Cohesin-mediated chromatin remodeling controls the differentiation and function of conventional dendritic cells (CUT&RUN of FL-BMDCs and HoxB8-FL progenitors)

The cohesin protein complex extrudes chromatin between CTCF binding sites and organizes it into topologically associated domains (TADs), yet the biological implications of this regulatory mechanism are poorly understood. We show that the cohesin subunit Smc3 is required for the postmitotic differentiation and function of antigen-presenting dendritic cells (DCs). In particular, Smc3 deletion impaired antigen cross-presentation and IL-12 secretion by type 1 conventional DCs (cDC1s), thereby crippling antimicrobial and antitumor immune responses. The chromatin profile of DCs was shaped by the interplay of cohesin and the cDC1-specifying transcription factor IRF8. Conversely, optimal expression of IRF8 itself required CTCF/cohesin-binding elements demarcating the Irf8 gene. Cohesin-mediated chromatin remodeling facilitated chromatin priming at activation-inducible genes; accordingly, deletion of CTCF/cohesin-binding sites flanking the Il12b gene reduced basal and activation-induced IL-12 production by cDC1s. Our data reveal an essential role for cohesin-mediated chromatin regulation in the differentiation and function of a key immune cell type.