Background The transcription factors interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are encoded by two of the strongest susceptibility genes for systemic lupus erythematosus (SLE).
Objective To investigate the target genes and functional roles of IRF5 and STAT4 in human peripheral blood mononuclear cells (PBMCs).
Methods Chromatin immunoprecipitation-sequencing (ChIP-seq) was performed in PBMCs stimulated to activate IRF5 and STAT4. The expression of the target genes of IRF5 and STAT4 was investigated in a publicly available dataset generated from PBMCs from patients with SLE and healthy controls. The genomic regions bound by the transcription complexes mediated by IRF5 and STAT4 were examined for transcription factor binding motifs and SLE-associated sequence variants.
Results More than 7000 target genes for IRF5 and STAT4 were identified in stimulated PBMCs. These genes were enriched to functional pathways in the type I interferon system, and have key roles in the inflammatory response. The expression patterns of the target genes were characteristic for patients with SLE. The transcription factors high mobility group-I/Y, specificity protein 1, and paired box 4 may function cooperatively with IRF5 and STAT4 in transcriptional regulation. Eight of the target regions for IRF5 and STAT4 contain SLE-associated sequence variants.
Conclusions By participating in transcription complex with other co-factors, IRF5 and STAT4 harbour the potential of regulating a large number of target genes, which may contribute to their strong association with SLE.
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Funding This work was supported by the Swedish Research Council for Medicine and Health (A0280001 to A-CS and A0258801 to LR); the Swedish Research Council for Science and Technology (90559401 to A-CS); the Knut and Alice Wallenberg Foundation (2011.0073 to A-CS and LR); the Alliance for Lupus Research; the Swedish Rheumatism Association; the Nilsson Foundation; and the King Gustaf V 80-year Foundation and COMBINE. The SNP&SEQ Technology Platform, Science for Life Laboratory in Uppsala, is supported by Uppsala University, Uppsala University Hospital and the Swedish Council for Research Infrastructures (80576801). The funding agencies played no role in the study design, the collection, analysis and interpretation of data, writing of the manuscript, or the decision to submit the manuscript for publication.
Competing interests None.
Patient consent None.
Ethics approval Ethical Committee in Uppsala.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The raw data from ChIP-seq analysis have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE38567.