BAF recruitment to GGAA microsatellites activates the Ewing sarcoma transcriptional program.
Major finding: BAF recruitment to GGAA microsatellites activates the Ewing sarcoma transcriptional program.
Mechanism: The prion-like domain in EWS–FLI1 is required for phase transitions that promote enhancer activation.
Impact: Prion-like domains can retarget chromatin remodeling complexes to promote oncogenic gene expression.
In Ewing sarcoma, a chromosomal translocation generates the oncogenic fusion protein EWS–FLI1, which drives tumorigenicity. EWS–FLI1 contains the ETS DNA binding domain of FLI1, but the functional role of the EWSR1 portion is not well understood, although it has been linked to transcriptional activation. EWS–FLI1 has been shown to act as a pioneer transcription factor by binding to GGAA microsatellite repeats to establish active enhancers and promote expression of Ewing sarcoma genes. However, the mechanism by which EWS–FLI1 facilitates chromatin remodeling has not been elucidated. Boulay, Sandoval, and colleagues found that both wild-type EWSR1 and EWS–FLI1 interacted with subunits of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex (also known as SWI/SNF). Mechanistically, EWS–FLI1, but not wild-type FLI1, recruited BAF complexes to tumor-specific GGAA microsatellite repeat enhancers to facilitate chromatin opening and EWS–FLI1-mediated target gene expression. EWSR1 contains an intrinsically disordered low-complexity prion-like domain that confers phase transition properties, which were required for EWS–FLI1 to act as a pioneer transcription factor. Tyrosine residues in the prion-like domain of EWS–FLI1 were necessary for phase transitions and enabled binding to GGAA microsatellites, BAF recruitment, and activation of tumor-specific de novo enhancers. Consistent with these findings, fusing small fragments of the disordered EWSR1 prion-like domain to the C-terminus of FLI1 was sufficient to recapitulate the chromatin binding and gene expression program of full length EWS–FLI1. In addition to elucidating a mechanism by which the EWSR1 portion of EWS–FLI1 can promote chromatin remodeling to facilitate the oncogenic effects of EWS–FLI1, these findings reveal that prion-like domains can promote retargeting of chromatin remodeling complexes to establish and maintain oncogenic gene expression programs. Further, these results reveal a role for the BAF complex in promoting tumorigenesis in the absence of genetic alterations in BAF subunits.
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