mSWI/SNF functional genomic characterization of SMARCB1 mutants in SMARCB1-null and heterozygous settings

Chromatin remodeling complexes regulate gene expression by shifting, evicting, and exchanging nucleosomes along the chromosomes of eukaryotic organisms. The mammalian SWI/SNF chromatin remodeling complex (mSWI/SNF or BAF) is mutated in over 20% of human cancers and loss of the SMARCB1 gene, encoding the BAF47 protein subunit, results in one of the most aggressive and lethal pediatric cancers. An accumulation of point mutations occurs at the C-terminal end of the protein, for which the functional ramifications are unknown. We previously demonstrated that reintroduction of SMARCB1 in SMARCB1-null malignant rhabdoid tumor cells results in a genome-wide increase of mSWI/SNF complex occupancy coupled with activation of PRC2-repressed genes. Here, we study the functional consequences that these point mutations exert on mSWI/SNF complex activity in SMARCB1-deficient tumor cells and extend this investigation to a CRISPR/Cas9-mediated SMARCB1-heterozygous mutant induced pluripotent stem cell. Intriguingly, we observe that the mutant complexes bind similarly to wild-type SMARCB1 complexes at enhancers throughout the genome but often fail to transcriptionally activate nearby genes in a cis-regulatory manner.