期刊
CANCER CELL
卷 26, 期 5, 页码 668-681出版社
CELL PRESS
DOI: 10.1016/j.ccell.2014.10.004
关键词
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资金
- NIH [HL007574-30]
- St. Baldrick's fellowship
- Swiss National Science Foundation [P3SMP3_148408]
- Nuovo Soldati Foundation
- Fond de perfectionnement CHUV
- Howard Hughes Medical Institute
- National Human Genome Research Institute (ENCODE) [U54 HG006991]
- Hyundai Hope on Wheels
- Burroughs Wellcome Fund
- Affymetrix
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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