Epigenetic and lineage-specific transcription factors regulate the cell type specific induction of type I and type III interferons 2307867

Abstract

Abstract Introduction Viral respiratory and mucosal infections affect millions of people in the USA and worldwide, creating a serious health burden. The body defends against these viruses using two main types of interferons: type I (IFN-I) and type III (IFN-III). Both types are activated by the same sensors in our cells. Different cell types make them at different times: pDCs produce IFN-I within 3-6 hours, whereas epithelial cells make IFN-III at ∼24-48 h with little IFN-I. Our early work suggests that turning on the right interferon quickly depends on how each cell type arranges its DNA, keeping some genes ready and others silent. This work aims to understand how unique combinations of chromatin landscape and transcription factors in each cell type sets this genetic context. Methods We studied interferon induction in primary human pDCs and the CAL-1 line, hepatocytes, and human intestinal organoids. After viral PAMP stimulation, we measured IFN-I/III transcripts by qPCR, chromatin was mapped by time-resolved ATAC-seq and CUT&RUN for IRF8, PU.1, RNA polymerase II (Ser5P, Ser2P), and histone marks (H3K27ac, H3K4me1/3, H3K27me3, H3K36me3, H3K9me3). Results pDCs produced IFN-I early; epithelial models produced mostly IFN-III with little IFN-I. ATAC-seq and Pol II (Ser5P, Ser2P) showed open chromatin, promoter engagement, and elongation at IFN-I loci in pDCs, but closed chromatin and weak polymerase at IFN-III. The opposite pattern was seen in epithelial cells. PH5CH8 cells and human gut organoids which shared the epithelial signature: higher baseline accessibility and stimulus-induced RNA polymerase binding at IFN-III and relative inactivity at IFN-I. Conclusion PU.1/IRF8 favors early IFN-I induction in pDCs; HNF4A/FOXA favors delayed IFN-III in epithelia. These understandings can help to devise chromatin-focused ways to boost IFN-III while limiting IFN-I-driven inflammation. Funding Source ITHS grants Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)