TY - JOUR T1 - The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000808 VL - 4 IS - 2 SP - e202000808 AU - Gaylor Boulay AU - Luisa Cironi AU - Sara P Garcia AU - Shruthi Rengarajan AU - Yu-Hang Xing AU - Lukuo Lee AU - Mary E Awad AU - Beverly Naigles AU - Sowmya Iyer AU - Liliane C Broye AU - Tugba Keskin AU - Alexandra Cauderay AU - Carlo Fusco AU - Igor Letovanec AU - Ivan Chebib AU - Petur Gunnalugur Nielsen AU - Stéphane Tercier AU - Stéphane Cherix AU - Tu Nguyen-Ngoc AU - Gregory Cote AU - Edwin Choy AU - Paolo Provero AU - Mario L Suvà AU - Miguel N Rivera AU - Ivan Stamenkovic AU - Nicolò Riggi Y1 - 2021/02/01 UR - https://www.life-science-alliance.org/content/4/2/e202000808.abstract N2 - Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent. ER -