The role of transposable elements in the regulation of IFN-[lamda]1 gene expression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 28; p. 11564
• Main Authors: Thomson, Scott J P, Goh, Fui G, Banks, Helen, Krausgruber, Thomas, Kotenko, Sergei V, Foxwell, Brian M J, Udalova, Irina A
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 14.07.2009
• Subjects: Cells; Cytokines; Deoxyribonucleic acid; DNA; Evolution; Gene expression; Genes
• ISSN: 0027-8424; 1091-6490

IFNs ...1, ...2, and ...3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-β gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-... gene expression. Studies of virus induction of IFN-...1 identified an essential role of IFN regulatory factors (IRF) 3 and 7, which bind to a regulatory DNA sequence near the start site of transcription. Here, we report that the proximal promoter region of the IFN-...1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-...B binding sites. Remarkably, these sites, which bind efficiently to NF-...B and function independently of the IRF3/7 binding sites, originate as transposable elements of the Alu and LTR families. We also show that depletion of the NF-...B RelA protein significantly reduces the level of the IFN-...1 gene expression. We conclude that IFN-...1 gene expression requires NF-...B, and we propose a model for IFN-...1 gene regulation, in which IRF and NF-...B activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-...1 and IFN-β promoters and directly implicate transposable elements in the regulation of the IFN-...1 gene by NF-...B. (ProQuest: ... denotes formulae/symbols omitted.)