Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1
Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1
复制标题
超级增强子相关的 MEIS1 与 EWS-FLI1 合作促进尤文肉瘤中的转录失调
DOI：
10.1093/nar/gky1207
复制
发表时间：
2019-02-20
影响因子：
14.9
通讯作者：
Koeffler, H. Phillip
中科院分区：
文献类型：
--
作者：
Lin, Lehang;Huang, Moli;Koeffler, H. Phillip
摘要尤文肉瘤是儿童和青少年第二常见的恶性骨肿瘤，它是由一种最常见的嵌合癌蛋白EWS-FLI 1引发和加重的。在这项研究中，我们应用表观基因组分析来表征这种癌症中的转录失调，重点研究超级增强子及其相关的转录调节机制。我们证明，超级增强子相关的成绩单显着丰富的EWS-FLI 1靶基因，有助于异常的转录网络的疾病，并介导的特殊敏感性尤文肉瘤转录抑制。通过整合分析，我们确定MEIS 1是一个超级增强子驱动的癌基因，它与EWS-FLI 1在转录调控中协同作用，在尤文肉瘤中起着关键的促生存作用。此外，APCDD 1，另一个超级增强子相关基因，作为MEIS 1和EWS-FLI 1的下游靶点，也被认为是这种恶性肿瘤中的一种新的促肿瘤因子。这些数据描绘了尤文肉瘤中超级增强子介导的转录失调，并揭示了许多候选癌基因，可用于进一步了解这种疾病的分子发病机制。
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.