活细胞<strong>RNA</strong>成像技术及其在生物医学中应用研究进展

doi:10.3724/zdxbyxb-2022-0017

浙江大学学报（医学版）

2022, Vol. 51

Issue (3): 362-372 DOI: 10.3724/zdxbyxb-2022-0017

综述

活细胞RNA成像技术及其在生物医学中应用研究进展

孙萍萍^1,²,邹炜^1,^2,*(

)

1. 浙江大学医学院附属第四医院，浙江义乌 322000
2. 浙江大学医学院转化医学研究院，浙江杭州 310058

Research progress of live-cell RNA imaging techniques

SUN Pingping^1,²,ZOU Wei^1,^2,*(

)

1. The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China;
2. Institute of Translational Medicine, Zhejiang University, Hangzhou 310058, China

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摘要：

RNA可与各种核酸及蛋白质相互作用，在多种生理和病理过程中发挥重要的调控作用，其生物学过程高度动态。追踪活细胞中的RNA动态对理解基因表达的时空调控以及RNA的调控功能至关重要。基于荧光蛋白的RNA标记系统包括MS2/MCP系统、PP7/PCP系统、boxB/λN22和CRISPR-Cas系统等，其中MS2/MCP系统目前应用最为广泛，其具有结合稳定、信噪比高等优点，局限性是RNA成像的实现需要对靶RNA进行基因编辑，这可能导致靶RNA特性的潜在改变。近期开发的CRISPR-dCas13系统不需要对RNA进行改造，但其局限性在于CRISPR RNA效率的不确定性，且信噪比较低。基于荧光染料的RNA标记系统包括分子信标和荧光基团-适体对，其中分子信标具有高特异性和较高信噪比，而荧光基团–适体对Pepper系统和Mango系统在RNA成像的信噪比上更具有优势，但也需要对靶RNA进行基因编辑。活细胞RNA成像技术可应用于观察并研究RNA转录、剪接、转运、翻译（特指信使RNA）和亚细胞定位，有助于研究细胞分化等生物学过程以及细胞适应外界环境时的转录调控机制，有利于理解RNA行为异常导致的各种疾病的致病机制以及寻找潜在的治疗靶点。本文综述了活细胞RNA成像技术的发展和运用，并比较了各种方法的优势和不足。

关键词： 活细胞RNA成像; 基因表达; 转录调控; 信使RNA; 非编码RNA；综述

Abstract:

RNA molecules play diverse roles in many physiological and pathological processes as they interact with various nucleic acids and proteins. The various biological processes of RNA are highly dynamic. Tracking RNA dynamics in living cells is crucial for a better understanding of the spatiotemporal control of gene expression and the regulatory roles of RNA. Genetically encoded RNA-tagging systems include MS2/MCP, PP7/PCP, boxB/λN22 and CRISPR-Cas. The MS2/MCP system is the most widely applied, and it has the advantages of stable binding and high signal-to-noise ratio, while the realization of RNA imaging requires gene editing of the target RNA, which may change the characteristics of the target RNA. Recently developed CRISPR-dCas13 system does not require RNA modification, but the uncertainty in CRISPR RNA (crRNA) efficiency and low signal-to-noise ratio are its limitations. Fluorescent dye-based RNA-tagging systems include molecular beacons and fluorophore-binding aptamers. The molecular beacons have high specificity and high signal-to-noise ratio; Mango and Peppers outperform the other RNA-tagging system in signal-to-noise, but they also need gene editing. Live-cell RNA imaging allows us to visualize critical steps of RNA activities, including transcription, splicing, transport, translation (for message RNA only) and subcellular localization. It will contribute to studying biological processes such as cell differentiation and the transcriptional regulation mechanism when cells adapt to the external environment, and it improves our understanding of the pathogenic mechanism of various diseases caused by abnormal RNA behavior and helps to find potential therapeutic targets. This review provides an overview of current progress of live-cell RNA imaging techniques and highlights their major strengths and limitations.

Key words: Live-cell RNA imaging Gene expression Transcriptional regulation Message RNA Non-coding RNA; Review

收稿日期: 2022-01-23 出版日期: 2022-09-21

CLC:

R394

基金资助: 国家自然科学基金（31970919）

通讯作者: 邹炜 E-mail: zouwei@zju.edu.cn

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引用本文:

孙萍萍,邹炜. 活细胞RNA成像技术及其在生物医学中应用研究进展[J]. 浙江大学学报（医学版）, 2022, 51(3): 362-372.

SUN Pingping,ZOU Wei. Research progress of live-cell RNA imaging techniques. J Zhejiang Univ (Med Sci), 2022, 51(3): 362-372.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0017 或 https://www.zjujournals.com/med/CN/Y2022/V51/I3/362

图 1 MS2/MCP系统成像技术原理示意图融合表达荧光蛋白的MCP二聚体与MS2茎环结合实现RNA成像. MCP：MS2衣壳蛋白.

图 2 PP7/PCP系统成像技术原理示意图融合表达荧光蛋白的PCP二聚体与PP7茎环结合实现RNA成像. PCP：PP7衣壳蛋白.

图 3 boxB/λN22系统成像技术原理示意图融合表达荧光蛋白的λN22单体与boxB茎环结合实现RNA成像.

图 4 CRISPR/dCas13系统成像技术原理示意图在crRNA介导下，融合表达荧光蛋白的dCas13蛋白靶向RNA，实现RNA成像. CRISPR: 成簇的、规律间隔的短回文重复序列； crRNA：CRISPR RNA；dCas：失活的Cas.

图 5 分子信标成像技术原理示意图分子信标探针的两端分别是荧光基团和猝灭基团，一旦与靶RNA结合，两端分开，荧光基团发光.

图 6 RNA适体成像原理示意图单独的染料和RNA适体都不发光，而两者结合会迸发出强烈的荧光.

表 1 活细胞RNA成像技术

图 7 神经元活细胞RNA转录、转运、定位以及翻译过程成像示意图利用活细胞成像技术，在神经元的细胞核中实现转录过程的可视化；也能实现树突和轴突中mRNA的转运、正确定位以及翻译过程的可视化. mRNA：信使RNA.

表 2 活细胞RNA成像技术的应用实例

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