Interferon regulatory factor 1 marks activated genes and can induce target gene expression in systemic lupus erythematosus.

Abstract

Interferon regulatory factor 1 (IRF-1) mediates both induction of interferons (IFNs) and responses to type I IFNs. It has been implicated as a critical mediator of inflammation in murine lupus models. In a previous study of chromatin modifications in monocytes from patients with systemic lupus erythematosus (SLE), IRF-1 was implicated as being associated with increased histone acetylation in this disease. The present study was undertaken to directly investigate IRF-1 binding sites on chromatin. Cells from 9 female SLE patients and 7 female controls were examined. Monocytes were purified from peripheral blood and subjected to library preparation using a validated antibody to IRF-1. IRF-1 binding sites on chromatin were identified by chromatin immunoprecipitation followed by sequencing. The effect of IRF-1 on target gene expression was confirmed using an overexpression system in cell lines, and coimmunoprecipitation was used to identify protein interactions. IRF-1 binding around transcribed regions was increased in SLE patient monocytes, but histone modifications at potential IRF-1 binding sites without detectable IRF-1 binding were increased as well. Overexpression of IRF-1 was sufficient to drive transcription of target genes. IRF-1 overexpression was also able to alter histone modifications at a focus set of target genes, and treatment with an IRF-1 inhibitor reduced both expression and histone modifications at target genes. IRF-1 was found to interact with a select set of histone-modifying enzymes and other transcription factors. IRF-1 is an important signaling protein in the interferon pathway. It not only activates gene expression as a transcription factor, but may perpetuate disease by leading to a dysregulated epigenome.