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

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

doi:10.1016/j.cell.2017.07.036

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.

Authors

Affiliations

¹ Department 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.
² Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, Switzerland.
⁴ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
⁶ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
⁷ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, Switzerland; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
⁸ Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: cigall_kadoch@dfci.harvard.edu.
⁹ Department 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. Electronic address: mnrivera@mgh.harvard.edu.

Abstract

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

Substances

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

Abstract

MeSH terms

Substances

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