Cohesin complex cooperates with PU.1 at super-enhancers to regulate the differentiation and identity of conventional dendritic cells

The dendritic cell (DC) network consists of two major subsets: conventional (cDC) and plasmacytoid (pDC). cDCs undergo chromatin reorganization during their differentiation from hematopoietic progenitors to establish a cDC-specific gene expression program. However, the requirement of architectural protein complex cohesin in cDC differentiation is poorly understood. Herein, we report that ablation of SMC3 or STAG2 subunits of the cohesin complex in DC-restricted progenitors leads to a decrease in cDC and an increase in pDC compartment size. Cohesin controls cDC function, such as antigen presentation and expression of co-stimulatory molecules. Cohesin loss represses the expression of cDC identity genes and de-represses the pDC-specific transcriptional signature in cDCs and pre-DCs. Mechanistically, cohesin promotes PU.1 binding at super-enhancers and supports chromatin loops favoring cDC differentiation. Notably, cohesin-deficient DCs disturb the steady-state hematopoiesis, leading to myeloid hyperplasia. Our results reveal a transcriptional node involving cohesin, PU.1, and super-enhancers in the regulation of the lineage-specific gene expression program in cDCs.