A Distal Enhancer in the Interferon-γ (IFN-γ) Locus Revealed by Genome Sequence Comparison*
By Dong U. Lee, O. Avni, Lin Chen, Anjana Rao. Journal of Biological Chemistry, 2003
144 citations recorded by the source corpus.
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-γ) gene. Comparison of human and mouse IFN-γ 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-γ-producing Th1 cells but not in Th2 cells that do not produce IFN-γ. 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-γ 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-γ cytokine locus and validate our approach as a successful method to detect cis-regulatory elements.
Subfields: Cancer Research, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/2ff86fc420d07505a33ca5295cd1761e7b756c46
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Citations in the corpus
- Epigenetic control of T-helper-cell differentiation (2009, background): “T H 1-cell differentiation in vitro and in response to infection in vivo leads to a marked increase in H3K4 dimethylation, H3 and/or H4 acetylation, the acquisition of DNaseI hypersensitive sites at regulatory elements within the Ifng locus and a complete loss of repressive H3K27 trimethylatio”
- Differentiation of Effector CD4 T Cell Populations (2010, unknown): “IfngCNS–6, located 6 kb upstream of the Ifng transcription start site, has enhancer activity consistent with an earlier report (260).”