biostudies-literatureLi JU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)U.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHS1081https://www.ebi.ac.uk/biostudies/studies/S-EPMC12852873biostudies-literatureUnknown17(1)Synovial sarcoma is a cancer driven by a fusion oncoprotein, SS18::SSX, that links SS18, a subunit of BAF-family chromatin remodeling complexes, to the carboxy terminus of SSX, which avidly binds nucleosomes with the histone post-translational modification H2AK119ub. Here, we show in mice that SS18::SSX expression redistributes non-canonical GBAF complexes broadly to promoters and distal enhancers marked by H2AK119ub, which causes developmental loci to lose H3K27me3 and become transcriptionally active. Canonical BAF containing SS18::SSX abandons its typical binding sites, is largely absent from H2AK119ub-marked sites, and instead distributes narrowly to transcription start sites with PBAF. Disruption of Arid1a or Arid1b (both CBAF-specific) retains synovial sarcoma character, while Smarcb1Nature communicationsSynovial sarcoma reprograms transcription by GBAF activation of polycomb targets and loss of CBAF enhancers.PMC12852873P30 CA042014U54 CA2316522P30CA042014-31R01 CA201396R01CA201396Li JJones KBCarroll LHill LAGuo YSmith-Fry KNielsen TOLi LUnderhill TMCairns BRFadlullah MZMorrison LHirst MGe XZhang XDavenport GNelson MLfalseSynovial sarcoma reprograms transcription by GBAF activation of polycomb targets and loss of CBAF enhancers.Synovial sarcoma is a cancer driven by a fusion oncoprotein, SS18::SSX, that links SS18, a subunit of BAF-family chromatin remodeling complexes, to the carboxy terminus of SSX, which avidly binds nucleosomes with the histone post-translational modification H2AK119ub. Here, we show in mice that SS18::SSX expression redistributes non-canonical GBAF complexes broadly to promoters and distal enhancers marked by H2AK119ub, which causes developmental loci to lose H3K27me3 and become transcriptionally active. Canonical BAF containing SS18::SSX abandons its typical binding sites, is largely absent from H2AK119ub-marked sites, and instead distributes narrowly to transcription start sites with PBAF. Disruption of Arid1a or Arid1b (both CBAF-specific) retains synovial sarcoma character, while Smarcb12025-01-01T00:00:00Z2025 Dec2026-06-16T03:10:21.554Z2026-06-16T03:07:00.673ZS-EPMC128528734142347210.1038/s41467-025-67841-y