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A stage-specific induction system reveals that the oncogenic fusion protein in synovial sarcoma, SS18-SSX, is a cellular context-dependent epigenetic modifier

ABSTRACT: We analyzed the effects of cellular context on the function of the synovial sarcoma-specific fusion protein, SS18-SSX, using human pluripotent stem cells containing the drug-inducible SS18-SSX gene. To investigate the cell-type-dependent effecfts of SS18-SSX, we performed gene expression profiling experiments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE63895 | GEO | 2016/04/13

SECONDARY ACCESSION(S): PRJNA269358

REPOSITORIES: GEO

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A stage-specific induction system reveals that the oncogenic fusion protein in synovial sarcoma, SS18-SSX, is a cellular context-dependent epigenetic modifier

Project description:We analyzed the effects of cellular context on the function of the synovial sarcoma-specific fusion protein, SS18-SSX, using human pluripotent stem cells containing the drug-inducible SS18-SSX gene. To investigate the cell-type-dependent effecfts of SS18-SSX, we performed gene expression profiling experiments. Comparison of global gene expressions of hPSCs, hPSC-NCCs, and hPSC-MSCs with or without the inductuion of SS18-SSX2

2016-04-13 | E-GEOD-63895 | biostudies-arrayexpress

The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma [ATAC-seq]

Project description:Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate a SS transcriptional signature we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.

2018-05-31 | GSE114487 | GEO

The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma [ChIP-Seq]

2018-05-31 | GSE108025 | GEO

The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma [RNA-Seq Tumor]

2018-05-31 | GSE108027 | GEO

The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma [RNA-Seq Cell]

2018-05-31 | GSE108026 | GEO

The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma [ChIP-seq]

Project description:Gene fusions arising from chromosomal translocations are key oncogenic drivers in soft tissue sarcomas but little is known about how they exert their oncogenic effects. Our study explores the molecular mechanisms by which the SS18-SSX fusion oncoprotein subverts epigenetic mechanisms of gene regulation to drive synovial sarcoma. Using functional genomics, we identify KDM2B – a histone demethylase and core component of a non-canonical Polycomb Repressive Complex 1 (PRC1.1) – as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands genome-wide. Via KDM2B, SS18-SSX binds and aberrantly activates expression of a series of developmentally regulated transcription factors that would otherwise be targets of polycomb-mediated repression, which is restored upon KDM2B depletion leading to irreversible mesenchymal differentiation. Thus, SS18-SSX de-regulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression.

2018-03-01 | GSE108926 | GEO

The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma [RNA-seq]

2018-03-01 | GSE108928 | GEO

The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma [ATAC-seq]

2018-03-01 | GSE108927 | GEO

The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma

Project description:Expression of the SS18/SYT-SSX fusion protein is believed to underlie the pathogenesis of synovial sarcoma (SS). Recent evidence suggests that deregulation of the Wnt pathway may play an important role in SS but the mechanisms whereby SS18-SSX might affect Wnt signaling remain to be elucidated. Here, we show that SS18/SSX tightly regulates the elevated expression of the key Wnt target AXIN2 in primary SS. SS18-SSX is shown to interact with TCF/LEF, TLE and HDAC but not Î² -catenin in vivo and to induce Wnt target gene expression by forming a complex containing promoter-bound TCF/LEF and HDAC but lacking Î² -catenin. Our observations provide a tumor-specific mechanistic basis for Wnt target gene induction in SS that can occur in the absence of Wnt ligand stimulation. SS18SSX expressing C3H cells vs control: no replicates. WNT-stimulated C3H cells vs controls: 3 replicates per condition

2016-02-23 | E-GEOD-78159 | biostudies-arrayexpress

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.

2023-05-24 | GSE233376 | GEO

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