Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain

Publication date: Available online 24 August 2017
Source:Cell
Author(s): Gaylor Boulay, Gabriel J. Sandoval, Nicolo Riggi, Sowmya Iyer, Rémi Buisson, Beverly Naigles, Mary E. Awad, Shruthi Rengarajan, Angela Volorio, Matthew J. McBride, Liliane C. Broye, Lee Zou, Ivan Stamenkovic, Cigall Kadoch, Miguel N. Rivera
Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.

Graphical abstract

Teaser

Phase transition properties of a prion-like domain in an oncogenic fusion protein are critical for retargeting BAF chromatin remodeling complexes and activating enhancers, thereby driving the transcriptional program that promotes Ewing sarcoma.


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