A non-canonical SWI/SNF complex underlies synthetic lethality in cancers driven by BAF complex perturbation [RNA-seq]

Mammalian SWI/SNF chromatin remodeling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF, and a newly characterized non-canonical complex, ncBAF. However, their complex-specific targeting on chromatin, functions and roles in disease remain largely unknown. Here, we comprehensively map complex assemblies on chromatin and find that ncBAF uniquely localizes to CTCF sites and promoters. We identified ncBAF subunits as major synthetic lethalities specific to human synovial sarcoma and malignant rhabdoid tumor, which share in common cBAF complex perturbation. Chemical degradation of the BRD9 subunit of ncBAF rapidly attenuates SS and MRT cell proliferation. Notably, in cBAF-perturbed cancers, ncBAF complexes retain their hallmark localization to CTCF sites and promoters, and maintain gene expression at retained mSWI/SNF sites to support cell proliferation in a manner distinct from fusion oncoprotein-mediated targeting. Taken together, these findings unmask the unique targeting and function of ncBAF complexes and present new cancer-specific therapeutic targets. Overall design: CRL7250 cells were treated in biological duplicate with either DMSO vehicle control , dBRD9 compound, or dBRD9 compound for 24h followed by lentiviral infection with construct containing V5-SS18-SSX1 to assess role of BRD9 in SS18-SSX1 gene activation. RNA-seq was performed in biological duplicate in SYO-1 synovial sarcoma cells upon chemical BRD9 degradation by dBRD9 compound or DMSO vehicle control at 3 days and 6 days to assess gene expression changes upon BRD9 perturbation. SYO-1 cells were lentivirally infected in biological duplicate with pGIPZ shControl, pGIPZ shBRD9, or pGIP shSMARCE1 to assess if BRD9 and SMARE1 knockdown are transcriptionally similar. RNA-seq was collected in biological duplicate from TTC1240 cells treated with either DMSO or dBRD9 as for SYO-1. To assess gene expression changes upon BRD9 loss, TTC1240 and MOLM-13 cells were treated with 250nM dBRD9 (1:10,000 dilution) or DMSO control for 7 days (TTC1240) or 6 days (MOLM-13) in duplicate.