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

ABSTRACT: 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 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE148723 | GEO | 2020/12/21

REPOSITORIES: GEO

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

Project description: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 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.

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Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability

Project description:The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.

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Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability

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SS18-SSX-mediated hijacking of BAF complexes drives synovial sarcoma

Project description:Synovial sarcoma (SS) is defined by a recurrent t(x;18) chromosomal translocation, which produces the hallmark SS18-SSX oncogenic fusion. Incorporation of SS18-SSX into BAF complexes renders BAF complexes aberrant in two distinct manners: the addition of 78aa of SSX onto SS18, and concomitant loss of BAF47 assembly. However, the importance and functional contributions of each of these perturbations on BAF complex targeting and gene expression regulation remain unclear. Here we use an integrative set of genomic approaches in human cancer cell lines and primary tumor samples to define the mechanistic consequences of the SS18-SSX fusion oncoprotein. We find that SS18-SSX hijacks BAF complexes to broad polycomb domains to activate bivalent genes, driving a unique gene expression program distinct from other loss-of-function BAF complex malignancies. Importantly, restoration of BAF47 rescues enhancer activation but is dispensable for proliferative arrest in cell lines. These results demonstrate that gain-of-function SS18-SSX-mediated BAF complex targeting and gene activation is the driving event in SS, and present a mechanism by which distinct functions of BAF complexes can be co-opted to drive oncogenesis.

| EGAS00001002920 | EGA

ena-DATASET-MDACC-29-05-2018-15:47:46:325-962 - samples

| EGAD00001004135 | EGA

An autoregulatory feedback loop converging on H2AK119ub1 drives synovial sarcoma [CUT&RUN]

Project description:The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of mSWI/SNF complex, to polycomb repressive complex 1 (PRC1) target genes. Here we show that the SSX C-terminus, via its SSXRD domain, directs SS18-SSX chromatin binding independently of SS18. SSXRD specific targeting is mediated by interaction with H2AK119ub1 and histone MacroH2A with which the fusion overlaps genome wide. Variant Polycomb Repressive Complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and consequently is required for SS18-SSX occupancy. Importantly, SSX C-terminus not only depends on H2AK119ub1 for localization but also further promotes it and consequently, high H2AK119ub1 levels are acquired during synovial sarcoma development. These results reveal an SS18-SSX/PRC1 autoregulatory feedback-loop that enforces fusion binding and could play a role in a wide-range of cancers and physiological settings where SSX proteins are overexpressed.

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