肝癌中增强子调控miRNA前馈环路的识别与功能分析

doi:10.13560/j.cnki.biotech.bull.1985.2018-0846

生物技术通报 ›› 2019, Vol. 35 ›› Issue (5): 140-145.doi: 10.13560/j.cnki.biotech.bull.1985.2018-0846

肝癌中增强子调控miRNA前馈环路的识别与功能分析

常允建¹, 康冉¹, 薛璇¹, 王韶畅¹, 赵庆文², 郭志云¹

1.西南交通大学生命科学与工程学院,成都 610031;
2.大同市第二人民医院肿瘤内科,大同 037000

收稿日期:2018-09-29 出版日期:2019-05-26 发布日期:2019-05-23
作者简介:常允建,男,E-mail：2402033268@qq.com
基金资助:
四川省科技厅项目（18YYJC0551）,国家大学生创新创业训练计划（201810613079）

Identification and Functional Analysis of Enhancers-regulated miRNA Feed-forward Loops in Hepatocellular Carcinoma

CHANG Yun-jian¹, KANG Ran¹, XUE Xuan¹, WANG Shao-chang¹, ZHAO Qing-wen², GUO Zhi-yun¹

1.School of Life Science and Engineering,Southwest Jiaotong University,Chengdu 610031;
2.Department of Medical Oncology,the Second People’s Hospital of Datong,Datong 037000

Received:2018-09-29 Published:2019-05-26 Online:2019-05-23

摘要/Abstract

摘要： 先前研究表明前馈环路（Feed-forward loops,FFLs）作为重要的网络单元在肿瘤疾病的发生发展中起着重要作用。microRNA（miRNA）、增强子、转录因子三类调控元件已被文献证实与肝肿瘤密切相关,然而三者形成何种FFL以及在肝癌中的特征目前并不清楚。基于肝癌细胞HepG2的DNase高敏位点以及H3K4me1、H3K27ac、H3K4me3三类组蛋白修饰信息的ChIP-seq数据识别了5 055个肝癌特异的增强子。此外,基于超几何检验及元件调控关系识别了2 070个TF-enhancer-miRNA FFL并对其中miRNA的靶基因进行了GO与KEGG功能富集分析。富集结果显示FFL中miRNA的靶基因显著富集于肿瘤或肝癌相关信号通路与生物进程。其中hsa-miR-574参与了99个FFL且在HepG2细胞中高表达,显著富集于已知的与抑制肝癌细胞增殖相关的cAMP信号通路。初步探讨了以增强子-miRNA为核心的FFL在肝细胞癌中的特征与功能,有望为基于网络模体为单位的肝肿瘤标志物识别奠定理论与数据基础。

关键词: 增强子, miRNA, 前馈环路, 肝癌, 转录因子

Abstract: Previous studies demonstrate that,as an important network motif,feed-forward loops（FFLs）play an important role in the development of tumor diseases. Three types of elements,namely miRNAs,enhancers,and transcription factors,are widely reported to be closely related to tumors. However,the characteristics of the FFLs and their function in hepatocellular carcinoma remain unclear. Here 5055 liver cancer-specific enhancers were identified based on the DNase high-sensitivity site of HepG2 cells and the ChIP-seq data of modification information of 3 three types of histone H3K4me1,H3K27ac and H3K4me3. In addition,2070 TF-enhancer-miRNA FFLs were identified based on hypergeometric test and component regulation relationship. The analysis result of miRNA target genes in FFLs by GO and KEGG functional enrichment showed that target genes of miRNAs in the FFLs were significantly enriched in tumor or hepatocellular carcinoma-related signaling pathways and biological processes. Among them,hsa-miR-574 was involved in 99 FFLs and highly expressed in HepG2 cells,and significantly enriched in the known cAMP signaling pathway in inhibiting the proliferation of hepatoma cells. These results preliminarily explored the characteristics and functions of the enhancer-miRNA-based FFLs in hepatocellular carcinoma,and it is expected to provide a theoretical and data basis for liver tumor marker recognition based on network motif.

Key words: enhancer, miRNA, feed-forward loop, liver cancer, transcription factor

常允建, 康冉, 薛璇, 王韶畅, 赵庆文, 郭志云. 肝癌中增强子调控miRNA前馈环路的识别与功能分析[J]. 生物技术通报, 2019, 35(5): 140-145.

CHANG Yun-jian, KANG Ran, XUE Xuan, WANG Shao-chang, ZHAO Qing-wen, GUO Zhi-yun. Identification and Functional Analysis of Enhancers-regulated miRNA Feed-forward Loops in Hepatocellular Carcinoma[J]. Biotechnology Bulletin, 2019, 35(5): 140-145.

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肝癌中增强子调控miRNA前馈环路的识别与功能分析

Identification and Functional Analysis of Enhancers-regulated miRNA Feed-forward Loops in Hepatocellular Carcinoma

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