The FUS::DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma.
The FUS::DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma.
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DOI：
10.1016/j.molcel.2022.03.019
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发表时间：
2022-05-05
期刊：
影响因子：
16
通讯作者：
Kadoch, Cigall
中科院分区：
文献类型：
--
作者：
Zullow, Hayley J.;Sankar, Akshay;Ingram, Davis R.;Guerra, Daniel D. Same;D'Avino, Andrew R.;Collings, Clayton K.;Lazcano, Rossana;Wang, Wei-Lien;Liang, Yu;Qi, Jun;Lazar, Alexander J.;Kadoch, Cigall
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. Zullow et al. demonstrate that the FUS-DDIT3 fusion oncoprotein inhibits the targeting and activity of the mSWI/SNF (BAF) chromatin remodeling complex in myxoid liposarcoma, driving the tumor’s unique gene expression signature, which is similar to that of other BAF loss-of-function tumors. BAF complex disruption similarly attenuates normal adipogenesis in MSCs.
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影响因子：
4.6
作者：
Gonzalez Porras MA;Stojkova K;Vaicik MK;Pelowe A;Goddi A;Carmona A;Long B;Qutub AA;Gonzalez A;Cohen RN;Brey EM
通讯作者：
Brey EM
影响因子：
--
作者：
Andersson MK;Ståhlberg A;Arvidsson Y;Olofsson A;Semb H;Stenman G;Nilsson O;Aman P
通讯作者：
Aman P
影响因子：
56.9
作者：
BISHOP, JM
通讯作者：
BISHOP, JM
影响因子：
--
作者：
Agaimy, Abbas
通讯作者：
Agaimy, Abbas
影响因子：
16
作者：
Barak, Y;Nelson, MC;Evans, RM
通讯作者：
Evans, RM