Specific Contributions of Cohesin-SA1 and Cohesin-SA2 to TADs and Polycomb Domains in Embryonic Stem Cells

Cohesin, a major genome organizer, exists in two variants that carry either STAG/SA1 or SA2. Here we have addressed their specific contributions to the unique spatial organization of the mouse embryonic stem cell (mESC) genome, which ensures super-enhancer dependent transcription of pluripotency factors and repression of lineage specification genes within Polycomb domains. We find that cohesin-SA1 preserves topological associating domain (TAD) boundaries and prevents excessive segregation of same-class compartment regions. Cohesin-SA2 contributes to Polycomb domain compaction through Polycomb Repressing Complex 1 (PRC1) recruitment and facilitates establishment of interaction networks between Polycomb-repressed promoters. Cohesin-SA1 hinders these interactions. The diverse effects of both complexes on genome topology likely reflect two modes of action of cohesin: one involving loop extrusion and CTCF, which establishes overall genome arrangement in TADs, and another required for the organization of local transcriptional hubs such as Polycomb domains and super-enhancers, which define cell identity.