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

Cohesin exists in two variants carrying either STAG/SA1 or SA2. Here we have addressed their specific contributions to the unique spatial organization of the mouse embryonic stem cell genome, which ensures super-enhancer-dependent transcription of pluripotency factors and repression of lineage-specification genes within Polycomb domains. We find that cohesin-SA2 facilitates Polycomb domain compaction through Polycomb repressing complex 1 (PRC1) recruitment and promotes the establishment of long-range interaction networks between distant Polycomb-bound promoters that are important for gene repression. Cohesin-SA1, in contrast, disrupts these networks, while preserving topologically associating domain (TAD) borders. The diverse effects of both complexes on genome topology may reflect two modes of action of cohesin. One, likely involving loop extrusion, establishes overall genome arrangement in TADs together with CTCF and prevents excessive segregation of same-class compartment regions. The other is required for organization of local transcriptional hubs such as Polycomb domains and super-enhancers, which define cell identity. [Display omitted] •Cohesin variants have distinct effects on mESC chromatin architecture and transcription•Cohesin-SA1 preferentially contributes to TAD boundary strength•Cohesin-SA2 facilitates Polycomb domain compaction through PRC1 recruitment•Cohesin-SA1 impedes and cohesin-SA2 promotes aggregation of distal Polycomb domains The unique chromatin architecture of mESCs ensures high transcription of pluripotency factors and repression of lineage-specification genes. Cuadrado et al. report that besides their differential contribution to genome organization in TADs, cohesin variants SA1 and SA2 have antagonistic effects on the establishment of long-range contacts between Polycomb-bound genes that are essential for repression.