Cargando…
EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma
Core 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 validat...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672457/ https://www.ncbi.nlm.nih.gov/pubmed/33080033 http://dx.doi.org/10.1093/nar/gkaa901 |
_version_ | 1783611140388945920 |
---|---|
author | Shi, Xianping Zheng, Yueyuan Jiang, Liling Zhou, Bo Yang, Wei Li, Liyan Ding, Lingwen Huang, Moli Gery, Sigal Lin, De-Chen Koeffler, H Phillip |
author_facet | Shi, Xianping Zheng, Yueyuan Jiang, Liling Zhou, Bo Yang, Wei Li, Liyan Ding, Lingwen Huang, Moli Gery, Sigal Lin, De-Chen Koeffler, H Phillip |
author_sort | Shi, Xianping |
collection | PubMed |
description | Core 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. |
format | Online Article Text |
id | pubmed-7672457 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-76724572020-11-24 EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma Shi, Xianping Zheng, Yueyuan Jiang, Liling Zhou, Bo Yang, Wei Li, Liyan Ding, Lingwen Huang, Moli Gery, Sigal Lin, De-Chen Koeffler, H Phillip Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Core 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. Oxford University Press 2020-10-20 /pmc/articles/PMC7672457/ /pubmed/33080033 http://dx.doi.org/10.1093/nar/gkaa901 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Gene regulation, Chromatin and Epigenetics Shi, Xianping Zheng, Yueyuan Jiang, Liling Zhou, Bo Yang, Wei Li, Liyan Ding, Lingwen Huang, Moli Gery, Sigal Lin, De-Chen Koeffler, H Phillip EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma |
title | EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma |
title_full | EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma |
title_fullStr | EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma |
title_full_unstemmed | EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma |
title_short | EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma |
title_sort | ews-fli1 regulates and cooperates with core regulatory circuitry in ewing sarcoma |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672457/ https://www.ncbi.nlm.nih.gov/pubmed/33080033 http://dx.doi.org/10.1093/nar/gkaa901 |
work_keys_str_mv | AT shixianping ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT zhengyueyuan ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT jiangliling ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT zhoubo ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT yangwei ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT liliyan ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT dinglingwen ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT huangmoli ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT gerysigal ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT lindechen ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma AT koefflerhphillip ewsfli1regulatesandcooperateswithcoreregulatorycircuitryinewingsarcoma |