The cell cycle control element of histone H4 gene transcription is maximally responsive to interferon regulatory factor pairs IRF-1/IRF-3 and IRF-1/IRF-7

Interferon regulatory factors (IRFs) are transcriptional mediators of inter feron-responsive signaling pathways that are involved in antiviral defense, immune response, and hell growth regulation. To investigate the role of IR F proteins in the regulation of histone H4 gene transcription, we compared the transcriptional contributions of IRF-1, IRF-2, IRF-3, and IRF-7 using t ransient transfection assays with H4 promoter/luciferase (Luc) reporter gen es. These IRF proteins up-regulate reporter gene expression but IRF-1, IRF- 3, and IRF-7 are more potent activators of the H4 promoter than IRF-2. Forc ed expression of different IRF combinations reveals that IRF-2 reduces IRF- 1 or IRF-3 dependent activation, but does not affect IRF-7 function. Thus, IRF-2 may have a dual function in histone H4 gene transcription by acting a s a weak activator at low dosage and a competitive inhibitor of other stron gly activating IRFs at high levels. IRF-1/IRF-3 and IRF-1/IRF-7 pairs each mediate the highest levels of site II-dependent promoter activity and can u p-regulate transcription by 120-150-fold. We also find that interferon gamm a up-regulates IRF-1 and site II-dependent promoter activity. This upregula tion is not observed when the IRF site is mutated or if cells are preloaded with IRF-1. Our results indicate that IRF-1, IRF-2, IRF-3, and IRF-7 can a ll regulate histone H4 gene expression. The pairwise utilization of distinc t IRF factors provides a flexible transcriptional mechanism for integration of diverse growth-related signaling pathways.