Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1

Lehang Lin; Moli Huang; Xianping Shi; Anand Mayakonda; Kaishun Hu; Yan Yi Jiang; Xiao Guo; Li Chen; Brendan Pang; Ngan Doan; Jonathan W. Said; Jianjun Xie; Sigal Gery; Xu Cheng; Zhaoyu Lin; Jinsong Li; Benjamin P. Berman; Dong Yin; De Chen Lin; H. Phillip Koeffler

doi:10.1093/nar/gky1207

Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1

Lehang Lin, Moli Huang, Xianping Shi, Anand Mayakonda, Kaishun Hu, Yan Yi Jiang, Xiao Guo, Li Chen, Brendan Pang, Ngan Doan, Jonathan W. Said, Jianjun Xie, Sigal Gery, Xu Cheng, Zhaoyu Lin, Jinsong Li, Benjamin P. Berman, Dong Yin, De Chen Lin^*, H. Phillip Koeffler

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epigenomic analysis to characterize the transcription dysregulation in this cancer, focusing on the investigation of super-enhancer and its associated transcriptional regulatory mechanisms. We demonstrate that super-enhancer-associated transcripts are significantly enriched in EWS-FLI1 target genes, contribute to the aberrant transcriptional network of the disease, and mediate the exceptional sensitivity of Ewing sarcoma to transcriptional inhibition. Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy. These data delineate super-enhancer-mediated transcriptional deregulation in Ewing sarcoma, and uncover numerous candidate oncogenes which can be exploited for further understanding of the molecular pathogenesis for this disease.

Original language	American English
Pages (from-to)	1255-12567
Number of pages	11313
Journal	Nucleic Acids Research
Volume	47
Issue number	3
DOIs	https://doi.org/10.1093/nar/gky1207
State	Published - 20 Feb 2019
Externally published	Yes

Bibliographical note

Funding Information:
National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014 to H.P.K.]; Singapore Ministry of Health's National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (to H.P.K.); Alan B. Slifka Foundation; Ewing's Sarcoma Research Foundation; National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]; Guangzhou Bureau of Science and Information Technology [201704030036]. Funding for open access charge: National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026].

Funding Information:
National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014 to H.P.K.]; Singapore Ministry of Health’s National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (to H.P.K.); Alan B. Slifka Foundation; Ewing’s Sarcoma Research Foundation; National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]; Guangzhou Bureau of Science and Information Technology [201704030036]. Funding for open access charge: National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]. Conflict of interest statement. None declared.

Publisher Copyright:
© The Author(s) 2018.

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Lin, L., Huang, M., Shi, X., Mayakonda, A., Hu, K., Jiang, Y. Y., Guo, X., Chen, L., Pang, B., Doan, N., Said, J. W., Xie, J., Gery, S., Cheng, X., Lin, Z., Li, J., Berman, B. P., Yin, D., Lin, D. C., & Koeffler, H. P. (2019). Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1. Nucleic Acids Research, 47(3), 1255-12567. https://doi.org/10.1093/nar/gky1207

@article{90b92edf8e274856b148624992da797e,

title = "Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1",

abstract = "As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epigenomic analysis to characterize the transcription dysregulation in this cancer, focusing on the investigation of super-enhancer and its associated transcriptional regulatory mechanisms. We demonstrate that super-enhancer-associated transcripts are significantly enriched in EWS-FLI1 target genes, contribute to the aberrant transcriptional network of the disease, and mediate the exceptional sensitivity of Ewing sarcoma to transcriptional inhibition. Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy. These data delineate super-enhancer-mediated transcriptional deregulation in Ewing sarcoma, and uncover numerous candidate oncogenes which can be exploited for further understanding of the molecular pathogenesis for this disease.",

author = "Lehang Lin and Moli Huang and Xianping Shi and Anand Mayakonda and Kaishun Hu and Jiang, {Yan Yi} and Xiao Guo and Li Chen and Brendan Pang and Ngan Doan and Said, {Jonathan W.} and Jianjun Xie and Sigal Gery and Xu Cheng and Zhaoyu Lin and Jinsong Li and Berman, {Benjamin P.} and Dong Yin and Lin, {De Chen} and Koeffler, {H. Phillip}",

note = "Funding Information: National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014 to H.P.K.]; Singapore Ministry of Health's National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (to H.P.K.); Alan B. Slifka Foundation; Ewing's Sarcoma Research Foundation; National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]; Guangzhou Bureau of Science and Information Technology [201704030036]. Funding for open access charge: National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]. Funding Information: National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014 to H.P.K.]; Singapore Ministry of Health{\textquoteright}s National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (to H.P.K.); Alan B. Slifka Foundation; Ewing{\textquoteright}s Sarcoma Research Foundation; National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]; Guangzhou Bureau of Science and Information Technology [201704030036]. Funding for open access charge: National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]. Conflict of interest statement. None declared. Publisher Copyright: {\textcopyright} The Author(s) 2018.",

year = "2019",

month = feb,

day = "20",

doi = "10.1093/nar/gky1207",

language = "American English",

volume = "47",

pages = "1255--12567",

journal = "Nucleic Acids Research",

issn = "0305-1048",

publisher = "Oxford University Press",

number = "3",

}

Lin, L, Huang, M, Shi, X, Mayakonda, A, Hu, K, Jiang, YY, Guo, X, Chen, L, Pang, B, Doan, N, Said, JW, Xie, J, Gery, S, Cheng, X, Lin, Z, Li, J, Berman, BP, Yin, D, Lin, DC & Koeffler, HP 2019, 'Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1', Nucleic Acids Research, vol. 47, no. 3, pp. 1255-12567. https://doi.org/10.1093/nar/gky1207

TY - JOUR

T1 - Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1

AU - Lin, Lehang

AU - Huang, Moli

AU - Shi, Xianping

AU - Mayakonda, Anand

AU - Hu, Kaishun

AU - Jiang, Yan Yi

AU - Guo, Xiao

AU - Chen, Li

AU - Pang, Brendan

AU - Doan, Ngan

AU - Said, Jonathan W.

AU - Xie, Jianjun

AU - Gery, Sigal

AU - Cheng, Xu

AU - Lin, Zhaoyu

AU - Li, Jinsong

AU - Berman, Benjamin P.

AU - Yin, Dong

AU - Lin, De Chen

AU - Koeffler, H. Phillip

N1 - Funding Information: National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014 to H.P.K.]; Singapore Ministry of Health's National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (to H.P.K.); Alan B. Slifka Foundation; Ewing's Sarcoma Research Foundation; National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]; Guangzhou Bureau of Science and Information Technology [201704030036]. Funding for open access charge: National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]. Funding Information: National Research Foundation Singapore under its Singapore Translational Research Investigator Award [NMRC/STaR/0021/2014 to H.P.K.]; Singapore Ministry of Health’s National Medical Research Council (NMRC); NMRC Centre Grant awarded to National University Cancer Institute; National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives (to H.P.K.); Alan B. Slifka Foundation; Ewing’s Sarcoma Research Foundation; National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]; Guangzhou Bureau of Science and Information Technology [201704030036]. Funding for open access charge: National Natural Science Foundation of China (NSFC) [81802692, 81872306, 81872140, 81572484, 81420108026]. Conflict of interest statement. None declared. Publisher Copyright: © The Author(s) 2018.

PY - 2019/2/20

Y1 - 2019/2/20

N2 - As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epigenomic analysis to characterize the transcription dysregulation in this cancer, focusing on the investigation of super-enhancer and its associated transcriptional regulatory mechanisms. We demonstrate that super-enhancer-associated transcripts are significantly enriched in EWS-FLI1 target genes, contribute to the aberrant transcriptional network of the disease, and mediate the exceptional sensitivity of Ewing sarcoma to transcriptional inhibition. Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy. These data delineate super-enhancer-mediated transcriptional deregulation in Ewing sarcoma, and uncover numerous candidate oncogenes which can be exploited for further understanding of the molecular pathogenesis for this disease.

AB - As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epigenomic analysis to characterize the transcription dysregulation in this cancer, focusing on the investigation of super-enhancer and its associated transcriptional regulatory mechanisms. We demonstrate that super-enhancer-associated transcripts are significantly enriched in EWS-FLI1 target genes, contribute to the aberrant transcriptional network of the disease, and mediate the exceptional sensitivity of Ewing sarcoma to transcriptional inhibition. Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy. These data delineate super-enhancer-mediated transcriptional deregulation in Ewing sarcoma, and uncover numerous candidate oncogenes which can be exploited for further understanding of the molecular pathogenesis for this disease.

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U2 - 10.1093/nar/gky1207

DO - 10.1093/nar/gky1207

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AN - SCOPUS:85066851405

SN - 0305-1048

VL - 47

SP - 1255

EP - 12567

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 3

ER -

Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1

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