STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma.

The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer-rich regions, and results in reprogramming of cis -chromatin interactions. Strikingly, in STAG2 knockout cells the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory, and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype. [Display omitted] • Cohesin-SA2 occupies enhancer and PRC2-marked regulatory regions in Ewing sarcoma • STAG2 depletion alters a subset of EWS/FLI1 anchored enhancer-promoter interactions • Loss of STAG2 modifies oncogenic and developmental transcriptional programs • STAG2 loss enhances the migratory and metastatic potential of Ewing sarcoma cells Adane et al. demonstrate that deletion of STAG2 changes the distribution of cohesin complexes and leads to reprograming of cis -chromatin interactions in Ewing sarcoma. STAG2 loss attenuated EWS/FLI1-driven oncogenic programs and disrupted PRC2-regulated developmental processes to enhance the metastatic potential of Ewing sarcoma cells. [ABSTRACT FROM AUTHOR]