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Abstract
BackgroundCellular antiviral activities are critically controlled by transcriptional activation of interferon-inducible genes, involving interferon regulatory factors (IRFs). Previous data suggested that IRF1 is an activator and IRF2 is a repressor, which functionally antagonize each other in transcriptional regulation. However, it is not clear how these two factors function to regulate cellular antiviral activities.ResultsWe show that IRF2 is critically required for the induction of the TLR3 and other interferon-inducible genes in a chromatin environment. While both IRF1 and IRF2 directly interact with the BAF chromatin remodeling complex, IRF2 is associated with the TLR3 promoter in the unstimulated state and IRF1 binding to the promoter is strongly induced by stimulation with interferon, suggesting that these two factors may function at different stages of gene induction in the recruitment of the BAF complex. IRF2 acts to maintain the basal level expression, an open chromatin structure, and active histone modification marks (H3K9, K14 acetylation and H3K4 tri-methylation) of the TLR3 promoter in the unstimulated state, while IRF1 serves to rapidly activate the promoter upon stimulation.ConclusionsIRF1 and IRF2 of the IRF family of transcription factors play distinct roles in cellular response to viral infection. IRF2 binds to TLR3 and other IFN-inducible gene promoters and maintains an active chromatin structure in the unstimulated state, which is required for their induction, while IRF1 binding to these promoters activates their transcription upon viral infection. Thus, the division of labor between the IRF transcription factor family members plays a pivotal role in coordinating the transcriptional activation in the cellular antiviral response.
Highlights
Cellular antiviral activities are critically controlled by transcriptional activation of interferon-inducible genes, involving interferon regulatory factors (IRFs)
How do the different family members contribute to the complexity and accuracy of their target genes regulation? To provide insights to this question, we decided to study the transcriptional regulation of toll-like receptor 3 (TLR3) by the interferon regulatory factors IRF1 and IRF2 [5]
In this study we present data to show the differential function of IRF1 and IRF2: IRF2 is associated with TLR3 and other IFN-inducible gene promoters in unstimulated states and potentiates their induction in response to viral infection by maintaining an active chromatin structure while IRF1 activates transcription of these genes in response to viral infection
Summary
Cellular antiviral activities are critically controlled by transcriptional activation of interferon-inducible genes, involving interferon regulatory factors (IRFs). Previous data suggested that IRF1 is an activator and IRF2 is a repressor, which functionally antagonize each other in transcriptional regulation. It is not clear how these two factors function to regulate cellular antiviral activities. Gene duplication in human genome results in the existence of multiple family members of transcription factors, which usually have highly conserved DNA-binding domains and recognize the same DNA sequence. Previous studies suggested that IRF1 is an activator and IRF2 is a repressor of transcription; and they function antagonistically by recognizing the same DNA motif [9]
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