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

Abstract

Objective IRF1 both mediates responses to type I interferons and the induction of interferons. It has been implicated in murine lupus models as a critical mediator of inflammation. A previous study of chromatin modifications in SLE patient monocytes implicated IRF1 as associated with increased histone acetylation in SLE patients. This study directly investigated IRF1 binding sites on chromatin using ChIP-seq. Methods Nine female SLE patients and seven female controls were examined. Monocytes were purified from peripheral blood and subjected to library preparation using a validated antibody to IRF1. The effect of IRF1 on target gene expression was confirmed using an overexpression system in cell lines and co-immunoprecipitation was used to define protein interactions. Results IRF1 binding around transcribed regions was increased in SLE patient monocytes but histone modifications at potential IRF1 binding sites without detectable IRF1 binding were also increased. IRF1 overexpression was sufficient to drive transcription of target genes. IRF1 overexpression was also able to alter histone modifications at a focus set of target genes and the use of an IRF1 inhibitor decreased both expression and histone modifications at target genes. IRF1 was found to interact with a select set of histone modifying enzymes and other transcription factors. Conclusions IRF1 is an important signaling protein in the interferon pathway. IRF1 not only activates gene expression as a transcription factor but may perpetuate disease by leading to a dysregulated epigenome.

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

“…Importantly, IRF1 has been identified as a central regulator of target genes in lupus monocytes(34) and has been reported as a transcription factor of caspase-1(35, 36). Our data support a parallel regulation of IRF1 and caspase-1 downstream of IFNα.…”

RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities

“…Another pathway, role of PKR in interferon induction and antiviral response , is affected in the same group of SLE patients involving transcripts of IRF1, TNFRSF1A, p53, MAP2K6 and MKK. Apart from the interferon induction, IRF1 also contributes to the dysregulated epigenome that leads to perpetuation of SLE [41]. These MAPK signaling molecules were observed to be hyperactivated and are shared among various networks in lupus [42].…”

Immunostimulatory Defective Viral Genomes from Respiratory Syncytial Virus Promote a Strong Innate Antiviral Response during Infection in Mice and Humans

“…HEp2 cells (HeLa-derived human epithelial cells, ATCC, #CCL23), A549 cells (human type II alveolar cells, ATCC, #CCL185), Vero cells (Cercopithecus aethiops kidney epithelial cells, ATCC, #CCL-81), D54MG cells (human glioma cells, kindly provided by Dr. Kathleen E. Sullivan), and wild type, Mavs -/- MEFs, Ifnar-/- MEFs were cultured in DMEM supplemented with 10% fetal bovine serum, 1 mM sodium pyruvate, 2 mL L-Glutamine, and 50 mg/ml gentamicin or penicillin and streptomycin. D54MG cells overexpressing IRF1(D54-IRF1) [ 54 ] were selected in the same culture medium with 20 μg/ml puromycin. All cell lines were treated with mycoplasma removal agent (MP Biomedicals) before use.…”