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- W2999161012 abstract "Abstract Core regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and young adults carrying few gene mutations. However, whether and how CRC contributes to transcription regulation in Ewing sarcoma is unknown. Here, we identify and functionally validate a CRC “trio” constituted by three transcription factors (TFs): KLF15, TCF4 and NKX2-2, in Ewing sarcoma cells. Epigenomic analyses demonstrate that EWS-FLI1, the primary fusion driver for this cancer, directly establishes super-enhancers of each of these three TFs to activate their transcription. In turn, KLF15, TCF4 and NKX2-2 co-bind to their own and each other’s super-enhancers and promoters, forming an inter-connected auto-regulatory loop. Functionally, CRC factors contribute significantly to cell proliferation of Ewing sarcoma both in vitro and in vivo , and are all overexpressed in this cancer. Mechanistically, CRC factors exhibit prominent capacity of co-regulating the epigenome in cooperation with EWS-FLI1, occupying 77.2% of promoters and 55.6% of enhancers genome-wide. Downstream, CRC TFs coordinately regulate gene expression networks in Ewing sarcoma, directly controlling important signaling pathways for cancer, such as lipid metabolism pathway, PI3K/AKT and MAPK signaling pathways. Together, molecular characterization of the oncogenic CRC model advances our understanding of the biology of Ewing sarcoma. Moreover, this study identifies CRC-downstream genes and signaling pathways, which may contain potential targets for therapeutic intervention for this malignancy." @default.
- W2999161012 created "2020-01-23" @default.
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- W2999161012 date "2020-01-16" @default.
- W2999161012 modified "2023-10-06" @default.
- W2999161012 title "EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma" @default.
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- W2999161012 doi "https://doi.org/10.1101/2020.01.15.908475" @default.
- W2999161012 hasPublicationYear "2020" @default.
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