Regulation of the type I interferon response by chromatin organization (RNA-seq of HoxB8-FL pDC activation)

Antiviral type I interferons (IFN-I) including IFN-ß and multiple subtypes of IFN-a are encoded within a single locus. Whereas most cell types produce primarily IFN-ß, plasmacytoid dendritic cells (pDCs) respond to viruses by rapidly producing all IFN-I subtypes. We show that during pDC differentiation, the IFN-I locus translocates from the nuclear periphery and undergoes reorganization of topologically associated domains (TADs). Accordingly, IFN-I production by pDCs was strictly dependent on the TAD-organizing cohesin complex. Promoters of Ifna genes in pDCs were poised, which was imparted by the pDC-enriched transcription factor IRF8. Finally, we identified two distal regulatory regions that facilitated the expression of adjacent IFN-I genes. Thus, the IFN-I response is controlled by multilevel chromatin organization of the IFN-I locus, including its unique poised state in pDCs. Overall design: RNA-seq was performed on purified HoxB8-FL pDCs stimulated with CpG-A for 6 hours and 24 hours, as well as unstimulated pDCs at the same timepoints as a control (3 replicates per stimulation condition and timepoint).