Biochemical and Functional Ramifications of SMARCE1 Loss in Clear Cell Meningioma and Coffin Siris Syndrome

Abstract

Mutations in SMARCE1, which encodes the BAF57 subunit of the mammalian Switch/Sucrose Non-Fermentable (mSWI/SNF) ATP-dependent chromatin remodeling complex, have been identified in patients afflicted with clear cell meningioma (CCM), a rare pediatric tumor with little mechanistic understanding, and no modern therapeutic insights. The current study aims to identify therapeutic vulnerabilities in CCM by probing the effect of SMARCE1 loss on the biochemical architecture of the multimeric mSWI/SNF (BAF) complex, and defining the transcriptional consequences that promotes aberrant BAF complex targeting genome-wide and oncogenic gene expression patterns. We find that SMARCE1 loss, uniquely impairs canonical BAF, increases the nucleation of noncanonical BAF, and identify downstream pathways amenable to therapeutic intervention. SMARCE1 mutations appear to cause CCM via a classical tumor suppressor mechanism whereby patients bear familial germline loss of one allele, concomitant with either loss or mutation of the second allele, culminating in complete loss of SMARCE1 protein. CCM is rare histological grade II neoplasm of the central nervous system (CNS) that disproportionally affects children and adolescents. Although surgical resection and radiation effectively treat most meningiomas, CCM exhibits uniquely aggressive clinical behavior, with a high rate of recurrence and extra-CNS metastasis. mSWI/SNF chromatin remodeling complexes are key transcriptional machines, ubiquitously expressed in every human cell type. mSWI/SNF complexes are fueled by ATP hydrolysis to orchestrate a diverse set of alterations to chromatin architecture (i.e. ejection, destabilization, or restructuring of nucleosomes), which grant transcription factors access to tightly packaged nucleosomal DNA, resulting in context-specific regulation of gene expression. Subunits of the mSWI/SNF complex are mutated in over 20% of cancers across a wide range of tissue types and often represent the most frequently mutated gene in these cancers. For instance, ARID1A and SMARCB1, each encoding subunits of the mSWI/SNF complex, are respectively mutated in >60% of ovarian clear cell tumors and >98% of childhood malignant rhabdoid tumors. Interestingly, genetic perturbations in mSWI/SNF have been shown to exhibit key synthetic lethal relationships with targets of established epigenetic drugs, prompting a surge of drug discovery efforts for mSWI/SNF-driven cancers. Owing to a lack of understanding regarding the mechanistic underpinnings of CCM, targeted therapeutics predicted to exhibit efficacy in this disease have yet been identified. Collectively, these studies offer therapeutic insights that can be translated in the clinic to chemically tackle CCM.