title: EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.
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.
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Riggi
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Knoechel
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gillespie
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Rheinbay
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Gaylor
authors.initials: G
authors.lastname: Boulay
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Mario L
authors.initials: ML
authors.lastname: Suvà
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Nikki E
authors.initials: NE
authors.lastname: Rossetti
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Wannaporn E
authors.initials: WE
authors.lastname: Boonseng
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Oksuz
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Cook
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Formey
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD, USA.|Department of Neurosurgery Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Anoop
authors.initials: A
authors.lastname: Patel
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts, USA.|Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gymrek
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Thapar
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Cancer Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Hornicek
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: G Petur
authors.initials: GP
authors.lastname: Nielsen
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Aryee
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
mesh_terms: D000818:Animals; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D011485:Protein Binding; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology*; D034802:RNA-Binding Protein EWS / Q000502:physiology*; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS