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Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions 非编码 RNA 可调控 Krm1 和 Dkk2 的表达,从而协同影响主动脉瓣病变。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1038/s12276-024-01256-5
Gaopeng Xian, Rong Huang, Minhui Xu, Hengli Zhao, Xingbo Xu, Yangchao Chen, Hao Ren, Dingli Xu, Qingchun Zeng
Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/β-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process. Calcific aortic valve disease (CAVD, a common heart condition) currently has no effective treatments. This research aimed to examine the role of non-coding RNAs (molecules that control gene activity) in CAVD, particularly circHIPK3 and miR-182-5p. Experiments were conducted on human heart valve cells and mice, showing that circHIPK3 can prevent heart valve hardening, while miR-182-5p can trigger a process that encourages hardening. The research also discovered a protein, Krm1, that can stop this hardening process. These results suggest that focusing on these non-coding RNAs and proteins could offer a new way to treat CAVD. However, more research is needed to fully comprehend these processes and their potential treatment implications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
钙化性主动脉瓣病(CAVD)正成为一个日益重要的全球性医疗问题,但却缺乏有效的药物治疗方法。非编码 RNA 在心血管疾病的进展中起着关键作用,但它们与 CAVD 的关系仍不清楚。测序数据显示,许多非编码 RNA 在正常主动脉瓣和钙化主动脉瓣中的表达存在差异,其中 circHIPK3 和 miR-182-5p 的表达差异显著。过表达 circHIPK3 能改善 CAVD 小鼠模型中主动脉瓣的病变。体外实验证明,circHIPK3能抑制主动脉瓣间质细胞的成骨反应。从机理上讲,DEAD-box螺旋酶5(DDX5)招募甲基转移酶3(METTL3)来促进circHIPK3的N6-甲基腺苷(m6A)修饰。此外,m6A修饰的circHIPK3会增加Kremen1(Krm1)mRNA的稳定性,而Krm1是Wnt/β-catenin通路的负调控因子。此外,miR-182-5p 还能抑制 Krm1 的配体 Dickkopf2(Dkk2)的表达,减弱 Krm1 介导的 Wnt 信号转导抑制作用。Wnt信号通路的激活在很大程度上促进了主动脉瓣的钙化。我们的研究描述了 Krm1-Dkk2 轴在抑制主动脉瓣 Wnt 信号传导中的作用,并表明非编码 RNA 是这一过程的上游调节因子。
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引用次数: 0
Author Correction: TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency 作者更正:TGF-β1/IL-11/MEK/ERK信号在应激诱导的Bmi-1缺乏症早衰模型中介导衰老相关的肺纤维化。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1038/s12276-024-01276-1
Haiyun Chen, Hongjie Chen, Jialong Liang, Xin Gu, Jiawen Zhou, Chunfeng Xie, Xianhui Lv, Rong Wang, Qing Li, Zhiyuan Mao, Haijian Sun, Guoping Zuo, Dengshun Miao, Jianliang Jin
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引用次数: 0
Molecular mechanisms of circular RNA translation 环状 RNA 翻译的分子机制。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1038/s12276-024-01220-3
Hyun Jung Hwang, Yoon Ki Kim
Circular RNAs (circRNAs) are covalently closed single-stranded RNAs without a 5′ cap structure and a 3′ poly(A) tail typically present in linear mRNAs of eukaryotic cells. CircRNAs are predominantly generated through a back-splicing process within the nucleus. CircRNAs have long been considered non-coding RNAs seemingly devoid of protein-coding potential. However, many recent studies have challenged this idea and have provided substantial evidence that a subset of circRNAs can associate with polysomes and indeed be translated. Therefore, in this review, we primarily highlight the 5’ cap-independent internal initiation of translation that occurs on circular RNAs. Several molecular features of circRNAs, including the internal ribosome entry site, N6-methyladenosine modification, and the exon junction complex deposited around the back-splicing junction after back-splicing event, play pivotal roles in their efficient internal translation. We also propose a possible relationship between the translatability of circRNAs and their stability, with a focus on nonsense-mediated mRNA decay and nonstop decay, both of which are well-characterized mRNA surveillance mechanisms. An in-depth understanding of circRNA translation will reshape and expand our current knowledge of proteomics. This research delves into the intricate realm of circular RNAs (circRNAs), a kind of RNA molecule that forms a covalently closed circular structure, making it more stable than its linear counterparts. Despite being plentiful in cells, the role of circRNAs is largely a mystery. The researchers provide a summary of the various ways circRNAs are created and outline the different functions they can have. They also explore the molecular specifics of how circRNAs are translated and consider the potential interaction between this translation and their stability. The research is a review, summarizing and analyzing existing studies on the subject and highlighting the role and potential impact of circRNAs in the regulation of gene expression. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
环状 RNA(circRNA)是共价封闭的单链 RNA,没有真核细胞线性 mRNA 中常见的 5'帽结构和 3'聚(A)尾。CircRNA 主要通过细胞核内的反向剪接过程产生。CircRNA 长期以来一直被认为是非编码 RNA,似乎没有编码蛋白质的潜力。然而,最近的许多研究对这一观点提出了质疑,并提供了大量证据表明,一部分 circRNA 可以与多聚体结合,并且确实可以被翻译。因此,在这篇综述中,我们主要强调环状 RNA 上发生的不依赖于 5' 帽的内部起始翻译。环状 RNA 的几个分子特征,包括内部核糖体进入位点、N6-甲基腺苷修饰以及反向剪接事件后沉积在反向剪接交界处周围的外显子交界复合物,在其高效内部翻译中起着关键作用。我们还提出了 circRNA 的可翻译性与其稳定性之间可能存在的关系,重点是无义介导的 mRNA 衰减和不停顿衰减,这两种机制都是已被证实的 mRNA 监控机制。对 circRNA 翻译的深入了解将重塑并扩展我们目前的蛋白质组学知识。
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引用次数: 0
Regulatory RNA: from molecular insights to therapeutic frontiers 调控 RNA:从分子洞察到治疗前沿。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1038/s12276-024-01267-2
TaeSoo Kim, Tae-Kyung Kim
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引用次数: 0
Inverted Alu repeats: friends or foes in the human transcriptome 反向 Alu 重复序列:人类转录组中的朋友还是敌人?
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1038/s12276-024-01177-3
Keonyong Lee, Jayoung Ku, Doyeong Ku, Yoosik Kim
Alu elements are highly abundant primate-specific short interspersed nuclear elements that account for ~10% of the human genome. Due to their preferential location in gene-rich regions, especially in introns and 3′ UTRs, Alu elements can exert regulatory effects on the expression of both host and neighboring genes. When two Alu elements with inverse orientations are positioned in close proximity, their transcription results in the generation of distinct double-stranded RNAs (dsRNAs), known as inverted Alu repeats (IRAlus). IRAlus are key immunogenic self-dsRNAs and post-transcriptional cis-regulatory elements that play a role in circular RNA biogenesis, as well as RNA transport and stability. Recently, IRAlus dsRNAs have emerged as regulators of transcription and activators of Z-DNA-binding proteins. The formation and activity of IRAlus can be modulated through RNA editing and interactions with RNA-binding proteins, and misregulation of IRAlus has been implicated in several immune-associated disorders. In this review, we summarize the emerging functions of IRAlus dsRNAs, the regulatory mechanisms governing IRAlus activity, and their relevance in the pathogenesis of human diseases. Understanding the role of Alu elements—short DNA sequences scattered throughout our genome—is crucial for grasping human genetics. These elements can affect how our genes function, and sometimes, their misregulation causes diseases. However, there’s still much we don’t know about their impact on gene regulation and cell signaling, including innate immune responses. Lee et al. summarized how Alu elements interact with our immune system by generating specific structures similar to ones from viruses. The authors suggest that further understanding of biological processes regulated by Alu elements could lead to advancements in the development of potential treatment for diseases linked to immune system dysfunction. Future research could explore how to manipulate these elements to benefit human health. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Alu元件是一种高度丰富的灵长类特异性短穿插核元件,约占人类基因组的10%。由于它们偏好位于基因丰富的区域,尤其是内含子和 3' UTR,Alu 元件可对宿主基因和邻近基因的表达产生调控作用。当两个方向相反的 Alu 元靠近时,它们的转录会产生不同的双链 RNA(dsRNA),即所谓的反向 Alu 重复序列(IRAlus)。IRAlus 是关键的免疫原性自dsRNA,也是转录后顺式调控元件,在环状 RNA 生物发生以及 RNA 运输和稳定性方面发挥作用。最近,IRAlus dsRNAs 成为转录调节剂和 Z-DNA 结合蛋白的激活剂。IRAlus 的形成和活性可通过 RNA 编辑以及与 RNA 结合蛋白的相互作用来调节,而 IRAlus 的失调与多种免疫相关疾病有关。在这篇综述中,我们总结了 IRAlus dsRNAs 的新功能、支配 IRAlus 活性的调控机制以及它们在人类疾病发病机制中的相关性。
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引用次数: 0
Elucidation of how the Mir-23-27-24 cluster regulates development and aging 阐明 Mir-23-27-24 簇如何调控发育和衰老。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1038/s12276-024-01266-3
Xin Le Yap, Jun-An Chen
MicroRNAs (miRNAs) are pivotal regulators of gene expression and are involved in biological processes spanning from early developmental stages to the intricate process of aging. Extensive research has underscored the fundamental role of miRNAs in orchestrating eukaryotic development, with disruptions in miRNA biogenesis resulting in early lethality. Moreover, perturbations in miRNA function have been implicated in the aging process, particularly in model organisms such as nematodes and flies. miRNAs tend to be clustered in vertebrate genomes, finely modulating an array of biological pathways through clustering within a single transcript. Although extensive research of their developmental roles has been conducted, the potential implications of miRNA clusters in regulating aging remain largely unclear. In this review, we use the Mir-23-27-24 cluster as a paradigm, shedding light on the nuanced physiological functions of miRNA clusters during embryonic development and exploring their potential involvement in the aging process. Moreover, we advocate further research into the intricate interplay among miRNA clusters, particularly the Mir-23-27-24 cluster, in shaping the regulatory landscape of aging. MicroRNAs significantly influence everything from growth to aging. However, the specific roles of certain miRNA clusters, like Mir-23-27-24, in aging are less understood. This review investigates the Mir-23-27-24 cluster’s function in embryonic growth and possible aging regulation. It’s a comprehensive review of how the Mir-23-27-24 cluster affects vital biological processes and aging, combining existing research to fill knowledge gaps. The Mir-23-27-24 cluster includes miRNAs vital in development stages and linked to various diseases, including cancer. Researchers underline the cluster’s role in embryonic development and its overlooked role in aging. They explore how these miRNAs control gene expression and contribute to the complexity of biological functions. This study implies that miRNA clusters like Mir-23-27-24 could be crucial in aging, opening new paths for aging research and potential treatments for age-related diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
微小核糖核酸(miRNA)是基因表达的关键调控因子,参与了从早期发育阶段到复杂衰老过程的生物过程。广泛的研究强调了 miRNA 在协调真核生物发育过程中的基本作用,miRNA 生物发生紊乱会导致早期死亡。此外,miRNA 功能的紊乱也与衰老过程有关,特别是在线虫和苍蝇等模式生物中。miRNA 在脊椎动物基因组中往往是成簇的,通过聚集在单个转录本中精细地调节一系列生物通路。虽然对它们在发育过程中的作用进行了广泛的研究,但 miRNA 簇在调控衰老过程中的潜在影响在很大程度上仍不清楚。在这篇综述中,我们以 Mir-23-27-24 集群为范例,揭示了 miRNA 集群在胚胎发育过程中的细微生理功能,并探讨了它们在衰老过程中的潜在参与。此外,我们主张进一步研究 miRNA 簇(尤其是 Mir-23-27-24 簇)之间错综复杂的相互作用,以塑造衰老的调控格局。
{"title":"Elucidation of how the Mir-23-27-24 cluster regulates development and aging","authors":"Xin Le Yap, Jun-An Chen","doi":"10.1038/s12276-024-01266-3","DOIUrl":"10.1038/s12276-024-01266-3","url":null,"abstract":"MicroRNAs (miRNAs) are pivotal regulators of gene expression and are involved in biological processes spanning from early developmental stages to the intricate process of aging. Extensive research has underscored the fundamental role of miRNAs in orchestrating eukaryotic development, with disruptions in miRNA biogenesis resulting in early lethality. Moreover, perturbations in miRNA function have been implicated in the aging process, particularly in model organisms such as nematodes and flies. miRNAs tend to be clustered in vertebrate genomes, finely modulating an array of biological pathways through clustering within a single transcript. Although extensive research of their developmental roles has been conducted, the potential implications of miRNA clusters in regulating aging remain largely unclear. In this review, we use the Mir-23-27-24 cluster as a paradigm, shedding light on the nuanced physiological functions of miRNA clusters during embryonic development and exploring their potential involvement in the aging process. Moreover, we advocate further research into the intricate interplay among miRNA clusters, particularly the Mir-23-27-24 cluster, in shaping the regulatory landscape of aging. MicroRNAs significantly influence everything from growth to aging. However, the specific roles of certain miRNA clusters, like Mir-23-27-24, in aging are less understood. This review investigates the Mir-23-27-24 cluster’s function in embryonic growth and possible aging regulation. It’s a comprehensive review of how the Mir-23-27-24 cluster affects vital biological processes and aging, combining existing research to fill knowledge gaps. The Mir-23-27-24 cluster includes miRNAs vital in development stages and linked to various diseases, including cancer. Researchers underline the cluster’s role in embryonic development and its overlooked role in aging. They explore how these miRNAs control gene expression and contribute to the complexity of biological functions. This study implies that miRNA clusters like Mir-23-27-24 could be crucial in aging, opening new paths for aging research and potential treatments for age-related diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular insights into regulatory RNAs in the cellular machinery 细胞机制中调控 RNA 的分子见解。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1038/s12276-024-01239-6
Sumin Yang, Sung-Hyun Kim, Eunjeong Yang, Mingon Kang, Jae-Yeol Joo
It is apparent that various functional units within the cellular machinery are derived from RNAs. The evolution of sequencing techniques has resulted in significant insights into approaches for transcriptome studies. Organisms utilize RNA to govern cellular systems, and a heterogeneous class of RNAs is involved in regulatory functions. In particular, regulatory RNAs are increasingly recognized to participate in intricately functioning machinery across almost all levels of biological systems. These systems include those mediating chromatin arrangement, transcription, suborganelle stabilization, and posttranscriptional modifications. Any class of RNA exhibiting regulatory activity can be termed a class of regulatory RNA and is typically represented by noncoding RNAs, which constitute a substantial portion of the genome. These RNAs function based on the principle of structural changes through cis and/or trans regulation to facilitate mutual RNA‒RNA, RNA‒DNA, and RNA‒protein interactions. It has not been clearly elucidated whether regulatory RNAs identified through deep sequencing actually function in the anticipated mechanisms. This review addresses the dominant properties of regulatory RNAs at various layers of the cellular machinery and covers regulatory activities, structural dynamics, modifications, associated molecules, and further challenges related to therapeutics and deep learning. Regulatory RNAs, such as long noncoding RNAs (lncRNAs, RNAs that do not code for proteins), microRNAs (miRNAs, small RNAs that regulate gene expression), and circular RNAs (circRNAs, RNAs that form a covalently closed continuous loop), are important in controlling gene expression. The exact ways and roles of these RNAs are not completely known. This study by Joo et al. reviews current knowledge on regulatory RNAs, focusing on their structure and function in cell parts. The authors talk about the different methods used to study these RNAs, including RNA-Chromatin, RNA-Protein, and RNA structure sequencing. They also emphasize the role of RNA modifications in controlling gene expression and the potential of deep learning (a type of machine learning) in predicting RNA functions. The study concludes that understanding regulatory RNAs better could lead to new treatment strategies for various diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
显然,细胞机制中的各种功能单元都来自 RNA。随着测序技术的发展,人们对转录组研究方法有了更深入的了解。生物体利用 RNA 管理细胞系统,有一类不同的 RNA 参与调控功能。特别是,人们越来越认识到,调控 RNA 参与了生物系统几乎所有层面的复杂功能机制。这些系统包括介导染色质排列、转录、亚细胞器稳定和转录后修饰的系统。任何一类具有调控活性的 RNA 都可称为一类调控 RNA,其典型代表是占基因组很大一部分的非编码 RNA。这些 RNA 的功能原理是通过顺式和/或反式调节改变结构,从而促进 RNA-RNA、RNA-DNA 和 RNA 蛋白之间的相互作用。通过深度测序发现的调控 RNA 是否真正按照预期的机制发挥作用,目前还没有明确的定论。本综述探讨了细胞机制各层中调控 RNA 的主要特性,涵盖了调控活动、结构动态、修饰、相关分子以及与治疗和深度学习相关的进一步挑战。
{"title":"Molecular insights into regulatory RNAs in the cellular machinery","authors":"Sumin Yang, Sung-Hyun Kim, Eunjeong Yang, Mingon Kang, Jae-Yeol Joo","doi":"10.1038/s12276-024-01239-6","DOIUrl":"10.1038/s12276-024-01239-6","url":null,"abstract":"It is apparent that various functional units within the cellular machinery are derived from RNAs. The evolution of sequencing techniques has resulted in significant insights into approaches for transcriptome studies. Organisms utilize RNA to govern cellular systems, and a heterogeneous class of RNAs is involved in regulatory functions. In particular, regulatory RNAs are increasingly recognized to participate in intricately functioning machinery across almost all levels of biological systems. These systems include those mediating chromatin arrangement, transcription, suborganelle stabilization, and posttranscriptional modifications. Any class of RNA exhibiting regulatory activity can be termed a class of regulatory RNA and is typically represented by noncoding RNAs, which constitute a substantial portion of the genome. These RNAs function based on the principle of structural changes through cis and/or trans regulation to facilitate mutual RNA‒RNA, RNA‒DNA, and RNA‒protein interactions. It has not been clearly elucidated whether regulatory RNAs identified through deep sequencing actually function in the anticipated mechanisms. This review addresses the dominant properties of regulatory RNAs at various layers of the cellular machinery and covers regulatory activities, structural dynamics, modifications, associated molecules, and further challenges related to therapeutics and deep learning. Regulatory RNAs, such as long noncoding RNAs (lncRNAs, RNAs that do not code for proteins), microRNAs (miRNAs, small RNAs that regulate gene expression), and circular RNAs (circRNAs, RNAs that form a covalently closed continuous loop), are important in controlling gene expression. The exact ways and roles of these RNAs are not completely known. This study by Joo et al. reviews current knowledge on regulatory RNAs, focusing on their structure and function in cell parts. The authors talk about the different methods used to study these RNAs, including RNA-Chromatin, RNA-Protein, and RNA structure sequencing. They also emphasize the role of RNA modifications in controlling gene expression and the potential of deep learning (a type of machine learning) in predicting RNA functions. The study concludes that understanding regulatory RNAs better could lead to new treatment strategies for various diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Optimal design of synthetic circular RNAs 合成环形 RNA 的优化设计。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1038/s12276-024-01251-w
Seo-Won Choi, Jin-Wu Nam
Circular RNAs are an unusual class of single-stranded RNAs whose ends are covalently linked via back-splicing. Due to their versatility, the need to express circular RNAs in vivo and in vitro has increased. Efforts have been made to efficiently and precisely synthesize circular RNAs. However, a review on the optimization of the processes of circular RNA design, synthesis, and delivery is lacking. Our review highlights the multifaceted aspects considered when producing optimal circular RNAs and summarizes the available options for each step of exogenous circular RNA design and synthesis, including circularization strategies. Additionally, this review describes several potential applications of circular RNAs. Circular RNAs were once considered errors in splicing. However, we now understand that circRNAs are common and play roles in health and disease, including potential use in creating vaccines. This review examines ways to create and use circRNAs, with a focus on improving their creation and delivery for medical purposes. They discuss various methods, including using natural and synthetic elements to enhance circRNA formation and stability. The main findings suggest that improving the creation and delivery of circRNAs could greatly enhance their medical potential. Researchers conclude that with more development, circRNAs could become powerful tools in gene therapy and vaccine creation, offering new ways to treat diseases. The future implications of this research could transform how we approach disease treatment and vaccine creation, making therapies more effective and long-lasting. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
环状 RNA 是一类不常见的单链 RNA,其末端通过反向剪接共价连接。由于环状 RNA 的多功能性,在体内和体外表达环状 RNA 的需求日益增加。人们一直在努力高效、精确地合成环状 RNA。然而,关于优化环状 RNA 设计、合成和递送过程的综述还很缺乏。我们的综述强调了在生产最佳环形 RNA 时所考虑的多方面问题,并总结了外源环形 RNA 设计和合成每个步骤的可用选项,包括环化策略。此外,本综述还介绍了环状 RNA 的几种潜在应用。
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引用次数: 0
Big data and deep learning for RNA biology 用于 RNA 生物学的大数据和深度学习。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-14 DOI: 10.1038/s12276-024-01243-w
Hyeonseo Hwang, Hyeonseong Jeon, Nagyeong Yeo, Daehyun Baek
The exponential growth of big data in RNA biology (RB) has led to the development of deep learning (DL) models that have driven crucial discoveries. As constantly evidenced by DL studies in other fields, the successful implementation of DL in RB depends heavily on the effective utilization of large-scale datasets from public databases. In achieving this goal, data encoding methods, learning algorithms, and techniques that align well with biological domain knowledge have played pivotal roles. In this review, we provide guiding principles for applying these DL concepts to various problems in RB by demonstrating successful examples and associated methodologies. We also discuss the remaining challenges in developing DL models for RB and suggest strategies to overcome these challenges. Overall, this review aims to illuminate the compelling potential of DL for RB and ways to apply this powerful technology to investigate the intriguing biology of RNA more effectively. This review spotlights the revolutionary role of deep learning (DL) in expanding the understanding of RNA. RNA is a fundamental biomolecule that shapes and regulates diverse phenotypes including human diseases. Understanding the principles governing the functions of RNA is a key objective of current biology. Recently, big data produced via high-throughput experiments have been utilized to develop DL models aimed at analyzing and predicting RNA-related biological processes. This review emphasizes the role of public databases in providing these big data for training DL models. The authors introduce core DL concepts necessary for training models from the biological data. By extensively examining DL studies in various fields of RNA biology, the authors suggest how to better leverage DL for revealing novel biological knowledge and demonstrate the potential of DL in deciphering the complex biology of RNA. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
RNA 生物学(RB)领域大数据的指数级增长促进了深度学习(DL)模型的发展,推动了重要发现的产生。正如其他领域的深度学习研究不断证明的那样,在 RB 中成功实施深度学习在很大程度上取决于对来自公共数据库的大规模数据集的有效利用。在实现这一目标的过程中,数据编码方法、学习算法以及与生物领域知识相匹配的技术发挥了关键作用。在本综述中,我们通过展示成功案例和相关方法,为将这些 DL 概念应用于 RB 中的各种问题提供了指导原则。我们还讨论了为遗传资源开发数字语言模型的其余挑战,并提出了克服这些挑战的策略。总之,本综述旨在阐明 DL 在 RB 方面令人瞩目的潜力,以及如何应用这一强大技术更有效地研究 RNA 这一引人入胜的生物学问题。
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引用次数: 0
The identification of effective tumor-suppressing neoantigens using a tumor-reactive TIL TCR-pMHC ternary complex 利用肿瘤反应性 TIL TCR-pMHC 三元复合物鉴定有效的肿瘤抑制新抗原。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-12 DOI: 10.1038/s12276-024-01259-2
Sang Hoon Kim, Bo Ryeong Lee, Sung-Min Kim, Sungsik Kim, Min-seok Kim, Jaehyun Kim, Inkyu Lee, Hee-Soo Kim, Gi-Hoon Nam, In-San Kim, Kyuyoung Song, Yoonjoo Choi, Dong-Sup Lee, Woong-Yang Park
Neoantigens are ideal targets for cancer immunotherapy because they are expressed de novo in tumor tissue but not in healthy tissue and are therefore recognized as foreign by the immune system. Advances in next-generation sequencing and bioinformatics technologies have enabled the quick identification and prediction of tumor-specific neoantigens; however, only a small fraction of predicted neoantigens are immunogenic. To improve the predictability of immunogenic neoantigens, we developed the in silico neoantigen prediction workflows VACINUSpMHC and VACINUSTCR: VACINUSpMHC incorporates physical binding between peptides and MHCs (pMHCs), and VACINUSTCR integrates T cell reactivity to the pMHC complex through deep learning-based pairing with T cell receptors (TCRs) of putative tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs). We then validated our neoantigen prediction workflows both in vitro and in vivo in patients with hepatocellular carcinoma (HCC) and in a B16F10 mouse melanoma model. The predictive abilities of VACINUSpMHC and VACINUSTCR were confirmed in a validation cohort of 8 patients with HCC. Of a total of 118 neoantigen candidates predicted by VACINUSpMHC, 48 peptides were ultimately selected using VACINUSTCR. In vitro validation revealed that among the 48 predicted neoantigen candidates, 13 peptides were immunogenic. Assessment of the antitumor efficacy of the candidate neoepitopes using a VACINUSTCR in vivo mouse model suggested that vaccination with the predicted neoepitopes induced neoantigen-specific T cell responses and enabled the trafficking of neoantigen-specific CD8 + T cell clones into the tumor tissue, leading to tumor suppression. This study showed that the prediction of immunogenic neoantigens can be improved by integrating a tumor-reactive TIL TCR-pMHC ternary complex. Cancer scientists have created a new way to identify and choose neoantigens (new proteins on cancer cells) for use in cancer vaccines. The research, led by Woong-Yang Park, included 33 patients with different cancer types. The scientists used a mix of computer-based prediction techniques and lab-based tests to find the most effective neoantigens. The results showed that the new technique, named VACINUS, was better at predicting effective neoantigens than older methods. The scientists concluded that the VACINUS technique could improve the immune response of predicted neoantigens, making them better at activating an immune reaction against cancer cells. This could result in the creation of more effective cancer vaccines in the future. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
新抗原是癌症免疫疗法的理想靶点,因为它们在肿瘤组织中从头表达,而在健康组织中不表达,因此被免疫系统识别为外来物。下一代测序和生物信息学技术的进步使得肿瘤特异性新抗原的快速鉴定和预测成为可能;然而,只有一小部分预测的新抗原具有免疫原性。为了提高免疫原性新抗原的可预测性,我们开发了硅学新抗原预测工作流 VACINUSpMHC 和 VACINUSTCR:VACINUSpMHC 结合了肽与 MHC(pMHC)之间的物理结合,而 VACINUSTCR 则通过基于深度学习的配对与假定的肿瘤反应性 CD8 肿瘤浸润淋巴细胞(TIL)的 T 细胞受体(TCR)结合,整合了 T 细胞对 pMHC 复合物的反应性。然后,我们在肝细胞癌(HCC)患者和 B16F10 小鼠黑色素瘤模型中对新抗原预测工作流程进行了体外和体内验证。VACINUSpMHC 和 VACINUSTCR 的预测能力在 8 例 HCC 患者的验证队列中得到了证实。在 VACINUSpMHC 预测的 118 个候选新抗原中,VACINUSTCR 最终筛选出 48 个肽段。体外验证显示,在 48 个预测的候选新抗原中,13 个肽具有免疫原性。使用 VACINUSTCR 体内小鼠模型评估候选新表位的抗肿瘤效果表明,接种预测的新表位可诱导新抗原特异性 T 细胞反应,并使新抗原特异性 CD8 + T 细胞克隆进入肿瘤组织,从而抑制肿瘤。这项研究表明,通过整合肿瘤反应性TIL TCR-pMHC三元复合物,可以改善免疫原性新抗原的预测。
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引用次数: 0
期刊
Experimental and Molecular Medicine
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