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

Gaylor Boulay1, Gabriel J Sandoval2, Nicolo Riggi3

  • 1Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

Cell
|August 29, 2017
PubMed

Insights

The BRG1/BRM-associated factor (BAF) complex interacts with EWSR1 in Ewing sarcoma, driven by the EWS-FLI1 fusion protein. Prion-like domains of EWSR1 are key to recruiting the BAF complex for oncogenic gene activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Transcriptional regulator alterations drive cancer gene expression.
  • BRG1/BRM-associated factor (BAF) chromatin remodeling complex is frequently mutated in human tumors.
  • EWSR1, a protein with prion-like domains, partners in oncogenic fusions.

Purpose of the Study:

  • Investigate the role of the BAF complex and EWSR1 in Ewing sarcoma.
  • Determine how the EWS-FLI1 fusion protein utilizes these components.
  • Elucidate the mechanism of oncogenic gene activation.

Main Methods:

  • Chromatin immunoprecipitation to identify BAF complex targets.
  • Analysis of EWS-FLI1 fusion protein interactions.
  • Mutational analysis of EWSR1 prion-like domain tyrosine residues.
  • Functional studies using EWSR1-FLI1 fusion fragments.

Main Results:

  • BAF complex is recruited by EWS-FLI1 to tumor-specific enhancers in Ewing sarcoma.
  • BAF recruitment leads to oncogenic target gene activation, a neomorphic function of EWS-FLI1.
  • EWSR1 prion-like domain tyrosine residues are essential for BAF complex retargeting and phase transitions.
  • Short EWSR1 fragments fused to FLI1 can recapitulate EWS-FLI1 activities.

Conclusions:

  • The physical properties of EWSR1's prion-like domain enable the retargeting of the BAF chromatin remodeling complex.
  • This retargeting is critical for establishing and maintaining oncogenic gene expression programs in Ewing sarcoma.
  • Prion-like domains can dictate the function of chromatin regulators in cancer.
Keywords:
EWS-FLI1Ewing sarcomaenhancersepigeneticsintrinsically disordered proteinsmSWI/SNF (BAF) complexesmicrosatellite repeatsphase transitionpioneer factorprion-like domains

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