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

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. ChIP-seq for cohesin subunits SMC1, SA1 and SA2 was performed in 3 different cell lines (MCF10A, HMEC, HCAEC) and peak calling was done against the input sample from the corresponding cell line. RNA-seq was performed in triplicates in MCF10A cells control depleated from SA1, SA2 or CTCF by means of Dharmacon SMART pool siRNAs. HiC-seq was performed in two replicates in MCF10A cells control and depleated from SA1 and SA2 by means of Dharmacon SMART pool siRNAs. 4C-seq was performed in MCF10A cells control and depleated from SA2 or CTCF.