Cell Mol Biol Lett. 2025 Sep 23. 30(1): 107
Malin Lindén,
Lisa Andersson,
Heba Albatrok,
Vilma Canfjorden,
Emma Jonasson,
Kajsa Grönqvist,
Daniel Sjövall,
Pekka Jaako,
Rossella Crescitelli,
Henrik Fagman,
Pierre Åman,
Anders Ståhlberg.
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.
Keywords: Ewing sarcoma; FET fusion oncoproteins; Myxoid liposarcoma; Quantitative mass spectrometry; SWI/SNF chromatin remodeling complex