Multi-omic profiling following loss of SWI/SNF reveals global changes in cohesin binding and sensitivity to cohesin perturbation

ABSTRACT: SWI/SNF is a family of multi-subunit chromatin remodelling complexes comprised of BAF, PBAF and ncBAF. These complexes have diverse roles in cellular processes including transcription, replication, and repair, and play an important role in maintaining genome stability, with over 20% of all cancers having deleterious mutations in a SWI/SNF subunit. We modelled SWI/SNF dysfunction in the widely used cell line, RPE1, by engineering loss of function mutations in both shared and complex-specific subunits, as well as using small molecule treatment to acutely degrade or inhibit SWI/SNF. To analyse the functional consequences of this dysfunction, we performed transcriptomic analysis and compared this with whole cell and chromatin-bound proteomes. Strikingly, SWI/SNF-dependent changes in the transcriptome correlated poorly with changes at the protein level, while changes at the whole protein level correlated well with changes in proteins bound to chromatin. Comparative analyses of protein dynamics revealed that both acute and chronic SWI/SNF loss led to decreased association of cohesin and CTCF with chromatin, and that SWI/SNF remodelling activity was required for the maintenance of cohesin on chromatin. Notably, SWI/SNF loss also led to cohesin and CTCF localising to novel regions in the genome, and the patterns of mislocalisation showed subunit-specific patterns, suggesting that different SWI/SNF complexes have non-redundant impacts on cohesin localisation. Importantly, we find that the relationship between SWI/SNF and cohesin is functionally important, and cells lacking SWI/SNF show significant sensitivity to perturbation of cohesin. Our results highlight SWI/SNF complexes as critical regulators of cohesin dynamics and uncover a vulnerability that has therapeutic potential for cancers driven by SWI/SNF dysregulation.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Graeme Benstead-Hume  

LAB HEAD: Jessica Downs

PROVIDER: PXD065273 | Pride | 2026-02-20

REPOSITORIES: Pride