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J. Biol. Chem., Vol. 279, Issue 39, 41249-41257, September 24, 2004
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A Distal Region in the Interferon-
Gene Is a Site of Epigenetic Remodeling and Transcriptional Regulation by Interleukin-2*
¶
From the
Lymphocyte and Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (NIH), Bethesda, Maryland 20892-1820, the ||Laboratory of Experimental Immunology, NCI, NIH, Frederick, Maryland 21702-1201, the **Department of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California 90048, the Laboratory of Molecular Immunology, NHLBI, NIH, Bethesda, Maryland 20892, and the Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
Interferon-
(IFN-) is a multifunctional cytokine that defines the development of Th1 cells and is critical for host defense against intracellular pathogens. IL-2 is another key immunoregulatory cytokine that is involved in T helper differentiation and is known to induce IFN- expression in natural killer (NK) and T cells. Despite concerted efforts to identify the one or more transcriptional control mechanisms by which IL-2 induces IFN- mRNA expression, no such genomic regulatory regions have been described. We have identified a DNase I hypersensitivity site 
3.5-4.0 kb upstream of the transcriptional start site. Using chromatin immunoprecipitation assays we found constitutive histone H3 acetylation in this distal region in primary human NK cells, which is enhanced by IL-2 treatment. This distal region is also preferentially acetylated on histones H3 and H4 in primary Th1 cells as compared with Th2 cells. Within this distal region we found a Stat5-like motif, and in vitro DNA binding assays as well as in vivo chromosomal immunoprecipitation assays showed IL-2-induced binding of both Stat5a and Stat5b to this distal element in the IFNG gene. We examined the function of this Stat5-binding motif by transfecting human peripheral blood mononuclear cells with -3.6 kb of IFNG-luciferase constructs and found that phorbol 12-myristate 13-acetate/ionomycin-induced transcription was augmented by IL-2 treatment. The effect of IL-2 was lost when the Stat5 motif was disrupted. These data led us to conclude that this distal region serves as both a target of chromatin remodeling in the IFNG locus as well as an IL-2-induced transcriptional enhancer that binds Stat5 proteins.
Received for publication, February 3, 2004 , and in revised form, June 16, 2004.
* This work was supported by federal funds from the National Institutes of Health, under Grant DK43211. 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.
¶ To whom correspondence may be addressed: Johns Hopkins Bloomberg School of Public Health, Dept. of International Health, Disease Prevention and Control Program, 615 N. Wolfe St. E5531, Baltimore, MD 21205-1901. Tel.: 410-502-2511; E-mail: jbream{at}jhsph.edu.
¶¶ To whom correspondence may be addressed: Cellular and Molecular Immunology Section, Laboratory of Experimental Immunology, NCI, NIH, Frederick, Bldg. 560, Rm. 31-23, Frederick, MD 21702-1201. Tel.: 301-846-5700; Fax: 301-846-1673; E-mail: youngh{at}ncifcrf.gov.
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