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

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 cDC-specific gene expression program. However, the requirement of architectural protein complex Cohesin in the differentiation of cDCs is poorly understood. Herein we report that ablation of SMC3 or STAG2 subunits of Cohesin complex in DC-restricted progenitors leads to decrease in cDC, and increase in pDC compartment size. Cohesin complex controlled the functions of cDCs, such as antigen presentation and the expression of co-stimulatory molecules. The ablation of Cohesin complex repressed the expression of cDC identity genes and de-repressed the pDC-specific transcriptional signature in cDCs and pre-DCs. Mechanistically, Cohesin complex promoted the binding of PU.1, an ETS family transcription factor, at super-enhancers and supported chromatin loops favouring cDC differentiation. Notably, Cohesin-deficient DCs disturbed the steady-state haematopoiesis leading to myeloid hyperplasia. Our results reveal a transcriptional node involving Cohesin complex, PU.1 and super-enhancers in the regulation of lineage-specific gene expression program in cDCs.