Interferon Regulatory Factor 1 Marks Activated Genes and Can Induce Target Gene Expression in Systemic Lupus Erythematosus

Arthritis and Rheumatology - Tập 67 Số 3 - Trang 785-796 - 2015
Zhe Zhang1, Lihua Shi1, Li Song1, Elshaddai Ephrem1, Michelle Petri2, Kathleen E. Sullivan1
1The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
2Johns Hopkins University School of Medicine, Baltimore, Maryland

Tóm tắt

ObjectiveInterferon 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.MethodsCells 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.ResultsIRF‐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.ConclusionIRF‐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.

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Arthritis and Rheumatology

Tập 67 Số 3

785-796

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