Year: 2025
Type: article
Abstract: BACKGROUND: FET (FUS, EWSR1, and TAF15) fusion oncoproteins are characteristic for several sarcomas and leukemias, including myxoid liposarcoma and Ewing sarcoma. FET oncoproteins interact with the SWI/SNF chromatin remodeling complex subtypes cBAF, PBAF, and GBAF, but their impact on SWI/SNF compositions, interactions, and downstream epigenetic effects remains elusive. METHODS: We employ a comprehensive immunoprecipitation and quantitative mass spectrometry approach to determine the impact of FET oncoproteins on SWI/SNF composition and their interactomes. Validation of complex composition and interaction partners is performed by glycerol gradient sedimentation assays and co-immunofluorescence analysis. Furthermore, we determine the differential chromatin accessibility and gene regulation in FET sarcomas using assay for transposase-accessible chromatin sequencing and RNA sequencing, respectively. RESULTS: Our data show that FET sarcomas have distinct SWI/SNF complex compositions, with different subunit paralogs and subtype-specific components that utilize distinct sets of interaction partners, including specific transcription factors. We show that FET oncoproteins cause no major disruption of the SWI/SNF complex composition. Instead, FUS::DDIT3-bound SWI/SNF complexes in myxoid liposarcoma cells are enriched in PBAF and GBAF components as well as most interaction partners. CONCLUSIONS: These data suggest that FET oncoproteins act together with fully assembled and functional SWI/SNF complexes and recruited interaction partners. Finally, our data reveal that the SWI/SNF compositions, interactomes, and epigenetic background contribute to the tumor type in FET sarcoma. Trial registration Clinical trial number: not applicable.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,890
Funders: Västra Götalandsregionen, Anna-Lisa och Bror Björnssons Stiftelse, Cancerfonden, Stiftelserna Wilhelm och Martina Lundgrens, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Stiftelsen Assar Gabrielssons Fond, Göteborgs Universitet, Magnus Bergvalls Stiftelse, Barncancerfonden, Science for Life Laboratory, Johan Jansson Foundation, Sahlgrenska Akademin, Uppsala Multidisciplinary Center for Advanced Computational Science
Awards: G1441096865, G1530032797, G2903271315, G3321450376, How Extracellular Vesicles in the Human Tumor Microenvironment Regulate Cancer Progression, G5409202568, G5563741915, G6305055822, G712881263, Targeted therapies and treatment monitoring in FET sarcomas, G7619433571, G7633537017, G7899675793, G796431723, G7974424369, G8708380117, Identifiering av nya läkemedelsmål och epigenetiska behandlingar i pediatriska sarkom
OpenAlex ID: W4414416197