Distinct roles of cohesin-SA1 and cohesin-SA2 in 3D chromosome organization

Two variant cohesin complexes containing SMC1, SMC3, RAD21 and either STAG/SA1 or SA2 are present in all cell types. We report here their genomic distribution and their specific contributions to genome organization in human cells. While both variants are found at CTCF sites, a fraction of cohesin-SA2 localizes to enhancers lacking CTCF, is linked to tissue-specific transcription and cannot be replaced by cohesin-SA1 when SA2 is absent, a condition observed in several tumours. Downregulation of either variant has different consequences for gene expression and genome architecture. Our results suggest that cohesin-SA1 preferentially contributes to the stabilization of TAD boundaries together with CTCF, while cohesin-SA2 promotes cell type-specific contacts between enhancers and promoters independently of CTCF. Loss of SA2 rewires local chromatin contacts and alters gene expression. These findings provide insights on how cohesin mediates chromosome folding and establish a novel framework to address the consequences of cohesin mutations in cancer.