The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies
Gaylor Boulay, Luisa Cironi, Sara P. Garcia, Shruthi Rengarajan, Yu‐Hang Xing, Lukuo Lee, Mary E. Awad, Beverly Naigles, Sowmya Iyer, Liliane C. Broye, Tugba Keskin, Alexandra Cauderay, Carlo Fusco, Igor Letovanec, Ivan Chebib, Petur Nielsen, Stéphane Tercier, Stéphane Cherix, Tu Nguyen‐Ngoc, Gregory M. Coté, Edwin Choy, Paolo Provero, Mario L. Suvà, Miguel N. Rivera, Ivan Stamenkovic, Nicolò Riggi
Abstract
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.