增强子的鉴定及其在肿瘤研究中的应用

doi:10.16288/j.yczz.20-097

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

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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)

Abstract

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

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

Figures/Tables 3

Fig. 2

Table 1

Common methods for the prediction and functional analysis of enhancers"

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

Table 1

Fig. 1

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The identification of enhancers and its application in cancer studies

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