STAG2 cohesin cooperates with DREAM to maintain quiescence and suppress tumourigenesis in the urothelium

The maintenance of quiescence is essential for tissue homeostasis. STAG2 is one of the few genes mutated in the normal urothelium of organ donors, with mutant cells undergoing positive selection 1. STAG2 is also a major tumour suppressor gene 2-4 and its inactivation is an early event in bladder carcinogenesis 1,3. However, how STAG2, a cohesin component, regulates urothelial homeostasis remains largely unknown. Here, we demonstrate that Stag2 inactivation in normal murine urothelial cells interferes with differentiation programs, triggers transient cell cycle entry, and primes cells for clonal expansion under stress. Moreover, STAG2 loss enhances tumor formation in urothelial cells expressing mutant FGFR3 - the key oncogene in bladder cancer 5. We reveal that STAG2 cooperates with the DREAM transcriptional complex, a master regulator of quiescence 6,7, by binding to shared genomic sites, including cell cycle control genes. STAG2 loss alters DREAM target expression, complex composition, and chromatin distribution, and leads to rewiring of chromatin interactions involving DREAM binding motifs in genes critical for cell cycle entry. Our findings provide compelling evidence that STAG2 loss disrupts in 3D genome organization through a novel mechanism involving the DREAM complex, thereby impairing homeostatic quiescence and increasing oncogenic sensitivity.