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Unraveling the intriguing interplay: Exploring the role of lncRNAs in caspase-independent cell death. 揭示耐人寻味的相互作用:探索lncRNA在不依赖于caspase的细胞死亡中的作用。
IF 7.3 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-01 DOI: 10.1002/wrna.1862
Yusuf Cem Ciftci, İpek Erdoğan Vatansever, Bünyamin Akgül

Cell death plays a crucial role in various physiological and pathological processes. Until recently, programmed cell death was mainly attributed to caspase-dependent apoptosis. However, emerging evidence suggests that caspase-independent cell death (CICD) mechanisms also contribute significantly to cellular demise. We and others have reported and functionally characterized numerous long noncoding RNAs (lncRNAs) that modulate caspase-dependent apoptotic pathways potentially in a pathway-dependent manner. However, the interplay between lncRNAs and CICD pathways has not been comprehensively documented. One major reason for this is that most CICD pathways have been recently discovered with some being partially characterized at the molecular level. In this review, we discuss the emerging evidence that implicates specific lncRNAs in the regulation and execution of CICD. We summarize the diverse mechanisms through which lncRNAs modulate different forms of CICD, including ferroptosis, necroptosis, cuproptosis, and others. Furthermore, we highlight the intricate regulatory networks involving lncRNAs, protein-coding genes, and signaling pathways that orchestrate CICD in health and disease. Understanding the molecular mechanisms and functional implications of lncRNAs in CICD may unravel novel therapeutic targets and diagnostic tools for various diseases, paving the way for innovative strategies in disease management and personalized medicine. This article is categorized under: RNA in Disease and Development > RNA in Disease.

细胞死亡在各种生理和病理过程中起着至关重要的作用。直到最近,程序性细胞死亡主要归因于依赖于caspase的细胞凋亡。然而,新出现的证据表明,不依赖于caspase的细胞死亡(CICD)机制也在很大程度上导致了细胞死亡。我们和其他人已经报道了许多长非编码 RNA(lncRNA),并对其功能进行了表征,这些 RNA 有可能以路径依赖的方式调节依赖于 caspase 的细胞凋亡途径。然而,lncRNA 与 CICD 通路之间的相互作用尚未得到全面记录。造成这种情况的一个主要原因是,大多数 CICD 通路都是最近才被发现的,其中一些在分子水平上还有部分特征。在这篇综述中,我们讨论了新出现的证据,这些证据表明特定的 lncRNA 与 CICD 的调控和执行有关。我们总结了 lncRNA 调节不同形式 CICD 的各种机制,包括铁凋亡、坏死凋亡、杯状凋亡等。此外,我们还强调了涉及 lncRNA、蛋白编码基因和信号通路的错综复杂的调控网络,这些网络协调了健康和疾病中的 CICD。了解CICD中lncRNAs的分子机制和功能意义可能会揭示各种疾病的新型治疗靶点和诊断工具,为疾病管理和个性化医疗的创新策略铺平道路。本文归类于疾病与发育中的 RNA > 疾病中的 RNA。
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引用次数: 0
Rules and impacts of nonsense-mediated mRNA decay in the degradation of long noncoding RNAs. 无义介导的 mRNA 衰减在长非编码 RNA 降解中的规则和影响。
IF 7.3 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-01 DOI: 10.1002/wrna.1853
Anand Kumar Singh

Nonsense-mediated mRNA decay (NMD) is a quality-control process that selectively degrades mRNAs having premature termination codon, upstream open reading frame, or unusually long 3'UTR. NMD detects such mRNAs and rapidly degrades them during initial rounds of translation in the eukaryotic cells. Since NMD is a translation-dependent cytoplasmic mRNA surveillance process, the noncoding RNAs were initially believed to be NMD-resistant. The sequence feature-based analysis has revealed that many putative long noncoding RNAs (lncRNAs) have short open reading frames, most of which have translation potential. Subsequent transcriptome-based molecular studies showed an association of a large set of such putative lncRNAs with translating ribosomes, and some of them produce stable and functionally active micropeptides. The translationally active lncRNAs typically have relatively longer and unprotected 3'UTR, which can induce their NMD-dependent degradation. This review defines the mechanism and regulation of NMD-dependent degradation of lncRNAs and its impact on biological processes related to the functions of lncRNAs or their encoded micropeptides. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease.

无义介导的 mRNA 降解(NMD)是一种质量控制过程,可选择性地降解具有过早终止密码子、上游开放阅读框或异常长的 3'UTR 的 mRNA。NMD 能检测到这类 mRNA,并在真核细胞的最初几轮翻译过程中迅速降解它们。由于 NMD 是一种依赖于翻译的细胞质 mRNA 监控过程,人们最初认为非编码 RNA 具有 NMD 抗性。基于序列特征的分析表明,许多推定的长非编码 RNA(lncRNA)具有短开放阅读框,其中大部分具有翻译潜力。随后进行的基于转录组的分子研究显示,大量此类推测的 lncRNA 与翻译核糖体有关联,其中一些会产生稳定且功能活跃的微肽。具有翻译活性的 lncRNA 通常具有相对较长和不受保护的 3'UTR,这可能会诱导其 NMD 依赖性降解。这篇综述阐述了 NMD 依赖性降解 lncRNAs 的机制和调控及其对与 lncRNAs 或其编码的微肽功能相关的生物过程的影响。本文归类于RNA 转录和监控 > 转录/监控机制 RNA 转录和监控 > RNA 稳定性的调控 RNA 在疾病和发育中的作用 > RNA 在疾病中的作用。
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引用次数: 0
Revealing the hidden RBP-RNA interactions with RNA modification enzyme-based strategies. 利用基于 RNA 修饰酶的策略揭示隐藏的 RBP-RNA 相互作用。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-01 DOI: 10.1002/wrna.1863
Hua Jin, Chong Li, Yunxiao Jia, Yuxuan Qi, Weilan Piao

RNA-binding proteins (RBPs) are powerful and versatile regulators in living creatures, playing fundamental roles in organismal development, metabolism, and various diseases by the regulation of gene expression at multiple levels. The requirements of deep research on RBP function have promoted the rapid development of RBP-RNA interplay detection methods. Recently, the detection method of fusing RNA modification enzymes (RME) with RBP of interest has become a hot topic. Here, we reviewed RNA modification enzymes in adenosine deaminases that act on RNA (ADAR), terminal nucleotidyl transferase (TENT), and activation-induced cytosine deaminase/ApoB mRNA editing enzyme catalytic polypeptide-like (AID/APOBEC) protein family, regarding the biological function, biochemical activity, and substrate specificity originated from enzyme selves, their domains and partner proteins. In addition, we discussed the RME activity screening system, and the RME mutations with engineered enzyme activity. Furthermore, we provided a systematic overview of the basic principles, advantages, disadvantages, and applications of the RME-based and cross-linking and immunopurification (CLIP)-based RBP target profiling strategies, including targets of RNA-binding proteins identified by editing (TRIBE), RNA tagging, surveying targets by APOBEC-mediated profiling (STAMP), CLIP-seq, and their derivative technology. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Processing > RNA Editing and Modification.

RNA 结合蛋白(RBPs)是生物体内强大而多变的调控因子,通过在多个水平上调控基因表达,在生物体发育、新陈代谢和各种疾病中发挥着基础性作用。对 RBP 功能深入研究的要求促进了 RBP-RNA 相互作用检测方法的快速发展。最近,RNA修饰酶(RME)与相关RBP的融合检测方法成为了一个热门话题。在此,我们综述了作用于 RNA 的腺苷脱氨酶(ADAR)、末端核苷酸转移酶(TENT)和活化诱导胞嘧啶脱氨酶/载脂蛋白 mRNA 编辑酶催化多肽样(AID/APOBEC)蛋白家族中的 RNA 修饰酶,从酶本身、其结构域和伙伴蛋白出发,探讨了它们的生物学功能、生化活性和底物特异性。此外,我们还讨论了 RME 活性筛选系统,以及具有工程酶活性的 RME 突变。此外,我们还系统概述了基于 RME 和基于交联和免疫纯化(CLIP)的 RBP 靶标分析策略的基本原理、优缺点和应用,包括通过编辑(TRIBE)、RNA 标记、APOBEC 介导的靶标分析(STAMP)、CLIP-seq 及其衍生技术识别的 RNA 结合蛋白靶标。本文归类于RNA 与蛋白质和其他分子的相互作用 > 蛋白质-RNA 识别 RNA 处理 > RNA 编辑和修饰。
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引用次数: 0
Untacking small RNA profiling and RNA fragment footprinting: Approaches and challenges in library construction. 解开小 RNA 分析和 RNA 片段足迹:文库构建的方法和挑战。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-01 DOI: 10.1002/wrna.1852
Zhaokang Shen, Muhammad Naveed, Jianqiang Bao

Small RNAs (sRNAs) with sizes ranging from 15 to 50 nucleotides (nt) are critical regulators of gene expression control. Prior studies have shown that sRNAs are involved in a broad range of biological processes, such as organ development, tumorigenesis, and epigenomic regulation; however, emerging evidence unveils a hidden layer of diversity and complexity of endogenously encoded sRNAs profile in eukaryotic organisms, including novel types of sRNAs and the previously unknown post-transcriptional RNA modifications. This underscores the importance for accurate, unbiased detection of sRNAs in various cellular contexts. A multitude of high-throughput methods based on next-generation sequencing (NGS) are developed to decipher the sRNA expression and their modifications. Nonetheless, distinct from mRNA sequencing, the data from sRNA sequencing suffer frequent inconsistencies and high variations emanating from the adapter contaminations and RNA modifications, which overall skew the sRNA libraries. Here, we summarize the sRNA-sequencing approaches, and discuss the considerations and challenges for the strategies and methods of sRNA library construction. The pros and cons of sRNA sequencing have significant implications for implementing RNA fragment footprinting approaches, including CLIP-seq and Ribo-seq. We envision that this review can inspire novel improvements in small RNA sequencing and RNA fragment footprinting in future. This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.

大小为 15 至 50 个核苷酸(nt)的小核糖核酸(sRNA)是基因表达控制的关键调节因子。先前的研究表明,sRNAs 参与了器官发育、肿瘤发生和表观基因组调控等广泛的生物过程;然而,新出现的证据揭示了真核生物内源性编码的 sRNAs 的多样性和复杂性,包括新型 sRNAs 和先前未知的转录后 RNA 修饰。这凸显了在各种细胞环境中准确、无偏见地检测 sRNA 的重要性。目前已开发出多种基于下一代测序(NGS)的高通量方法来解读 sRNA 的表达及其修饰。然而,与 mRNA 测序不同的是,sRNA 测序的数据经常出现不一致和高变异,这源于适配器污染和 RNA 修饰,它们在整体上歪曲了 sRNA 文库。在此,我们总结了 sRNA 测序方法,并讨论了 sRNA 文库构建策略和方法的注意事项和挑战。sRNA 测序的利弊对实施 RNA 片段足迹分析方法(包括 CLIP-seq 和 Ribo-seq)具有重要影响。我们希望这篇综述能为今后小 RNA 测序和 RNA 片段足迹分析带来新的启发。本文归类于RNA 进化与基因组学 > RNA 的计算分析 RNA 处理 > 小 RNAs 的处理 调控 RNAs/RNAi/Riboswitches > 效应小 RNAs 的生物发生。
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引用次数: 0
Role of epigenetics and alterations in RNA metabolism in leukodystrophies. 白质营养不良症中表观遗传学的作用和 RNA 代谢的改变。
IF 6.4 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-01 DOI: 10.1002/wrna.1854
Federica Rey, Letizia Esposito, Erika Maghraby, Alessia Mauri, Clarissa Berardo, Eleonora Bonaventura, Davide Tonduti, Stephana Carelli, Cristina Cereda

Leukodystrophies are a class of rare heterogeneous disorders which affect the white matter of the brain, ultimately leading to a disruption in brain development and a damaging effect on cognitive, motor and social-communicative development. These disorders present a great clinical heterogeneity, along with a phenotypic overlap and this could be partially due to contributions from environmental stimuli. It is in this context that there is a great need to investigate what other factors may contribute to both disease insurgence and phenotypical heterogeneity, and novel evidence are raising the attention toward the study of epigenetics and transcription mechanisms that can influence the disease phenotype beyond genetics. Modulation in the epigenetics machinery including histone modifications, DNA methylation and non-coding RNAs dysregulation, could be crucial players in the development of these disorders, and moreover an aberrant RNA maturation process has been linked to leukodystrophies. Here, we provide an overview of these mechanisms hoping to supply a closer step toward the analysis of leukodystrophies not only as genetically determined but also with an added level of complexity where epigenetic dysregulation is of key relevance. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNA RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

白质营养不良症是一类罕见的异质性疾病,会影响大脑白质,最终导致大脑发育障碍,并对认知、运动和社交沟通能力的发展造成破坏性影响。这些疾病具有很大的临床异质性和表型重叠性,部分原因可能是环境刺激造成的。正是在这种情况下,我们亟需研究还有哪些因素可能会导致疾病的发生和表型的异质性,而新的证据正在引起人们对表观遗传学和转录机制研究的关注,这些机制可以在遗传学之外影响疾病的表型。表观遗传学机制的改变,包括组蛋白修饰、DNA甲基化和非编码RNA失调,可能是这些疾病发病的关键因素,此外,RNA成熟过程异常也与白质营养不良症有关。在此,我们对这些机制进行了综述,希望能为分析白质营养不良症迈出更近一步,不仅将其视为由遗传决定的疾病,而且还将其视为表观遗传失调具有关键意义的复杂疾病。本文归类于调控 RNAs/RNAi/Riboswitches > 调控 RNA RNA 在疾病和发育中的作用 > RNA 在疾病中的作用 RNA 在疾病和发育中的作用 > RNA 在发育中的作用。
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引用次数: 0
The protein-only RNase Ps, endonucleases that cleave pre-tRNA: Biological relevance, molecular architectures, substrate recognition and specificity, and protein interactomes. 只含蛋白质的 RNase Ps,可裂解前 tRNA 的内切核酸酶:生物学相关性、分子结构、底物识别和特异性以及蛋白质相互作用组。
IF 7.3 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-01 DOI: 10.1002/wrna.1836
Catherine A Wilhelm, Kipchumba Kaitany, Abigail Kelly, Matthew Yacoub, Markos Koutmos

Protein-only RNase P (PRORP) is an essential enzyme responsible for the 5' maturation of precursor tRNAs (pre-tRNAs). PRORPs are classified into three categories with unique molecular architectures, although all three classes of PRORPs share a mechanism and have similar active sites. Single subunit PRORPs, like those found in plants, have multiple isoforms with different localizations, substrate specificities, and temperature sensitivities. Most recently, Arabidopsis thaliana PRORP2 was shown to interact with TRM1A and B, highlighting a new potential role between these enzymes. Work with At PRORPs led to the development of a ribonuclease that is being used to protect against plant viruses. The mitochondrial RNase P complex, found in metazoans, consists of PRORP, TRMT10C, and SDR5C1, and has also been shown to have substrate specificity, although the cause is unknown. Mutations in mitochondrial tRNA and mitochondrial RNase P have been linked to human disease, highlighting the need to continue understanding this complex. The last class of PRORPs, homologs of Aquifex RNase P (HARPs), is found in thermophilic archaea and bacteria. This most recently discovered type of PRORP forms a large homo-oligomer complex. Although numerous structures of HARPs have been published, it is still unclear how HARPs bind pre-tRNAs and in what ratio. There is also little investigation into the substrate specificity and ideal conditions for HARPs. Moving forward, further work is required to fully characterize each of the three classes of PRORP, the pre-tRNA binding recognition mechanism, the rules of substrate specificity, and how these three distinct classes of PRORP evolved. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems.

纯蛋白 RNase P(PRORP)是一种负责前体 tRNA(前 tRNA)5'成熟的重要酶。PRORPs 可分为三类,具有独特的分子结构,但所有三类 PRORPs 都具有相同的机制和相似的活性位点。单亚基 PRORPs(如植物中发现的 PRORPs)有多种异构体,其定位、底物特异性和温度敏感性各不相同。最近,拟南芥 PRORP2 与 TRM1A 和 TRM1B 相互作用,突显了这些酶之间新的潜在作用。通过研究拟南芥 PRORPs,开发出了一种核糖核酸酶,这种酶被用于抵御植物病毒。线粒体 RNase P 复合物存在于变态类动物中,由 PRORP、TRMT10C 和 SDR5C1 组成,也被证明具有底物特异性,但原因不明。线粒体 tRNA 和线粒体 RNase P 的突变与人类疾病有关,因此有必要继续了解这一复合体。最后一类 PRORPs,即 Aquifex RNase P 的同源物(HARPs),存在于嗜热古细菌和细菌中。这种最新发现的 PRORP 形成了一个大型同源异构体复合物。虽然已经公布了许多 HARPs 的结构,但仍不清楚 HARPs 如何结合前 tRNA 以及结合的比例。对 HARPs 的底物特异性和理想条件的研究也很少。展望未来,还需要进一步研究这三类 PRORP 的特性、前 tRNA 结合识别机制、底物特异性规则以及这三类不同的 PRORP 是如何进化的。本文归类于RNA 结构与动力学 > RNA 结构、动力学与化学 RNA 结构与动力学 > RNA 结构在生物系统中的影响。
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引用次数: 0
Target-directed microRNA degradation: Mechanisms, significance, and functional implications. 靶向 microRNA 降解:机制、意义和功能影响。
IF 7.3 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-01 DOI: 10.1002/wrna.1832
Nicholas M Hiers, Tianqi Li, Conner M Traugot, Mingyi Xie

MicroRNAs (miRNAs) are small non-coding RNAs that play a fundamental role in enabling miRNA-mediated target repression, a post-transcriptional gene regulatory mechanism preserved across metazoans. Loss of certain animal miRNA genes can lead to developmental abnormalities, disease, and various degrees of embryonic lethality. These short RNAs normally guide Argonaute (AGO) proteins to target RNAs, which are in turn translationally repressed and destabilized, silencing the target to fine-tune gene expression and maintain cellular homeostasis. Delineating miRNA-mediated target decay has been thoroughly examined in thousands of studies, yet despite these exhaustive studies, comparatively less is known about how and why miRNAs are directed for decay. Several key observations over the years have noted instances of rapid miRNA turnover, suggesting endogenous means for animals to induce miRNA degradation. Recently, it was revealed that certain targets, so-called target-directed miRNA degradation (TDMD) triggers, can "trigger" miRNA decay through inducing proteolysis of AGO and thereby the bound miRNA. This process is mediated in animals via the ZSWIM8 ubiquitin ligase complex, which is recruited to AGO during engagement with triggers. Since its discovery, several studies have identified that ZSWIM8 and TDMD are indispensable for proper animal development. Given the rapid expansion of this field of study, here, we summarize the key findings that have led to and followed the discovery of ZSWIM8-dependent TDMD. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA in Disease and Development > RNA in Development.

微小RNA(miRNA)是一种小型非编码RNA,在miRNA介导的目标抑制中发挥着基础性作用,这是一种转录后基因调控机制,在元古宙中得以保留。某些动物 miRNA 基因的缺失会导致发育异常、疾病和不同程度的胚胎死亡。这些短 RNA 通常会引导 Argonaute(AGO)蛋白找到靶 RNA,进而抑制靶 RNA 的翻译并使其不稳定,从而沉默靶 RNA,以微调基因表达并维持细胞稳态。数以千计的研究对 miRNA 介导的靶衰变进行了深入探讨,然而,尽管进行了这些详尽的研究,人们对 miRNA 如何以及为何被定向衰变的了解却相对较少。多年来的一些重要观察发现了 miRNA 快速更替的情况,这表明动物有诱导 miRNA 降解的内源性手段。最近,有研究发现,某些靶标,即所谓的靶标引导的 miRNA 降解(TDMD)触发器,可以通过诱导 AGO 蛋白分解从而 "触发 "miRNA 的降解。在动物体内,这一过程是通过 ZSWIM8 泛素连接酶复合物介导的。自 ZSWIM8 和 TDMD 被发现以来,已有多项研究发现它们对动物的正常发育不可或缺。鉴于这一研究领域的迅速扩展,我们在此总结了发现 ZSWIM8 依赖性 TDMD 之前和之后的主要发现。本文归类于调控 RNAs/RNAi/Riboswitches > 调控 RNAs RNA 更替与监控 > 更替/监控机制 RNA 在疾病与发育中的作用 > RNA 在发育中的作用。
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引用次数: 0
Stoichiometry of long noncoding RNA interactions with other RNAs: Insights from OIP5-AS1. 长非编码 RNA 与其他 RNA 相互作用的计量:来自 OIP5-AS1 的启示
IF 7.3 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-01 DOI: 10.1002/wrna.1841
Jen-Hao Yang, Dimitrios Tsitsipatis, Myriam Gorospe

Long noncoding (lnc)RNAs modulate gene expression programs in a range of developmental processes in different organs. In skeletal muscle, lncRNAs have been implicated in myogenesis, the process whereby muscle precursor cells form muscle fibers during embryonic development and regenerate muscle fibers in the adult. Here, we discuss OIP5-AS1, a lncRNA that is highly expressed in skeletal muscle and is capable of coordinating protein expression programs during myogenesis. Given that several myogenic functions of OIP5-AS1 involve interactions with MEF2C mRNA and with the microRNA miR-7, it was critical to carefully evaluate the precise levels of OIP5-AS1 during myogenesis. We discuss the approaches used to examine lncRNA copy number using OIP5-AS1 as an example, focusing on quantification by quantitative PCR analysis with reference to nucleic acids of known abundance, by droplet digital (dd)PCR measurement, and by microscopic visualization of individual lncRNAs in cells. We discuss considerations of RNA stoichiometry in light of developmental processes in which lncRNAs are implicated. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.

长非编码(lnc)RNA 在不同器官的一系列发育过程中调节基因表达程序。在骨骼肌中,lncRNA 与肌生成有关,肌生成是肌肉前体细胞在胚胎发育过程中形成肌纤维并在成年后再生肌纤维的过程。在这里,我们讨论了 OIP5-AS1,它是一种在骨骼肌中高表达的 lncRNA,能够在肌生成过程中协调蛋白质表达程序。鉴于OIP5-AS1的几种肌生成功能涉及与MEF2C mRNA和microRNA miR-7的相互作用,因此仔细评估肌生成过程中OIP5-AS1的精确水平至关重要。我们以OIP5-AS1为例,讨论了用于检测lncRNA拷贝数的方法,重点是参照已知丰度的核酸进行定量PCR分析、液滴数字(dd)PCR测量以及细胞中单个lncRNA的显微可视化。我们根据与 lncRNAs 有关的发育过程,讨论了对 RNA 平衡度的考虑。本文归类于调控 RNAs/RNAi/Riboswitches > 调控 RNAs。
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引用次数: 0
Beyond reader proteins: RNA binding proteins and RNA modifications in conversation to regulate gene expression. 超越读者蛋白:RNA 结合蛋白与 RNA 修饰对话调节基因表达。
IF 7.3 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-01 DOI: 10.1002/wrna.1834
Christian Fagre, Wendy Gilbert

Post-transcriptional mRNA modifications play diverse roles in gene expression and RNA function. In many cases, RNA modifications function by altering how cellular machinery such as RNA binding proteins (RBPs) interact with RNA substrates. For instance, N6-methyladenosine (m6A) is recognized by the well-characterized YTH domain-containing family of "reader" proteins. For other mRNA modifications, similar global readers of modification status have not been clearly defined. Rather, most interactions between RBPs and RNA modifications have a more complicated dependence on sequence context and binding modality. The current handful of studies that demonstrate modifications impacting protein binding likely represent only a fraction of the full landscape. In this review, we dissect the known instances of RNA modifications altering RBP binding, specifically m6A, N1-methyladenosine (m1A), 5-methylcytosine (m5C), pseudouridine (Ψ), and internal N7-methylguanosine. We then review the biochemical properties of these and other identified mRNA modifications including dihydrouridine (D), N4-acetylcytosine (ac4C), and 2'-O-Methylation (Nme). We focus on how these properties would be likely to impact RNA:RBP interactions, including by changes to hydrogen bond potential, base-stacking efficiency, and RNA conformational preferences. The effects of RNA modifications on secondary structure have been well-studied, and we briefly discuss how structural effects imparted by modifications can lead to protein binding changes. Finally, we discuss strategies for uncovering as-yet-to-be identified modification-sensitive RBP:RNA Interactions. Coordinating future efforts to intersect the epitranscriptome and the RNA-protein interactome will illuminate the rules governing RNA modification recognition and the mechanisms responsible for the biological consequences of mRNA modification. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Processing > RNA Editing and Modification.

转录后 mRNA 修饰在基因表达和 RNA 功能中发挥着不同的作用。在许多情况下,RNA修饰通过改变细胞机制(如 RNA 结合蛋白(RBPs))与 RNA 底物的相互作用而发挥作用。例如,N6-甲基腺苷(m6A)可被特征明确的含 YTH 结构域的 "阅读器 "蛋白家族识别。对于其他 mRNA 修饰,类似的修饰状态全局阅读器尚未明确定义。相反,大多数 RBPs 与 RNA 修饰之间的相互作用对序列上下文和结合方式的依赖更为复杂。目前证明修饰会影响蛋白质结合的少量研究可能只代表了全部研究的一小部分。在这篇综述中,我们剖析了已知的 RNA 修饰改变 RBP 结合的实例,特别是 m6A、N1-甲基腺苷(m1A)、5-甲基胞嘧啶(m5C)、假尿苷(Ψ)和内部 N7-甲基鸟苷。然后,我们回顾了这些修饰和其他已确定的 mRNA 修饰(包括二氢尿嘧啶(D)、N4-乙酰胞嘧啶(ac4C)和 2'-O- 甲基化(Nme))的生化特性。我们重点研究了这些特性可能会如何影响 RNA 与 RBP 的相互作用,包括氢键势能、碱基堆积效率和 RNA 构象偏好的变化。我们对 RNA 修饰对二级结构的影响进行了深入研究,并简要讨论了修饰对结构的影响如何导致蛋白质结合发生变化。最后,我们讨论了揭示尚未发现的对修饰敏感的 RBP:RNA 相互作用的策略。协调未来的努力,交叉表转录组和 RNA 蛋白相互作用组,将阐明 RNA 修饰识别的规则以及造成 mRNA 修饰生物学后果的机制。本文归类于RNA 结构和动力学 > RNA 结构、动力学和化学 RNA 与蛋白质和其他分子的相互作用 > 蛋白质-RNA 识别 RNA 处理 > RNA 编辑和修饰。
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引用次数: 0
The spectrum of pre-mRNA splicing in autism. 自闭症的前核糖核酸剪接谱。
IF 7.3 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-03-01 DOI: 10.1002/wrna.1838
Eden Engal, Zhenwei Zhang, Ophir Geminder, Shiri Jaffe-Herman, Gillian Kay, Asa Ben-Hur, Maayan Salton

Disruptions in spatiotemporal gene expression can result in atypical brain function. Specifically, autism spectrum disorder (ASD) is characterized by abnormalities in pre-mRNA splicing. Abnormal splicing patterns have been identified in the brains of individuals with ASD, and mutations in splicing factors have been found to contribute to neurodevelopmental delays associated with ASD. Here we review studies that shed light on the importance of splicing observed in ASD and that explored the intricate relationship between splicing factors and ASD, revealing how disruptions in pre-mRNA splicing may underlie ASD pathogenesis. We provide an overview of the research regarding all splicing factors associated with ASD and place a special emphasis on five specific splicing factors-HNRNPH2, NOVA2, WBP4, SRRM2, and RBFOX1-known to impact the splicing of ASD-related genes. In the discussion of the molecular mechanisms influenced by these splicing factors, we lay the groundwork for a deeper understanding of ASD's complex etiology. Finally, we discuss the potential benefit of unraveling the connection between splicing and ASD for the development of more precise diagnostic tools and targeted therapeutic interventions. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Evolution and Genomics > Computational Analyses of RNA RNA-Based Catalysis > RNA Catalysis in Splicing and Translation.

时空基因表达紊乱可导致非典型大脑功能。具体来说,自闭症谱系障碍(ASD)的特点是前核糖核酸(pre-mRNA)剪接异常。在自闭症谱系障碍患者的大脑中发现了异常的剪接模式,并且发现剪接因子的突变导致了与自闭症谱系障碍相关的神经发育迟缓。在此,我们回顾了一些研究,这些研究揭示了剪接在 ASD 中的重要性,探讨了剪接因子与 ASD 之间错综复杂的关系,揭示了前核糖核酸(pre-mRNA)剪接紊乱可能是 ASD 发病机制的基础。我们概述了与 ASD 相关的所有剪接因子的研究情况,并特别强调了五个已知会影响 ASD 相关基因剪接的特定剪接因子--HNRNPH2、NOVA2、WBP4、SRRM2 和 RBFOX1。在讨论受这些剪接因子影响的分子机制时,我们为深入了解 ASD 的复杂病因奠定了基础。最后,我们讨论了揭示剪接与 ASD 之间的联系对于开发更精确的诊断工具和有针对性的治疗干预措施的潜在益处。本文归类于疾病和发育中的 RNA > 疾病中的 RNA RNA 进化和基因组学 > RNA 和核糖核蛋白进化 RNA 进化和基因组学 > RNA 的计算分析 RNA 催化 > 剪接和翻译中的 RNA 催化。
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Wiley Interdisciplinary Reviews: RNA
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