GSE174360
Cancer-specific deficiency of SMARCE1, a module-linking subunit, generates a targetable chromatin regulatory dependency in clear cell meningioma
Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes are critical for establishing and maintaining chromatin accessibility and gene expression and are frequently perturbed in human disease. Select rare cancer types are characterized uniformly by mSWI/SNF subunit perturbations, underscoring their driving roles. Clear cell meningioma (CCM), an aggressive CNS tumor, is driven by loss of the SMARCE1 subunit, found in ~100% of cases. Here we identify an unexpected and evolutionarily conserved structural role for SMARCE1 in selectively stabilizing the cBAF complex core -ATPase module interaction. SMARCE1 is required for stable docking of cBAF complexes to nucleosomes via ATPase rigidification. In CCM, cBAF complexes selectively fail to stabilize on nucleosome substrates and chromatin and residual cores increase the formation of BRD9-containing ncBAF complexes. Combined attenuation of cBAF complex function and ncBAF complex activity generate the CCM-specific gene expression profile, which is distinct from NF2 loss. Importantly, SMARCE1-deficient cells exhibit heightened sensitivity to small molecule inhibition of ncBAF complexes. These data inform on the function of a previously elusive subunit and suggest new therapeutic approaches for highly aggressive SMARCE1-deficient CCM. Overall design: ChIP-seq, Cut & Tag, RNA-seq, and ATAC-seq in BT549 (SMARCE1-null breast cancer cell), AC7 (Human meningeal cell), and fresh frozen primary CCM tumors to investigate the genomic ramification of SMARCE1 loss. **Raw data for the primary meningioma tumor samples were not provided due to patient privacy concerns and will be submitted to dbGaP**