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

Cell. 2017 Sep 21;171(1):163-178.e19. doi: 10.1016/j.cell.2017.07.036. Epub 2017 Aug 24.


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.

Keywords: EWS-FLI1; Ewing sarcoma; enhancers; epigenetics; intrinsically disordered proteins; mSWI/SNF (BAF) complexes; microsatellite repeats; phase transition; pioneer factor; prion-like domains.

MeSH terms

  • Calmodulin-Binding Proteins / chemistry*
  • Calmodulin-Binding Proteins / metabolism*
  • Cell Line, Tumor
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Humans
  • Mesenchymal Stem Cells / metabolism
  • Microsatellite Repeats
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion / metabolism*
  • Prion Proteins / metabolism
  • Protein Domains
  • Proto-Oncogene Protein c-fli-1 / metabolism*
  • RNA-Binding Protein EWS / metabolism*
  • RNA-Binding Proteins / chemistry*
  • RNA-Binding Proteins / metabolism*
  • Sarcoma, Ewing / genetics*
  • Sarcoma, Ewing / pathology


  • BANF1 protein, human
  • Calmodulin-Binding Proteins
  • DNA-Binding Proteins
  • EWS-FLI fusion protein
  • EWSR1 protein, human
  • FLI1 protein, human
  • Multiprotein Complexes
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Prion Proteins
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • RNA-Binding Proteins