The transcriptional activation of the genes encoding type I interferons (IFNs) in infected cells is critical to the antiviral response. Like some other cytokine genes, IFN-β expression is stochastic (not all infected cells express the gene) and mostly monoallelic. Secretion of type I IFNs and activation of their receptors on infected and uninfected cells triggers the activation of other antiviral genes. Transcriptional activation of IFN-β requires the temporally coordinated assembly of transcription factors to an enhancer element upstream of its promoter. Nuclear factor κB (NF-κB) binds first, followed by interferon regulatory factor 1 (IRF-1), activating transcription factor 2 (ATF-2), and c-Jun. Last to join this complex (the enhanceosome) is IRF-7, which binds just before transcription begins. Apostolou and Thanos speculated that the inherent complexity of enhanceosome formation might itself be responsible for the stochastic pattern of IFN-β expression. By comparing viral-induced IFN-β expression in control HeLa cells with that in cells overexpressing the individual transcription factors, the authors found that cellular concentrations of all components of the enhanceosome were limiting. Circular chromosome conformation capture (4C) assays, chromatin immunoprecipitations, and DNA fluorescence in situ hybridization (FISH) experiments demonstrated the viral-induced interaction of the IFN-β enhancer with three gene loci (only one of which was on the same chromosome as IFN-β), which was dependent on NF-κB binding to these loci. This led to the transfer of NF-κB to the IFN-β enhancer, enhanceosome formation, and monoallelic IFN-β expression. In a second phase, IFN-β signaling induced IRF-7 expression in infected and uninfected cells, which promoted enhanceosome formation and IFN-β expression independently of interchromosomal interactions. As Schoenfelder and Fraser discuss, this study underlines the need to think of gene regulation in three-dimensional space.
E. Apostolou, D. Thanos, Virus infection induces NF-κB-dependent interchromosomal associations mediating monoallelic IFN-β gene expression. Cell 134, 85-96 (2008). [PubMed]
S. Schoenfelder, P. Fraser, Interchromosomal huddle kickstarts antiviral defense. Cell 134, 14-16 (2008). [PubMed]