The FUS-DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma

Mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes play critical roles in governing genomic architecture and gene expression and are frequently perturbed in human cancers. Transcription factors (TFs), including fusion oncoproteins, can bind to BAF complex surfaces to direct chromatin targeting and accessibility, often activating oncogenic gene loci. Here, we demonstrate that the FUS-DDIT3 fusion oncoprotein hallmark to myxoid liposarcoma (MLPS) inhibits BAF complex-mediated remodeling of adipogenic enhancer sites via sequestration of the adipogenic TF, CEBPB, from the genome. In mesenchymal stem cells, small molecule inhibition of BAF complex ATPase activity attenuates adipogenesis via failure of BAF-mediated DNA accessibility and gene activation at CEBPB target sites genome-wide. BAF chromatin targeting and gene expression profiles of FUS-DDIT3-expressing cell lines and primary tumors exhibit similarity to SMARCB1-deficient BAF loss-of-function tumor types. These data present a novel mechanism by which fusion oncoproteins generate BAF complex loss-of-function phenotypes, independent of deleterious subunit mutations. Overall design: ChIP-seq, Cut & Run, RNA-seq, and ATAC-seq in MLPS-1765-92 (FUS-DDIT3 fusion), MLPS-402-91 (FUS-DDIT3 fusion), 1BD5 (MLPS-1765-92 SMARCB1-null), 3AA3 (MLPS-1765-92 SMARCB1-null), hTERT-MSC, AD-MSC, and MLPS primary tumors to investigate the role of the FUS-DDIT3 fusion oncoprotein on BAF complex targeting and activity, especially in the context of Myxoid Liposarcoma and adipogenesis