Characterization and Prediction of ISRE Binding Patterns Across Cell Types Under Type I Interferon Stimulation

Abstract

Stimulation of cells by type I interferons (IFN) leads to the differential expression of 100s of genes known as interferon stimulated genes, ISGs. The collection of ISGs differentially expressed under IFN stimulation, referred to as the IFN signature, varies across cell types. Non-canonical IFN signaling has been clearly associated with variation in IFN signature across cell types, but the existence of variation in canonical signaling and its impact on IFN signatures is less clear. The canonical IFN signaling pathway involves binding of the transcription factor ISGF3 to IFN-stimulated response elements, ISREs. We examined ISRE binding patterns under IFN stimulation across six cell types using existing ChIPseq datasets available on the GEO and ENCODE databases. We find that ISRE binding is cell specific, particularly for ISREs distal to transcription start sites, potentially associated with enhancer elements, while ISRE binding in promoter regions is more conserved. Given variation of ISRE binding across cell types, we investigated associations between the cell type, homeostatic state and ISRE binding patterns. Taking a machine learning approach and using existing ATACseq and ChIPseq datasets available on GEO and ENCODE, we show that the epigenetic state of an ISRE locus at homeostasis and the DNA sequence of the ISRE locus are predictive of the ISRE’s binding under IFN stimulation in a cell type, specific manner, particularly for ISRE distal to transcription start sites.