Cohesin-mediated chromatin organization controls the differentiation and function of dendritic cells

The cohesin complex extrudes chromatin loops, stopping at sites bound by CCCTC-binding factor (CTCF) and organizing chromosomes into topologically associated domains, yet biological implications of this process remain obscure. We show that cohesin controls the in vivo differentiation and function of murine antigen-presenting dendritic cells (DCs), particularly antigen cross-presentation and interleukin-12 (IL-12) secretion by type 1 conventional DCs (cDC1s). The chromatin organization of DCs was shaped by cohesin and the transcription factor IRF8, which facilitated chromatin looping and chromosome compartmentalization, respectively. Optimal expression of IRF8 itself required CTCF/cohesin binding sites demarcating the Irf8 gene. During DC activation, cohesin enabled the induction of a subset of genes that were preferentially located in Polycomb-repressed regions and enriched in more distal enhancers. Accordingly, deletion of CTCF sites flanking the Il12b gene in mice reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin folding in cell differentiation and function in vivo and its bidirectional cross-talk with lineage-specifying transcription factors.