Please use this identifier to cite or link to this item: https://doi.org/10.1093/nar/gkaa901
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dc.titleEWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma
dc.contributor.authorShi, X.
dc.contributor.authorZheng, Y.
dc.contributor.authorJiang, L.
dc.contributor.authorZhou, B.
dc.contributor.authorYang, W.
dc.contributor.authorLi, L.
dc.contributor.authorDing, L.
dc.contributor.authorHuang, M.
dc.contributor.authorGery, S.
dc.contributor.authorLin, D.-C.
dc.contributor.authorKoeffler, H.P.
dc.date.accessioned2021-08-25T14:16:09Z
dc.date.available2021-08-25T14:16:09Z
dc.date.issued2020
dc.identifier.citationShi, X., Zheng, Y., Jiang, L., Zhou, B., Yang, W., Li, L., Ding, L., Huang, M., Gery, S., Lin, D.-C., Koeffler, H.P. (2020). EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma. Nucleic Acids Research 48 (20) : 11434-11451. ScholarBank@NUS Repository. https://doi.org/10.1093/nar/gkaa901
dc.identifier.issn3051048
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/199379
dc.description.abstractCore regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and adolescents 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. 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, 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, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy. © 2020 The Author(s).
dc.publisherOxford University Press
dc.rightsAttribution-NonCommercial 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.sourceScopus OA2020
dc.typeArticle
dc.contributor.departmentPATHOLOGY
dc.contributor.departmentMEDICINE
dc.description.doi10.1093/nar/gkaa901
dc.description.sourcetitleNucleic Acids Research
dc.description.volume48
dc.description.issue20
dc.description.page11434-11451
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