增强子的鉴定及其在肿瘤研究中的应用

doi:10.16288/j.yczz.20-097

遗传 ›› 2020, Vol. 42 ›› Issue (9): 817-831.doi: 10.16288/j.yczz.20-097

• 综述 • 下一篇

增强子的鉴定及其在肿瘤研究中的应用

刘倩¹, 李春燕^1,²()

^1. 北京航空航天大学,大数据精准医疗高精尖创新中心和医学科学与工程学院,北京 100191
^2. 工业和信息化部大数据精准医疗重点实验室(北京航空航天大学),北京 100191;

收稿日期:2020-04-09 修回日期:2020-07-23 出版日期:2020-09-20 发布日期:2020-08-04
通讯作者: 李春燕 E-mail:lichunyan@buaa.edu.cn
作者简介:刘倩,在读硕士研究生,专业方向：生物医学工程。E-mail: ZY1910219@buaa.edu.cn
基金资助:
国家自然科学基金青年科学基金项目资助编号:(31801094)

The identification of enhancers and its application in cancer studies

Qian Liu¹, Chunyan Li^1,²()

^1. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine & School of Medical Sciences and Engineering, Beihang University, Beijing 100191, China;
^2. Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology, Beijing 100191, China;

Received:2020-04-09 Revised:2020-07-23 Online:2020-09-20 Published:2020-08-04
Contact: Li Chunyan E-mail:lichunyan@buaa.edu.cn
Supported by:
Supported by the National Natural Science Foundation of China No(31801094)

摘要/Abstract

摘要：

增强子是一类增强靶基因转录活性的DNA顺式作用元件。但是增强子与靶基因的方向和距离不确定,大大增加了研究增强子调控的靶基因及其作用机制的困难。已有大量研究显示,增强子的突变或功能异常与疾病发生发展相关;仅有少量研究报道增强子通过促进靶基因的表达,引发癌症或产生抗药性。目前与癌症发生发展和在癌症治疗过程中抗药性产生相关的增强子尚未得到充分鉴定,这些增强子的调控机制也未得到充分解析。本文对目前可在全基因组水平上预测和鉴定增强子以及解析增强子调控机制的方法进行总结和对比,并对近几年增强子在肿瘤诊断、治疗和发生发展机制中的研究进展进行综述。期望本文为筛选与癌症发生发展相关的增强子和解析这些增强子的调控机制提供参考,为提高癌症的诊断和制定癌症的治疗策略提供新的视角。

关键词: 增强子, 超级增强子, 鉴定, 肿瘤

Abstract:

Enhancers are a type of cis-acting DNA elements that enhance transcriptional activity of target genes. However, the uncertainty in the orientation and distance between enhancers and target genes could post significant difficulties in identifying the target genes and the regulatory mechanisms of the enhancers. Numerous studies have shown that the mutations and/or abnormalities in the functions of enhancers are associated with development of diseases. A few studies have reported that enhancers could activate cancer development or drug resistance by promoting the expression of target genes. At present, enhancers involved in carcinogenesis and drug resistance have not been fully identified, and the underlying mechanism are still largely unknown. This paper summarizes the main methods used in identifying and characterizing enhancers and analyzing the regulatory mechanism at the genome-wide level. It further reviews the recent research progress of enhancers in cancer diagnosis, treatment, and the underlying mechanism during carcinogenesis, thereby providing a reference for the screening of these enhancers involved in carcinogenesis and drug resistance and exploring their regulatory mechanisms of target genes. It also provides a new perspective for improving the diagnosis of cancer and insights for formulating cancer therapeutic strategies.

Key words: enhancer, super enhancer, identification, cancer

刘倩, 李春燕. 增强子的鉴定及其在肿瘤研究中的应用[J]. 遗传, 2020, 42(9): 817-831.

Qian Liu, Chunyan Li. The identification of enhancers and its application in cancer studies[J]. Hereditas(Beijing), 2020, 42(9): 817-831.

图/表 3

图2

表1

增强子预测和功能解析的常用方法"

方法	描述	优势	局限性
ChIP-Seq	一种将染色质免疫沉淀与高通量测序技术相结合所产生的技术	高分辨率、低噪、高覆盖率、样本需求较少	与ChIP芯片技术相比成本较高,数据质量依赖抗体质量
DNase-Seq	一种结合高通量测序技术鉴定全基因组内DNase I超敏位点的方法,进行全基因组假定增强子等调控区域的预测	提供的信息比ChIP-Seq,更广泛	样本需求较大,重复性较差;DNase I对DNA的切割具有序列依赖性,测序误差较大;不能保证切割后的结果,就完全是蛋白质覆盖的区域
ATAC-Seq	利用转座酶研究染色质可进入性的高通量测序技术,利用DNA转座酶技术实现染色质可及性分析	样本需求量少,灵敏度高,操作简单,耗时短,实验重复性好,能同时揭示开放染色质的基因组位置,DNA结合蛋白,转录结合位点的相互作用	有一半DNA片段无法利用,无法进行PCR富集,DNA剪切效果仍需优化
RNA-Seq	一种全基因组水平的基因表达差异研究,用于分析基因表达水平以了解细胞在不同状态下的基因表达差异	高通量,高灵敏度,可重复性高,检测范围广	检测细胞内累积的RNA,包括来自核糖体线粒体的RNA,影响RNA表达水平的准确性
3C	一种结合免疫共沉淀和PCR扩增研究两个位点之间的相互作用的技术	—	覆盖范围通常小于1 Mb;只能研究点对点的互作方式
4C	在全基因组范围研究一个特定基因与所有互作基因之间的相互作用的高通量测序技术	覆盖全基因组范围	只能研究与一个特定基因互作的所有基因
5C	研究多基因与多基因之间的相互作用高通量测序技术	可以研究多个位点与其相互作用的所有位点之间的相互作用	覆盖范围有限,通常小于1 Mb
Hi-C	在全基因组范围研究所有染色体和染色体外的相互作用的高通量测序技术	覆盖全基因组范围,操作时间短,花费少	分辨率低,噪声高
ChIA-PET	一种整合了免疫共沉淀、染色质铰链、双末端标签及高通量测序的技术,可以在全基因组范围研究染色质的相互作用	能够确定蛋白质结合位点间的相互作用;使用超声打断DNA-蛋白质复合体,避免使用限制性内切酶引入染色质随机连接	无法检测出不依赖蛋白质因子的染色体相互作用;抗体的纯度、质量、特异性要求较高
CRISPR	将Cas9核酸酶与向导RNA(gRNA)结合,可在基因组的特定位点切割,从而实现基因的移除、添加或替换	在内源性环境中研究增强子,对靶向位点进行修饰,操作简单、快速	易脱靶,有效切割效率低

表1

图1

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增强子的鉴定及其在肿瘤研究中的应用

The identification of enhancers and its application in cancer studies

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