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 journalArticlepeer-review

51 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 languageAmerican English
Pages (from-to)1255-12567
Number of pages11313
JournalNucleic Acids Research
Volume47
Issue number3
DOIs
StatePublished - 20 Feb 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© The Author(s) 2018.

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