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The FUS::DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma
Hayley J Zullow1, Akshay Sankar2, Davis R Ingram3
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard/MIT Medical Scientist Training Program, Boston, MA, USA.
Abstract:
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. BAF chromatin occupancy and gene expression profiles of FUS::DDIT3-expressing cell lines and primary tumors exhibit similarity to SMARCB1-deficient tumor types. These data present a mechanism by which a fusion oncoprotein generates a BAF complex loss-of-function phenotype, independent of deleterious subunit mutations.
Insights
The FUS::DDIT3 oncoprotein in myxoid liposarcoma sequesters CEBPB, inhibiting BAF complex chromatin remodeling. This fusion oncoprotein mimics BAF complex loss-of-function without subunit mutations.
Area of Science:
- Molecular Biology
- Cancer Biology
- Epigenetics
Background:
- Mammalian SWI/SNF (mSWI/SNF or BAF) complexes are crucial for gene regulation and genomic organization.
- These complexes are often altered in human cancers, with transcription factors directing their activity.
- Fusion oncoproteins can hijack BAF complexes to promote oncogenesis.
Purpose of the Study:
- To investigate the mechanism by which the FUS::DDIT3 fusion oncoprotein affects BAF complex function in myxoid liposarcoma.
- To determine if FUS::DDIT3 can induce a BAF complex loss-of-function phenotype.
Main Methods:
- Studied the interaction between FUS::DDIT3 and the BAF complex in mesenchymal stem cells.
- Utilized small-molecule inhibitors to assess the impact of BAF complex ATPase activity on adipogenesis.
- Analyzed BAF chromatin occupancy and gene expression in FUS::DDIT3-expressing cells and tumors.
Main Results:
- FUS::DDIT3 inhibits BAF complex remodeling of adipogenic enhancers by sequestering the transcription factor CEBPB.
- Inhibition of BAF complex ATPase activity impairs adipogenesis by blocking DNA accessibility and gene activation at CEBPB target sites.
- BAF complex profiles in FUS::DDIT3 tumors resemble those in SMARCB1-deficient cancers.
Conclusions:
- Fusion oncoproteins can cause a BAF complex loss-of-function phenotype independently of subunit mutations.
- This mechanism provides insight into oncogenesis driven by chromatin remodeling alterations.
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