Abstract
Interferon (IFN) therapy is effective in treating cancers, haematological and virus induced diseases. The classical Jak/Stat pathway of IFN signal transduction leading to changes in transcriptional activity is well established but alone does not explain the whole spectrum of cellular responses to IFN. Gene promoters contain cis-acting sequences that allow precise and contextual binding of transcription factors, which control gene expression. Using the transcriptional response to IFN as a starting point we report a high frequency of tandem GGAA motifs in the proximal promoters of Interferon stimulated genes, suggesting a key regulatory action. Utilizing the well-characterized anti-viral gene, OAS1, as an example Interferon stimulated gene promoter containing such a duplicated GGAA motif, we have demonstrated a regulatory role of this promoter in response to IFN by mutation analysis. Furthermore, we identified ELF-1 as a direct binding factor at this motif. Additionally, recruitment of RB1 and SP1 factors to the promoter following IFN stimulation is shown. ELF-1 overexpression enhanced and knockdown of ELF-1 inhibited full activation of OAS1 by IFN stimulation. Collectively, ELF-1 binds an important duplicated GGAA cis-acting element at the OAS1 promoter and in cooperation with RB1 and SP1 recruitment contributes to regulation in response to IFN stimulation.
Highlights
The regulation of gene expression by extracellular signals requires the interplay between multiple transcription factors that selectively bind to gene promoters with spatial and temporal precision
Several duplicated GGAA motifs were found in close proximity to the TSSs of several ISGs25, we further investigated the prevalence of these motifs in a wider selection of human interferon-stimulated genes (ISGs)
From the computer assisted analysis as described in Methods, we discovered that duplicated GGAA motifs (GGAA motifs with spacers of between 0 and 10 bp are reported) are over-represented in the majority of promoter regions immediately upstream of ISGs (81%)
Summary
The regulation of gene expression by extracellular signals requires the interplay between multiple transcription factors that selectively bind to gene promoters with spatial and temporal precision. From the study of cellular differentiation in macrophages, essential duplicated GGAA-motifs which are recognized by various transcription factors including ETS family proteins[1], were discovered in the promoters of human PARG2 and IGHMBP2 genes[3]. The duplicated GGAA motifs are frequently found in immune-function associated promoters including human ISG15 and CD40 genes[4]. These observations suggested that duplicated GGAA-motifs are common cis-acting elements that respond to activation of immune responses. For the first time, we report that ELF-1 recognizes and directly binds to a duplicated GGAA motif proximal to the transcription start site of the 2′ -5′ -Oligoadenylate synthetase 1 (OAS1) gene. Our results have implications for development of novel IFN-based cancer therapies, such as artificially controlled ELF-1 expression and gene therapy
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call