Cohesin mediates sister chromatid cohesion and contributes to the organization of interphase chromatin through DNA looping. In vertebrate somatic cells, cohesin consists of Smc1, Smc3, Rad21, and either SA1 or SA2. Three additional factors Pds5, Wapl, and Sororin bind to cohesin and modulate its dynamic association with chromatin. There are two Pds5 proteins in vertebrates, Pds5A and Pds5B, but their functional specificity remains unclear. Here, we demonstrate that Pds5 proteins are essential for cohesion establishment by allowing Smc3 acetylation by the cohesin acetyl transferases (CoATs) Esco1/2 and binding of Sororin. While both proteins contribute to telomere and arm cohesion, Pds5B is specifically required for centromeric cohesion. Furthermore, reduced accumulation of Aurora B at the inner centromere region in cells lacking Pds5B impairs its error correction function, promoting chromosome mis-segregation and aneuploidy. Our work supports a model in which the composition and function of cohesin complexes differs between different chromosomal regions.

Chromatin structure imposed by condensin II at centromeres enables xHJURP-mediated incorporation of CENP-A.

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.

Highlights d Cohesin variants have distinct effects on mESC chromatin architecture and transcription d Cohesin-SA1 preferentially contributes to TAD boundary strength d Cohesin-SA2 facilitates Polycomb domain compaction through PRC1 recruitment d Cohesin-SA1 impedes and cohesin-SA2 promotes aggregation of distal Polycomb domains

In addition to mediating sister chromatid cohesion, cohesin plays a central role in DNA looping and segmentation of the genome into contact domains (TADs). Two variant cohesin complexes that contain either STAG/SA1 or SA2 are present in all cell types. Here we addressed their specific contribution to genome architecture in non-transformed human cells. We found that cohesin-SA1 drives stacking of cohesin rings at CTCF-bound sites and thereby contributes to the stabilization and preservation of TAD boundaries. In contrast, a more dynamic cohesin-SA2 promotes cell type-specific contacts between enhancers and promoters within TADs independently of CTCF. SA2 loss, a condition frequently observed in cancer cells, results in increased intra-TAD interactions, likely altering the expression of key cell identity genes.