The role of transposable elements in the regulation of IFN-lambda1 gene expression.
IFNs lambda1, lambda2, and lambda3, 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-beta gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-lambda gene expression. Studies of virus induction of IFN-lambda1 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-lambda1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-kappaB binding sites. Remarkably, these sites, which bind efficiently to NF-kappaB 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-kappaB RelA protein significantly reduces the level of the IFN-lambda1 gene expression. We conclude that IFN-lambda1 gene expression requires NF-kappaB, and we propose a model for IFN-lambda1 gene regulation, in which IRF and NF-kappaB activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-lambda1 and IFN-beta promoters and directly implicate transposable elements in the regulation of the IFN-lambda1 gene by NF-kappaB.
Thomson
Scott J P
SJ
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology, and Medicine, London W6 8LH, United Kingdom.
Goh
Fui G
FG
Banks
Helen
H
Krausgruber
Thomas
T
Kotenko
Sergei V
SV
Foxwell
Brian M J
BM
Udalova
Irina A
IA
D001665:Binding Sites / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics*; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases; D022423:Myeloid Cells / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D000095022:Interferon Lambda
D017931:DNA Primers; D004251:DNA Transposable Elements; D007372:Interferons; D007378:Interleukins; D008156:Luciferases; D016328:NF-kappa B; C000624353:interferon-lambda, human; D000095022:Interferon Lambda