Chromatin Architecture Explains Why Immune Cells and Epithelial Cells Produce Different Interferon Responses
Researchers have identified the molecular mechanism explaining why plasmacytoid dendritic cells (pDCs) rapidly produce type I interferons while intestinal epithelial cells mount a slower type III interferon response to viral infection. Using ATAC-seq in primary human cells, the study found that opposing chromatin accessibility landscapes at interferon gene loci are established before infection occurs, with ETS-IRF composite elements — particularly PU.1 and IRF8 — maintaining the type I interferon locus in an open, poised state exclusively in pDCs. This finding clarifies a long-standing immunological puzzle and suggests that antiviral response timing and type are epigenetically predetermined by cell lineage rather than dynamically regulated upon infection.
A new preprint study on bioRxiv reports that the divergent interferon responses of plasmacytoid dendritic cells (pDCs) and intestinal epithelial cells are governed by constitutively established chromatin accessibility patterns set before any viral encounter. Using ATAC-seq on primary human pDCs and intestinal epithelial cells, researchers found that the type I interferon (IFN-I) gene locus is broadly open in pDCs but constitutively closed in epithelial cells, while the type III interferon (IFN-III) locus shows the reciprocal pattern. The key molecular drivers in pDCs are ETS-IRF composite elements — specifically the transcription factors PU.1 and IRF8 — which bind IFN-I promoters and intergenic enhancer regions, keeping the locus in a poised, transcription-ready state. Epithelial cells lack PU.1 and IRF8, rendering the IFN-I locus epigenetically silent, while their open IFN-III locus still produces a delayed response due to intrinsically weaker promoter activity compared to IFN-I promoters. The study also identified candidate enhancer elements marked by histone modifications H3K4me1 and H3K27ac and RNA Polymerase II occupancy across the IFN-I locus in pDCs, suggesting a broader regulatory network anchored by ETS-IRF composite elements. These findings establish that lineage-specific epigenetic programming, rather than post-infection signaling differences, is the primary determinant of which interferon subtype a cell produces and how quickly.
What's missing
As a preprint, this study has not yet undergone formal peer review, and its findings should be interpreted with caution. The study relies on in vitro and ex vivo chromatin profiling and does not directly demonstrate that disrupting ETS-IRF composite elements in vivo alters antiviral outcomes. It is also unclear whether these chromatin landscapes are conserved across species or vary with infection context, inflammatory state, or donor variability in primary human cells.
What different sources said
- bioRxivCenter
Lineage-specific chromatin poising enforced by ETS-IRF composite elements determines the divergent interferon responses of plasmacytoid dendritic cells and epithelial cells
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