RI 2600, Indianapolis, IN 46202. E-mail address: mkaplan2{at}iupui.edu

³ Abbreviations used in this paper: CNC, conserved non-coding sequence; WT, wild type; TSS, transcriptional start site; DH, DNase hypersensitivity; ChIP, chromatin immunoprecipitation.