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J. Biol. Chem., Vol. 279, Issue 6, 4802-4810, February 6, 2004
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(IFN-) Locus Revealed by Genome Sequence Comparison*
¶**
From the
Center for Blood Research and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115 and the ||Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0215
Large-scale cross-species DNA sequence comparison has become a powerful tool to identify conserved cis-regulatory modules of genes. However, bioinformatic analysis alone cannot reveal how an evolutionarily conserved region regulates gene expression: whether it functions as an enhancer, silencer, or insulator; whether its function is cell-type restricted; and whether biologically relevant transcription factors bind to the element. Here we combine bioinformatics with wet-lab techniques to illustrate a general and systematic method of identifying functional conserved regulatory regions of genes. We applied this approach to the interferon-gamma (IFN-
) gene. Comparison of human and mouse IFN- reveals a highly conserved non-coding sequence located 
5 kb 5' of the transcription start site. This region coincides with constitutive and inducible DNase I hypersensitivity sites present in IFN--producing Th1 cells but not in Th2 cells that do not produce IFN-. Histone methylation at the 5' conserved non-coding sequences indicates a more accessible chromatin structure in Th1 cells compared with Th2 cells. This element binds two transcription factors known to be essential for IFN- expression: nuclear factor of activated T cells, an inducible transcription factor, and T-box protein expressed in T cells, a cell lineage-restricted transcription factor. Together, these findings identify a highly conserved distal enhancer in the IFN- cytokine locus and validate our approach as a successful method to detect cis-regulatory elements.
Received for publication, July 21, 2003 , and in revised form, October 23, 2003.
* This work was supported by National Institutes of Health Grants AI-44432 and HL-67664 (to A. R.) and a National Institutes of Health training grant (to D. U. L.). 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.
¶ Supported by postdoctoral fellowships from the Cancer Research Institute and the Dorot Foundation.
** To whom correspondence should be addressed: Harvard Medical School and The Center for Blood Research Institute for Biomedical Research, Alpert Bldg. Rm. 152, 200 Longwood Ave., Boston, MA 02115. Tel.: 617-278-3260/3261; Fax: 617-278-3280; E-mail: arao{at}cbr.med.harvard.edu.
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