Dynamic cohesin-mediated chromatin architecture controls epithelial-mesenchymal plasticity in cancer

Epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET) are important interconnected events in tumorigenesis controlled by complex genetic networks. However, the cues that activate EMT‐initiating factors and the mechanisms that reversibly connect EMT/MET are not well understood. Here, we show that cohesin‐mediated chromatin organization coordinates EMT/MET by regulating mesenchymal genes. We report that RAD21, a subunit of the cohesin complex, is expressed in epithelial breast cancer cells, whereas its expression is decreased in mesenchymal cancer. Depletion of RAD21 in epithelial cancer cells causes transcriptional activation of TGFB1 and ITGA5 , inducing EMT. Reduced binding of RAD21 changes intrachromosomal chromatin interactions within the TGFB1 and ITGA5 loci, creating an active transcriptional environment. Similarly, stem cell‐like cancer cells also show an open chromatin structure at both genes, which correlates with high expression levels and mesenchymal fate characteristics. Conversely, overexpression of RAD21 in mesenchymal cancer cells induces MET‐specific expression patterns. These findings indicate that dynamic cohesin‐mediated chromatin structures are responsible for the initiation and regulation of essential EMT‐related cell fate changes in cancer. Synopsis RAD21‐containing cohesin complexes form repressive higher‐order chromatin structures at the mesenchymal TGFB1 and ITGA5 loci, thereby maintaining epithelial cancer features. This study highlights dynamic cohesin‐mediated 3D structures as regulators of EMT/MET‐specific cell fate changes in cancer. RAD21 expression in mesenchymal cancer is reduced compared to epithelial cancer. RAD21 depletion in epithelial cancer causes induction of TGFB1 and ITGA5, which induces mesenchymal‐like properties. Gene‐specific intrachromosomal interactions at the TGFB1 and ITGA5 loci change upon RAD21 depletion. Altered chromatin structures at the TGFB1 and ITGA5 loci induced by RAD21 depletion facilitate activated transcription. Graphical Abstract RAD21‐containing cohesin complexes form repressive higher order chromatin structures at the mesenchymal TGFB1 and ITGA5 loci, thereby maintaining epithelial cancer features. This study highlights dynamic cohesin‐mediated 3D structures as regulators of EMT/MET‐specific cell fate changes in cancer.