Genomic regulatory landscape underlying the antiviral response of Atlantic salmon

Abstract

All jawed vertebrates have a highly coordinated innate immune response to viral infections driven by a core set of interferon responsive genes (ISGs), but interspecies variation remains substantial. In this study, we examined the genome-wide regulatory basis for antiviral gene expression responses in Atlantic salmon (Salmo salar), representing a teleost family that underwent a whole genome duplication (WGD) event ~100 Mya. We stimulate fish systemically with polyinosinic:polycytidylic acid (poly I:C), a synthetic viral mimic, and profile transcriptomic and epigenomic responses in the primary hematopoietic and lymphoid tissue. We used ATAC-seq and ChIP-seq (H3K27ac and H3K27me3), combined with mRNA-seq, to comprehensively examine modifications in gene regulation following stimulation. We identified a set of 197 ISGs with regulatory elements showing increased chromatin accessibility and H3K27ac signal in concert with increased gene expression in response to poly I:C. Fifty-four of these genes were conserved ISGs in rainbow trout, zebrafish, and human. Our analysis provides evidence for conserved transcription factors (TFs) driving the interferon response by binding ISG promoters, including IRF8, IRF9, STAT1, and STAT2. Regulatory elements within differentially expressed genes were enriched for predicted binding sites for STAT6, PRDM1, IRF6, JDP2, NR2E1, and BCL6, suggesting a central role for these TFs in the antiviral response. Finally, we demonstrate paralog-specific enrichment of interferon-stimulated response element (ISRE) motifs in poly I:C activated promoters of ISGs retained as duplicates from the salmonid WGD. Overall, this study provides novel insights into the genomic regulatory landscape underlying antiviral immunity in a farmed fish with a complex genome.