Chromatin-mediated anticipatory control of type I interferon production in plasmacytoid dendritic cells (Combined snRNA-seq and snATAC-seq of ?TB pDC activation)

Type I interferons (IFN-I) including IFN-ß and multiple IFN-a subtypes are key antiviral proteins encoded within a single locus. The antiviral response of most cell types involves primarily IFN-ß, whereas professional IFN-I-producing plasmacytoid dendritic cells (pDCs) secrete all IFN-I subtypes. We report that the IFN-I locus in quiescent pDCs showed multiple distinct features, including i) localization in the active intranuclear chromosomal compartment; ii) distinct three-dimensional chromatin organization, and iii) poised promoters at multiple Ifna genes. Accordingly, IFN-I production specifically by pDCs was dependent on the chromatin-organizing cohesin complex. The intranuclear translocation and promoter poising were mediated by the pDC-enriched transcription factor IRF8. Finally, we identified several IRF8- and/or cohesin-binding regulatory regions across the IFN-I locus. One of these enhanced IFN-ß induction in all cells, whereas two others enhanced pDC-specific induction of adjacent Ifna genes. Thus, the unique IFN-I-producing capacity of pDCs is facilitated by the anticipatory chromatin organization imparted by IRF8 and cohesin. Overall design: Combined snRNA-seq and snATAC-seq was performed on pDCs from unstimulated or CpG-stimulated FL-BMDC cultures derived from mice expressing green fluorescent protein (GFP) transgene driven by the CAGGS promoter (control) and Ifn?TB2/TB3/TB4 (?TB) mice.