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Cancer Cell. 2014 Nov 10;26(5):668-681. doi: 10.1016/j.ccell.2014.10.004. Epub 2014 Oct 30.

EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.

Author information

1
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
5
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
6
Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
7
Department of Neurosurgery Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
8
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts, USA.
9
Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts, USA.
10
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
11
Cancer Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
12
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
13
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Contributed equally

Abstract

The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation.

PMID:
25453903
PMCID:
PMC4492343
DOI:
10.1016/j.ccell.2014.10.004
[Indexed for MEDLINE]
Free PMC Article

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