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Synovial sarcoma reprograms transcription by GBAF activation of polycomb targets and loss of CBAF enhancers
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Synovial sarcoma reprograms transcription by GBAF activation of polycomb targets and loss of CBAF enhancers
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Journal Article
Synovial sarcoma reprograms transcription by GBAF activation of polycomb targets and loss of CBAF enhancers
2025
Overview
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.
Synovial sarcoma (SyS) is a cancer driven by a fusion oncoprotein, SS18::SSX, but the mechanism underlying the oncoprotein-mediated tumorigenesis remains unclear. Here, the authors employ transgenic mouse models and multi-omics to show how SS18:SSX modifies the activity and recruitment of BAF-family chromatin remodeling complexes to drive SyS tumorigenesis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 45/91
/ 64/110
/ 82/51
/ Animals
/ Cancer
/ Cells
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Gene Expression Regulation, Neoplastic
/ Genes
/ Genomes
/ Histones
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Neoplasm Proteins - genetics
/ Neoplasm Proteins - metabolism
/ Oncogene Proteins, Fusion - genetics
/ Oncogene Proteins, Fusion - metabolism
/ Polycomb-Group Proteins - genetics
/ Polycomb-Group Proteins - metabolism
/ Proto-Oncogene Proteins - genetics
/ Proto-Oncogene Proteins - metabolism
/ Sarcoma
/ Sarcoma, Synovial - genetics
/ Sarcoma, Synovial - metabolism
/ Sarcoma, Synovial - pathology
/ Science
/ Transcription Factors - genetics
/ Transcription Factors - metabolism
/ Tumors
