EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.
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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. |
Year of Publication | 2014
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Journal | Cancer Cell
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Volume | 26
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Issue | 5
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Pages | 668-81
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Date Published | 2014 Nov 10
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ISSN | 1878-3686
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DOI | 10.1016/j.ccell.2014.10.004
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PubMed ID | 25453903
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PubMed Central ID | PMC4492343
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Grant list | U54 HG006991 / HG / NHGRI NIH HHS / United States
T32 HL007574 / HL / NHLBI NIH HHS / United States
T32 HL007574-30 / HL / NHLBI NIH HHS / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States
Howard Hughes Medical Institute / United States
K12 CA087723 / CA / NCI NIH HHS / United States
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