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A distal region in the interferon-gamma gene is a site of epigenetic remodeling and transcriptional regulation by interleukin-2

  1. Author:
    Bream, J. H.
    Hodge, D. L.
    Gonsky, R.
    Spolski, R.
    Leonard, W. J.
    Krebs, S.
    Targan, S.
    Morinobu, A.
    O'Shea, J. J.
    Young, H. A.
  2. Author Address

    NCI, Cellular & Mol Immunol Sect, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. NIAMSD, Lymphocyte & Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Dept Gastroenterol, Los Angeles, CA 90048 USA. NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Kobe Univ, Grad Sch Med, Dept Clin Pathol & Immunol, Chuo Ku, Kobe, Hyogo 6500017, Japan Bream, JH, NCI, Cellular & Mol Immunol Sect, Expt Immunol Lab, NIH, Frederick, MD 21702 USA
    1. Year: 2004
    2. Date: SEP 24
  1. Journal: Journal of Biological Chemistry
    1. 279
    2. 39
    3. Pages: 41249-41257
  2. Type of Article: Article
  1. Abstract:

    Interferon-gamma (IFN-gamma) 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-gamma 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-gamma mRNA expression, no such genomic regulatory regions have been described. We have identified a DNase I hypersensitivity site similar to3.5-4.0 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

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  1. WOS: 000223916800124

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