| First Author | Li J | Year | 2025 |
| Journal | Nat Commun | Volume | 17 |
| Issue | 1 | Pages | 1081 |
| PubMed ID | 41423472 | Mgi Jnum | J:378799 |
| Mgi Id | MGI:8283988 | Doi | 10.1038/s41467-025-67841-y |
| Citation | Li J, et al. (2025) Synovial sarcoma reprograms transcription by GBAF activation of polycomb targets and loss of CBAF enhancers. Nat Commun 17(1):1081 |
| abstractText | 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 Smarcb1 (PBAF- and CBAF-specific) or Pbrm1 (PBAF-specific) disruption does not, although all accelerate SS18::SSX-driven tumorigenesis in mice. Thus, the synovial sarcomagenesis mechanism involves SS18::SSX reprogramming transcription positively through GBAF redistribution to activate polycomb-targeted developmental genes, and negatively by loss of normal CBAF localization and function. |
