Congrats to Hayley Zullow of @kadochlab @HarvardMITmdphd @BBS_Harvard programs and our team, including @akshaysci, @JunQiLab, @ar_davino, and many others, on this exciting new study out today in @MolecularCell @CellPressNews ! Tweetorial below: (1/7) cell.com/molecular-cell…
Here, we explore the impact of the #fusion oncoprotein hallmark to #myxoidliposarcoma, FUS-DDIT3, and its impact on #BAF #SWISNF complex-mediated #chromatin remodeling activities genome wide. (2/7)
We previously showed that fusions such as SS18-SSX and EWS-FLI1, in #synovialsarcoma and #Ewingsarcoma, respectively, interact with BAF complexes and direct their genomic occupancy in a cancer-specific, gain-of-function manner. (3/7)
Surprisingly, FUS-DDIT3 acts by *sequestering* BAF complexes away from CEBPB target sites, which are critical for proper adipogenic (fat cell) differentiation, resulting in stalled #adipogenesis. (4/7)
BAF complexes are essential for #adipogenesis, as shown using #smallmolecule inhibition of BAF complex ATPase activities in cell model systems. (5/7)
Interestingly, the FUS-DDIT3-mediated loss-of-function impact on BAF complexes that we uncovered closely mirrors BAF loss-of-function in SMARCB1-deficient cancers and others driven by BAF complex compromise in cell lines and primary tumors. (6/7)
Thus, these findings present an example of BAF complex perturbation (loss-of-function) in the absence of BAF subunit gene mutations, identifying a new mechanistic category for #fusiononcoproteins. (7/7)
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