BRD9 functions as a negative regulator of GBAF in synovial sarcoma

Synovial sarcoma (SyS) incorporates the SS18::SSX fusion oncoprotein into GLTSCR1-containing BRG1/BRM and associated factors (GBAF) complexes, and demonstrated a dependency on GBAF subunit, BRD9. However, SyS clinical trials with multiple BRD9 degraders failed to achieve clinically impactful remissions. Here, we provide a mechanistic framework to explain these results. BRD9 depletion serves to blunt proliferation in SySs harboring minimal genomic alterations, rare in trial participants. In cultured cells, xenografts, and recombinant purified complexes, BRD9 loss does not impact GBAF assembly. Although BRD9 degradation in SyS reduces GBAF enrichment at target loci, BRD9-less complexes maintain or increase chromatin accessibility and associated gene transcription. Biochemical assays with purified recombinant GBAF demonstrate markedly increased nucleosome sliding in the absence of BRD9. Thus, BRD9 restrains GBAF activity, with BRD9 degradation increasing enzymatic remodeling and target gene expression by fusion oncoprotein-distributed GBAFs in SyS. This subtle epigenetic disturbance creates a low hurdle for SyS to surpass.