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EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.
Riggi, Nicolò; Knoechel, Birgit; Gillespie, Shawn M; Rheinbay, Esther; Boulay, Gaylor; Suvà, Mario L; Rossetti, Nikki E; Boonseng, Wannaporn E; Oksuz, Ozgur; Cook, Edward B; Formey, Aurélie; Patel, Anoop; Gymrek, Melissa; Thapar, Vishal; Deshpande, Vikram; Ting, David T; Hornicek, Francis J; Nielsen, G Petur; Stamenkovic, Ivan; Aryee, Martin J; Bernstein, Bradley E; Rivera, Miguel N.
Afiliação
  • Riggi N; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Knoechel B; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gillespie SM; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Rheinbay E; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Boulay G; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Suvà ML; Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
  • Rossetti NE; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Boonseng WE; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Oksuz O; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Cook EB; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Formey A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Patel A; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Gymrek M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Thapar V; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Deshpande V; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ting DT; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Hornicek FJ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Nielsen GP; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Stamenkovic I; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Aryee MJ; Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
  • Bernstein BE; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Rivera MN; Department of Neurosurgery Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Cancer Cell ; 26(5): 668-681, 2014 Nov 10.
Article em En | MEDLINE | ID: mdl-25453903
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sarcoma de Ewing / Neoplasias Ósseas / Proteínas de Fusão Oncogênica / Proteína EWS de Ligação a RNA / Montagem e Desmontagem da Cromatina / Proteína Proto-Oncogênica c-fli-1 Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sarcoma de Ewing / Neoplasias Ósseas / Proteínas de Fusão Oncogênica / Proteína EWS de Ligação a RNA / Montagem e Desmontagem da Cromatina / Proteína Proto-Oncogênica c-fli-1 Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article