Chromatin-mediated anticipatory control of type I interferon production in plasmacytoid dendritic cells

Type I interferons (IFN-I), including IFN-β and multiple IFN-α subtypes, are key antiviral proteins encoded within a single large locus. Here, we studied how the chromatin organization of this locus controls cell-type-specific IFN-I responses. The professional IFN-I-producing plasmacytoid dendritic cells (pDCs) simultaneously induced nearly all IFN-I subtypes across the locus. During pDC differentiation, the IFN-I locus translocated into the active intranuclear chromosomal compartment. It also underwent cohesin-dependent reorganization of its three-dimensional chromatin structure; accordingly, IFN-I production by pDCs was cohesin dependent. The promoters of most IFN-I genes harbored open chromatin peaks specifically in pDCs. The preemptive intranuclear translocation and promoter opening of IFN-I genes in pDCs were mediated by the pDC-enriched transcription factor interferon regulatory factor (IRF)8. Several IRF8- and/or cohesin-binding regulatory regions within the IFN-I locus facilitated IFN-I gene induction in pDCs, as confirmed by single-cell multiome analysis. Thus, the unique IFN-I-producing capacity of pDCs is facilitated by anticipatory chromatin organization imparted by IRF8 and cohesin.