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

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

Author information

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

PMID:
28844694
DOI:
10.1016/j.cell.2017.07.036
[Indexed for MEDLINE]

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