RNA转录后代谢时空精密控制技术

doi:10.12211/2096-8280.2022-050

合成生物学 ›› 2023, Vol. 4 ›› Issue (1): 141-164.DOI: 10.12211/2096-8280.2022-050

RNA转录后代谢时空精密控制技术

刘韧玫¹^,²^,³, 李乐诗¹^,², 杨小燕¹^,², 陈显军¹^,², 杨弋¹^,²

^1.华东理工大学光遗传学与合成生物学交叉学科研究中心，生物反应器工程国家重点实验室，上海 200237
^2.华东理工大学药学院，上海市细胞代谢光遗传学技术前沿科学研究基地，上海 200237
^3.华东理工大学生物工程学院，上海 200237

收稿日期:2022-09-13 修回日期:2022-11-18 出版日期:2023-02-28 发布日期:2023-03-07
通讯作者: 杨弋
作者简介:刘韧玫（1989—），女，博士，讲师。研究方向为光遗传学与合成生物学（细胞代谢监测与控制技术）。E-mail：renmei2018@ecust.edu.cn
杨弋（1973—），男，教授，博士生导师。研究方向为控制与监测细胞内分子过程的合成生物技术与光遗传学前沿技术、癌症及代谢类疾病药理及药物筛选技术、蛋白质特异性标记与翻译后修饰的鉴定、细胞内原位成像、蛋白质药物生产技术等。E-mail：yiyang@ecust.edu.cn
第一联系人：刘韧玫（1989—），女，博士，讲师。研究方向为光遗传学与合成生物学（细胞代谢监测与控制技术）。
基金资助:
国家重点研发计划(2022YFC3400100);国家自然科学基金(32121005)

Technologies for precise spatiotemporal control of post-transcriptional RNA metabolism

Renmei LIU¹^,²^,³, Leshi LI¹^,², Xiaoyan YANG¹^,², Xianjun CHEN¹^,², Yi YANG¹^,²

^1.Optogenetics & Synthetic Biology Interdisciplinary Research Center，State Key Laboratory of Bioreactor Engineering，East China University of Science and Technology，Shanghai 200237，China
^2.Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism，School of Pharmacy，East China University of Science and Technology，Shanghai 200237，China
^3.School of Bioengineering，East China University of Science and Technology，Shanghai 200237，China

Received:2022-09-13 Revised:2022-11-18 Online:2023-02-28 Published:2023-03-07
Contact: Yi YANG

摘要/Abstract

摘要：

RNA种类繁多且功能多样，是细胞活动的核心分子之一。RNA代谢调控对于基因和RNA功能研究、细胞生命活动解析以及疾病治疗手段的开发都是至关重要的。为了深入研究RNA时间、空间分布以及功能机制，科学家们一直在追求可以在活细胞内对RNA分子活动进行精密控制的技术，这也是近些年生命科学领域的研究热点之一。目前基于基因编辑、转录调控等可以控制RNA转录生成的技术已较为成熟，但对于RNA转录后代谢的控制技术尚在发展与突破阶段。此前，RNA转录后代谢调控工具是通过调节RNA或基于RNA结合蛋白的RNA效应因子来实现的，但它们的时空分辨率较低，很难对RNA转录后代谢进行定时、定量和定位精密调控。光遗传学凭借其独特的高时空分辨率、非侵入性等优势已经被逐步用于发展活细胞RNA代谢时空精确控制技术。目前，基于核苷酸光化学修饰、遗传编码光响应因子的光遗传学工具已经可实现在转录或转录后水平对RNA多种代谢活动的时空精密控制，包括生成、运输、翻译、降解等。本文将介绍RNA代谢调控系统的研究进展，并聚焦于RNA转录后代谢的光遗传学调控技术，同时对其未来发展前景进行了展望。

关键词: 光遗传学, RNA代谢, RNA功能, 时空精密控制, 光控RNA结合蛋白

Abstract:

RNA exhibits complex dynamics and functions at specific times and locations inside cells, which include changes in their expression, degradation, translocation, splicing and other chemical modifications. The precise regulation of RNA metabolism is crucial for the studies of gene and RNA functions, the analysis of cellular activities, as well as the development of treatments for diseases. In order to deeply understand the temporal and spatial distribution and functional mechanism of RNA, scientists are always pursuing technologies that can precisely control the activity of RNA molecules in live cells. There are several gene editing- or transcriptional regulation-based methodologies that can regulate RNA synthesis in live cells. However, technologies for controlling the post-transcriptional metabolic behaviors of RNA are highly desirable, but they are less attained. Traditional methodologies for regulating RNA metabolism, e.g., regulatory RNA or RNA-binding proteins-based synthetic RNA effectors, suffer from low spatiotemporal resolution, making them difficult to dynamically regulate the post-transcriptional RNA metabolism in real time. Optogenetics has been used for precise spatiotemporal control of RNA metabolism in live cells due to its unique advantages of high spatiotemporal resolution and non-invasiveness. At present, photochemical modifications of nucleotides and genetically encoded photosensitive factors-based optogenetic tools have been applied for spatiotemporal control of various RNA metabolism at transcriptional or post-transcriptional levels, including transcription, translocation, translation and degradation. This article introduces recent progress in regulation of RNA metabolism, in particular the optogenetic control of post-transcriptional RNA metabolism, including technologies based on photochemical modified nucleotides, light-induced protein heterodimerization combined with RNA tethering, light-induced interactions between RNA-binding proteins and their cognate RNA motifs. Finally, we highlight prospects on technologies for precise spatiotemporal control of post-transcriptional RNA metabolism. {L-End}

Key words: optogenetics, RNA metabolism, RNA function, precise spatiotemporal control, light-switchable RNA-binding proteins

中图分类号:

Q816

刘韧玫, 李乐诗, 杨小燕, 陈显军, 杨弋. RNA转录后代谢时空精密控制技术[J]. 合成生物学, 2023, 4(1): 141-164.

Renmei LIU, Leshi LI, Xiaoyan YANG, Xianjun CHEN, Yi YANG. Technologies for precise spatiotemporal control of post-transcriptional RNA metabolism[J]. Synthetic Biology Journal, 2023, 4(1): 141-164.

图/表 8

表1 RNA转录后代谢调控系统

项目	基于调节RNA的RNA效应因子	基于RNA结合蛋白的RNA效应因子	基于光化学修饰的核苷酸	基于光笼蛋白质或其配体	基于光诱导蛋白异二聚化和RNA结合蛋白	基于光控RNA结合蛋白PAL的RNA效应因子	基于光控RNA结合蛋白LicV的RNA效应因子
工作原理	自带或招募内源功能蛋白或空间位阻效应	RNA结合蛋白与不同功能结构域融合获得系列人工合成RNA效应因子	DNA/RNA中引入光化学修饰的寡核苷酸，光照调控DNA/RNA活性	利用光可移除的囚笼基团对RNA结合蛋白或其配体活性进行调控	光诱导蛋白异二聚化来调控RNA结合蛋白的活性	光诱导的PAL蛋白与RNA适配体的结合	光诱导的LicV与RAT RNA的结合
诱导条件	无	无	多数为UV光，少量为可见光	UV光	蓝光	蓝光	蓝光
细胞毒性	低	低	高	高	低	低	低
制备方法	遗传编码	遗传编码	体外合成	体外合成	遗传编码	遗传编码	遗传编码
制备方法	或体外合成	遗传编码	体外合成	体外合成	遗传编码	遗传编码	遗传编码
可调性	难	难	适中	适中	容易	容易	容易
时间分辨率	低	低	适中	适中	高	高	高
空间分辨率	低	低	高	高	高	高	高
普适性	高	高	低	低	未知	未知	高

图1 基于调节RNA的人工合成RNA效应因子

Fig. 1 Engineered RNA effectors based on regulatory RNAs

图2 基于RNA结合蛋白的人工合成RNA效应因子

Fig. 2 Engineered RNA effectors based on RNA-binding proteins

图3 基于核苷酸光化学修饰的调控技术（a）几种不同的寡核苷酸功能光调节方法。（b）利用光可转换基团邻硝基苄基（oNB）或偶氮苯（AzoB）对RNA代谢的调控：①oNB修饰的LDSSO对RNA剪接的调控；②通过核碱基笼状反义剂对基因沉默的光激活；③通过光诱导形成发夹，从而对反义剂进行光化学失活；④使用偶氮苯修饰的哑铃反义寡脱氧核苷酸进行RNA降解的光响应调节；⑤PC-cap对翻译的可逆光调节；⑥siRNAzos的光诱导失活和再激活。（c）Were-1核糖开关的翻译调节。在没有配体的情况下，核糖体结合位点（RBS）暴露并翻译荧光素酶，而在存在amino-tSS的情况下，RBS被隔离，从而Fluc不表达。342 nm光照射下，Amino-tSS切换为Amino-cSS构象，使得Were-1构象发生变化，进而重新激活RBS活性

Fig. 3 Regulation technology based on photochemical modifications of nucleotides(a) Different approaches for regulating oligonucleotide functions by light. (b) Regulation of RNA metabolism by photoswitchable o-nitrobenzyl (oNB) or azobenzene (AzoB). ① Regulation of RNA splicing by oNB-modified LDSSOs; ② Light-activation of gene silencing through nucleobase-caged antisense agents; ③ Optochemical deactivation of an antisense agent through light-induced hairpin formation; ④ Photoregulating RNA digestion using azobenzene linked dumbbell antisense oligodeoxynucleotides; ⑤ Light-mediated reversible activation of translation via PC-cap; ⑥ Photoinduced inactivation and reactivation of siRNAzos. (c) Translation regulation by the Were-1 riboswitch. In absence of the ligand, the ribosomal binding site (RBS) is exposed, and luciferase is translated, whereas in presence of amino-tSS, the RBS is sequestered, repressing the expression of Fluc. With light (342 nm) irradiation, amino-tSS is switched to amino-cSS conformation, causing theconformation change of Were-1 to activate RBS activities.

图4 基于光笼蛋白质配体的调控技术（a）“光笼”效应小分子。（b）“光笼”氨基酸。（c）基于分裂CaVT系统和光笼甲氧苄啶-HaloTag配体的光诱导翻译激活。光介导TMP-HL去除光笼，使得TMP-HL介导MS2CP-eDHFR和HaloTag-VPg（FCV）发生相互作用。由此产生的MS2CP-eDHFR-HaloTag-VPg（FCV）复合物可激活含有1xMS2（U）site1-hmAG1基序的靶modRNA的翻译。（d）基于光笼TMP与融合有响应TMP的去稳定域的CaVT（DD-CaVT）的光诱导翻译激活。光介导TMP去除光笼，使得TMP与DD-CaVT发生相互作用，从而防止DD-CaVT的快速降解。稳定的DD-CaVT与含有弱结合基序1xMS2（U） site2-hmAG1的靶modRNA结合并激活其翻译

Fig. 4 Regulatory technology based on photocage protein ligands(a) Photocaged small effector molecules. (b) Photocaged amino acids. (c) Light-inducible translational activation by split CaVT systems and photocaged trimethoprim-HaloTag ligand through light-mediated removal of the photocage from TMP-HL to enable the TMP-HL-mediated interactions between MS2CP-eDHFR and HaloTag-VPg(FCV), resulting MS2CP-eDHFR-HaloTag-VPg (FCV) complex to activate the translation of target modRNA containing a motif (1xMS2(U)site1-hmAG1). (d) Light-inducible translational activation by photocaged TMP and TMP-responsive destabilizing domain-fused CaVT (DD-CaVT) through light-mediated removal of the photocage from TMP to enable the interaction between TMP and DD-CaVT, preventing the rapid degradation of DD-CaVT for binding to a target modRNA with a weak binding motif (1xMS2(U) site2-hmAG1) and activate its translation.

图5 基于CRY2/CIB1异源二聚化的mRNA定位和翻译的光遗传学控制技术

Fig. 5 Optogenetic control of mRNA localization and translation based on CRY2/CIB1 heterodimerization

图6 基于PAL同源二聚化的RNA转录和转录后的光遗传学控制

Fig. 6 Optoribogenetic control of RNA transcription and post-transcription based on PAL homodimerization

图7 基于LicV光诱导同源二聚化的RNA功能与代谢的光遗传学控制（a）蓝光可诱导LicV同源二聚化，使其与RAT短发夹RNA结合；（b）～（e）利用LicV-RAT光诱导相互作用实现RNA定位（b）、剪接（c）、翻译（d）和降解（e）的光遗传学控制；（f）LA-CRISPR系统原理；将LicV-RAT光诱导相互作用引入CRISPR-Cas系统，可实现对基因转录的光遗传学控制

Fig. 7 Optogenetic control of RNA function and metabolism based on light-induced homodimerization of LicVBlue light induced homodimerization of LicV for its binding to RAT short hairpin RNA (a). Optogenetic control of RNA through light-induced LicV-RAT interaction for localization (b), splicing (c), translation (d), and degradation (e). The LA-CRISPR system based on the introduction of the light-induced LicV-RAT interaction into the CRISPR-Cas system to enable optogenetic control of gene transcription (f)..

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RNA转录后代谢时空精密控制技术

Technologies for precise spatiotemporal control of post-transcriptional RNA metabolism

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