Regulation of the type I interferon response by chromatin organization (RNA-seq of SMC3 KO 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 pDCs purified from 4-OHT-treated FL-BMDC cultures from R26CreER/+ or R26CreER/+ Smc3fl/fl mice and stimulated with CpG-A for 6 or 24 hours or left unstimulated as a control for 6 hours (3 replicates per genotype and stimulation condition).