Pluto Biosciences, Inc

GSE148723: The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies [RNA-seq]

Bulk RNA sequencing

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 geneSS18to one of threeSSXgenes. 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 ofde novoactive regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and confer vulnerability to USP7 loss, a core member of ncPRC1.1. SyS organoids thus provide a powerful model to define mechanisms of epigenetic dysregulation on which SyS cells are dependent. SOURCE: Sowmya Iyer (sowmya.iyer@mgh.harvard.edu) - Massachusetts General Hospital

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