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

Nicolò Riggi; Birgit Knoechel; Shawn M Gillespie; Esther Rheinbay; Gaylor Boulay; Mario L Suvà; Nikki E Rossetti; Wannaporn E Boonseng; Ozgur Oksuz; Edward B Cook; Aurélie Formey; Anoop Patel; Melissa Gymrek; Vishal Thapar; Vikram Deshpande; David T Ting; Francis J Hornicek; G Petur Nielsen; Ivan Stamenkovic; Martin J Aryee; Bradley E Bernstein; Miguel N Rivera

doi:10.1016/j.ccell.2014.10.004

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

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

Authors

Nicolò Riggi^#^{1

2}, Birgit Knoechel^#^{1

2

3

4}, Shawn M Gillespie^#^{1

2

5}, Esther Rheinbay^{1

2}, Gaylor Boulay^{1

2}, Mario L Suvà^{1

2}, Nikki E Rossetti¹, Wannaporn E Boonseng¹, Ozgur Oksuz¹, Edward B Cook¹, Aurélie Formey⁶, Anoop Patel^{5

7}, Melissa Gymrek^{8

9

10}, Vishal Thapar¹¹, Vikram Deshpande¹², David T Ting¹¹, Francis J Hornicek¹³, G Petur Nielsen¹², Ivan Stamenkovic⁶, Martin J Aryee^{1

2}, Bradley E Bernstein^#^{1

2

5}, Miguel N Rivera^#^{1

2}

Affiliations

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.

^# 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Bone Neoplasms / genetics*
Bone Neoplasms / metabolism
Cell Line, Tumor
Chromatin Assembly and Disassembly*
Enhancer Elements, Genetic
Gene Expression Regulation, Neoplastic
Humans
Mice, Inbred NOD
Mice, SCID
Neoplasm Transplantation
Oncogene Proteins, Fusion / physiology*
Protein Binding
Proto-Oncogene Protein c-fli-1 / physiology*
RNA-Binding Protein EWS / physiology*
Sarcoma, Ewing / genetics*
Sarcoma, Ewing / metabolism

Substances

EWS-FLI fusion protein
Oncogene Proteins, Fusion
Proto-Oncogene Protein c-fli-1
RNA-Binding Protein EWS

Abstract

Publication types

MeSH terms

Substances

Grants and funding