Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells

How chromosome organization is related to genome function remains poorly understood. Cohesin, loop extrusion, and CCCTC-binding factor (CTCF) have been proposed to create topologically associating domains (TADs) to regulate gene expression. Here, we examine chromosome conformation in embryonic stem cells lacking cohesin and find, as in other cell types, that cohesin is required to create TADs and regulate A/B compartmentalization. However, in the absence of cohesin, we identify a series of long-range chromosomal interactions that persist. These correspond to regions of the genome occupied by the polycomb repressive system and are dependent on PRC1. Importantly, we discover that cohesin counteracts these polycomb-dependent interactions, but not interactions between super-enhancers. This disruptive activity is independent of CTCF and insulation and appears to modulate gene repression by the polycomb system. Therefore, we discover that cohesin disrupts polycomb-dependent chromosome interactions to modulate gene expression in embryonic stem cells. [Display omitted] •Interaction between polycomb target genes in ESCs occurs independently of cohesin•Loop extrusion by cohesin disrupts interactions between polycomb target genes•Cohesin removal enhances repression at polycomb target genes with increased interactions Using Hi-C, Capture-C, and DNA-FISH, Rhodes et al. discover that interactions between polycomb target genes occur independently of cohesin in embryonic stem cells. This relies on PRC1, and these interactions are disrupted by cohesin-mediated loop extrusion. Upon removal of cohesin, gene repression is enhanced at polycomb-occupied genes with increased interactions.