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Assessment of different enrichment methods revealed the optimal approach to identify bovine circRnas. 对不同富集方法的评估揭示了识别牛 circRnas 的最佳方法。
IF 4.1 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-01 Epub Date: 2024-05-26 DOI: 10.1080/15476286.2024.2356334
Yixin Wang, Jian Wang, Robert J Gruninger, Tim A McAllister, Mingzhou Li, Le Luo Guan

Although circular RNAs (circRNAs) play important roles in regulating gene expression, the understanding of circRNAs in livestock animals is scarce due to the significant challenge to characterize them from a biological sample. In this study, we assessed the outcomes of bovine circRNA identification using six enrichment approaches with the combination of ribosomal RNAs removal (Ribo); linear RNAs degradation (R); linear RNAs and RNAs with structured 3' ends degradation (RTP); ribosomal RNAs coupled with linear RNAs elimination (Ribo-R); ribosomal RNA, linear RNAs and RNAs with poly (A) tailing elimination (Ribo-RP); and ribosomal RNA, linear RNAs and RNAs with structured 3' ends elimination (Ribo-RTP), respectively. RNA-sequencing analysis revealed that different approaches led to varied ratio of uniquely mapped reads, false-positive rate of identifying circRNAs, and the number of circRNAs per million clean reads (Padj <0.05). Out of 2,285 and 2,939 highly confident circRNAs identified in liver and rumen tissues, respectively, 308 and 260 were commonly identified from five methods, with Ribo-RTP method identified the highest number of circRNAs. Besides, 507 of 4,051 identified bovine highly confident circRNAs had shared splicing sites with human circRNAs. The findings from this work provide optimized methods to identify bovine circRNAs from cattle tissues for downstream research of their biological roles in cattle.

尽管环状 RNA(circRNA)在调控基因表达方面发挥着重要作用,但由于从生物样本中鉴定环状 RNA 所面临的巨大挑战,人们对家畜体内环状 RNA 的了解还很少。在这项研究中,我们使用六种富集方法,结合核糖体 RNAs 去除(Ribo)、线性 RNAs 降解(R)、线性 RNAs 和具有结构化 3' 末端的 RNAs 降解(RTP),评估了牛 circRNA 鉴定的结果;核糖体 RNA 与线性 RNAs 结合消除(Ribo-R);核糖体 RNA、线性 RNAs 和 RNAs 与聚(A)尾消除(Ribo-RP);核糖体 RNA、线性 RNAs 和 RNAs 与结构化 3'末端消除(Ribo-RTP)。RNA 测序分析表明,不同的方法会导致不同的唯一映射读数比率、识别 circRNA 的假阳性率以及每百万清晰读数的 circRNA 数量(Padj)。
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引用次数: 0
The catalytic activity of methyltransferase METTL15 is dispensable for its role in mitochondrial ribosome biogenesis. 甲基转移酶 METTL15 在线粒体核糖体生物发生过程中的作用离不开其催化活性。
IF 3.6 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 Epub Date: 2024-06-24 DOI: 10.1080/15476286.2024.2369374
Christian D Mutti, Lindsey Van Haute, Michal Minczuk

Ribosomes are large macromolecular complexes composed of both proteins and RNA, that require a plethora of factors and post-transcriptional modifications for their biogenesis. In human mitochondria, the ribosomal RNA is post-transcriptionally modified at ten sites. The N4-methylcytidine (m4C) methyltransferase, METTL15, modifies the 12S rRNA of the small subunit at position C1486. The enzyme is essential for mitochondrial protein synthesis and assembly of the mitoribosome small subunit, as shown here and by previous studies. Here, we demonstrate that the m4C modification is not required for small subunit biogenesis, indicating that the chaperone-like activity of the METTL15 protein itself is an essential component for mitoribosome biogenesis.

核糖体是由蛋白质和 RNA 组成的大分子复合体,其生物生成需要大量的因子和转录后修饰。在人类线粒体中,核糖体 RNA 经过十个位点的转录后修饰。N4-甲基胞嘧啶(m4C)甲基转移酶 METTL15 在 C1486 位修饰小亚基的 12S rRNA。如本文和之前的研究所示,该酶对线粒体蛋白质合成和 mitoribosome 小亚基的组装至关重要。在这里,我们证明了小亚基的生物发生不需要 m4C 修饰,这表明 METTL15 蛋白本身的类似伴侣的活性是 mitoribosome 生物发生的重要组成部分。
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引用次数: 0
Small molecule inhibition of RNA binding proteins in haematologic cancer. 小分子抑制血液肿瘤中的 RNA 结合蛋白。
IF 4.1 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-01 Epub Date: 2024-02-08 DOI: 10.1080/15476286.2024.2303558
Amit K Jaiswal, Michelle L Thaxton, Georgia M Scherer, Jacob P Sorrentino, Neil K Garg, Dinesh S Rao

In recent years, advances in biomedicine have revealed an important role for post-transcriptional mechanisms of gene expression regulation in pathologic conditions. In cancer in general and leukaemia specifically, RNA binding proteins have emerged as important regulator of RNA homoeostasis that are often dysregulated in the disease state. Having established the importance of these pathogenetic mechanisms, there have been a number of efforts to target RNA binding proteins using oligonucleotide-based strategies, as well as with small organic molecules. The field is at an exciting inflection point with the convergence of biomedical knowledge, small molecule screening strategies and improved chemical methods for synthesis and construction of sophisticated small molecules. Here, we review the mechanisms of post-transcriptional gene regulation, specifically in leukaemia, current small-molecule based efforts to target RNA binding proteins, and future prospects.

近年来,生物医学的进步揭示了转录后基因表达调控机制在病理状态下的重要作用。在癌症,特别是白血病中,RNA 结合蛋白已成为 RNA 平衡的重要调节因子,在疾病状态下往往会出现失调。在确定了这些致病机制的重要性之后,人们已经做出了许多努力,利用基于寡核苷酸的策略以及有机小分子来靶向 RNA 结合蛋白。随着生物医学知识、小分子筛选策略以及用于合成和构建复杂小分子的化学方法的改进,该领域正处于一个令人兴奋的拐点。在此,我们将回顾转录后基因调控(尤其是白血病)的机制、目前基于小分子靶向 RNA 结合蛋白的研究工作以及未来前景。
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引用次数: 0
Endogenous ZAP affects Zika virus RNA interactome. 内源性 ZAP 影响寨卡病毒 RNA 交互组。
IF 3.6 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-01-01 Epub Date: 2024-08-25 DOI: 10.1080/15476286.2024.2388911
Ahmad Jawad Sabir, Nguyen Phuong Khanh Le, Prince Pal Singh, Uladzimir Karniychuk

One of the most recent advances in the analysis of viral RNA-cellular protein interactions is the Comprehensive Identification of RNA-binding Proteins by Mass Spectrometry (ChIRP-MS). Here, we used ChIRP-MS in mock-infected and Zika-infected wild-type cells and cells knockout for the zinc finger CCCH-type antiviral protein 1 (ZAP). We characterized 'ZAP-independent' and 'ZAP-dependent' cellular protein interactomes associated with flavivirus RNA and found that ZAP affects cellular proteins associated with Zika virus RNA. The ZAP-dependent interactome identified with ChIRP-MS provides potential ZAP co-factors for antiviral activity against Zika virus and possibly other viruses. Identifying the full spectrum of ZAP co-factors and mechanisms of how they act will be critical to understanding the ZAP antiviral system and may contribute to the development of antivirals.

在分析病毒 RNA 与细胞蛋白相互作用方面的最新进展之一是利用质谱法(ChIRP-MS)全面鉴定 RNA 结合蛋白。在这里,我们在模拟感染和 Zika 感染的野生型细胞以及锌指 CCCH 型抗病毒蛋白 1 (ZAP) 基因敲除细胞中使用了 ChIRP-MS。我们鉴定了与黄病毒 RNA 相关的 "ZAP 依赖性 "和 "ZAP 非依赖性 "细胞蛋白相互作用组,发现 ZAP 会影响与寨卡病毒 RNA 相关的细胞蛋白。利用 ChIRP-MS 鉴定出的 ZAP 依赖性相互作用组提供了潜在的 ZAP 辅助因子,可用于抗击寨卡病毒和其他可能的病毒。全面鉴定 ZAP 辅助因子及其作用机制对了解 ZAP 抗病毒系统至关重要,并可能有助于开发抗病毒药物。
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引用次数: 0
Post-transcriptional capping generates coenzyme A-linked RNA. 转录后封顶产生辅酶a连接RNA。
IF 4.1 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-01 Epub Date: 2023-11-30 DOI: 10.1080/15476286.2023.2288740
Krishna Sapkota, Jordyn K Lucas, Jarrett W Faulkner, Matt F Lichte, Yan-Lin Guo, Donald H Burke, Faqing Huang

NAD can be inserted co-transcriptionally via non-canonical initiation to form NAD-RNA. However, that mechanism is unlikely for CoA-linked RNAs due to low intracellular concentration of the required initiator nucleotide, 3'-dephospho-CoA (dpCoA). We report here that phosphopantetheine adenylyltransferase (PPAT), an enzyme of CoA biosynthetic pathway, accepts RNA transcripts as its acceptor substrate and transfers 4'-phosphopantetheine to yield CoA-RNA post-transcriptionally. Synthetic natural (RNAI) and small artificial RNAs were used to identify the features of RNA that are needed for it to serve as PPAT substrate. RNAs with 4-10 unpaired nucleotides at the 5' terminus served as PPAT substrates, but RNAs having <4 unpaired nucleotides did not undergo capping. No capping was observed when the +1A was changed to G or when 5' triphosphate was removed by RNA pyrophosphohydrolase (RppH), suggesting the enzyme recognizes pppA-RNA as an ATP analog. PPAT binding affinities were equivalent for transcripts with +1A, +1 G, or 5'OH (+1A), indicating that productive enzymatic recognition is driven more by local positioning effects than by overall binding affinity. Capping rates were independent of the number of unpaired nucleotides in the range of 4-10 nucleotides. Capping was strongly inhibited by ATP, reducing CoA-RNA production ~70% when equimolar ATP and substrate RNA were present. Dual bacterial expression of candidate RNAs with different 5' structures followed by CoA-RNA CaptureSeq revealed 12-fold enrichment of the better PPAT substrate, consistent with in vivo CoA-capping of RNA transcripts by PPAT. These results suggest post-transcriptional RNA capping as a possible mechanism for the biogenesis of CoA-RNAs in bacteria.

NAD可以通过非规范起始共转录插入形成NAD- rna。然而,由于所需的启动核苷酸3'-去磷酸辅酶a (dpCoA)的细胞内浓度较低,因此这种机制不太可能用于辅酶a连接rna。我们报道了磷酸蚁氨酸腺苷转移酶(PPAT)是辅酶a生物合成途径的一种酶,它接受RNA转录物作为受体底物,并经转录后将4'-磷酸蚁氨酸转移产生辅酶a -RNA。合成天然RNA (RNAI)和小的人工RNA被用来鉴定作为PPAT底物所需的RNA的特征。在5'端具有4-10个未配对核苷酸的RNA作为PPAT底物,但在体内具有coa盖顶的RNA转录物被PPAT盖顶。这些结果表明转录后RNA盖帽可能是细菌中辅酶a -RNA生物发生的一种机制。
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引用次数: 0
Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance. 非酒精性脂肪肝中的环状 RNA:功能和临床意义
IF 4.1 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-01 Epub Date: 2023-12-19 DOI: 10.1080/15476286.2023.2290769
Qingmin Zeng, Chang-Hai Liu, Javier Ampuero, Dongbo Wu, Wei Jiang, Lingyun Zhou, Hong Li, Lang Bai, Manuel Romero-Gómez, Hong Tang

Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global population, is an urgent health issue leading to various metabolic comorbidities. Circular RNAs (circRNAs), covalently closed RNA molecules, are characterized by ubiquity, diversity, stability, and conservatism. Indeed, they participate in various biological processes via distinct mechanisms that could modify the natural history of NAFLD. In this review, we briefly introduce the biogenesis, characteristics, and biological functions of circRNAs. Furthermore, we summarize circRNAs expression profiles in NAFLD by intersecting seven sequencing data sets and describe the cellular roles of circRNAs and their potential advantages as biomarkers of NAFLD. In addition, we emphatically discuss the exosomal non-coding RNA sorting mechanisms and possible functions in recipient cells. Finally, we extensively discuss the potential application of targeting disease-related circRNAs and competing endogenous RNA networks through gain-of-function and loss-of-function approaches in targeted therapy of NAFLD.

非酒精性脂肪肝(NAFLD)影响着全球约 25% 的人口,是一个亟待解决的健康问题,会导致各种代谢并发症。环状 RNA(circRNA)是共价封闭的 RNA 分子,具有普遍性、多样性、稳定性和保守性等特点。事实上,它们通过不同的机制参与各种生物过程,可改变非酒精性脂肪肝的自然病史。在这篇综述中,我们简要介绍了 circRNA 的生物发生、特点和生物学功能。此外,我们还通过交叉七组测序数据总结了非酒精性脂肪肝中 circRNAs 的表达谱,并描述了 circRNAs 的细胞作用及其作为非酒精性脂肪肝生物标志物的潜在优势。此外,我们还着重讨论了外泌体非编码 RNA 的分选机制以及在受体细胞中可能发挥的功能。最后,我们广泛讨论了在非酒精性脂肪肝的靶向治疗中,通过功能增益和功能缺失方法靶向疾病相关的 circRNA 和竞争性内源性 RNA 网络的潜在应用。
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引用次数: 0
Structure and function of the pseudouridine 5'-monophosphate glycosylase PUMY from Arabidopsis thaliana. 拟南芥中假尿苷-5'-单磷酸糖基化酶 PUMY 的结构和功能。
IF 4.1 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-01 Epub Date: 2023-12-20 DOI: 10.1080/15476286.2023.2293340
Jeongyun Lee, Sang-Hoon Kim, Sangkee Rhee

Pseudouridine is a noncanonical C-nucleoside containing a C-C glycosidic linkage between uracil and ribose. In the two-step degradation of pseudouridine, pseudouridine 5'-monophosphate glycosylase (PUMY) is responsible for the second step and catalyses the cleavage of the C-C glycosidic bond in pseudouridine 5'-monophosphate (ΨMP) into uridine and ribose 5'-phosphate, which are recycled via other metabolic pathways. Structural features of Escherichia coli PUMY have been reported, but the details of the substrate specificity of ΨMP were unknown. Here, we present three crystal structures of Arabidopsis thaliana PUMY in different ligation states and a kinetic analysis of ΨMP degradation. The results indicate that Thr149 and Asn308, which are conserved in the PUMY family, are structural determinants for recognizing the nucleobase of ΨMP. The distinct binding modes of ΨMP and ribose 5'-phosphate also suggest that the nucleobase, rather than the phosphate group, of ΨMP dictates the substrate-binding mode. An open-to-close transition of the active site is essential for catalysis, which is mediated by two α-helices, α11 and α12, near the active site. Mutational analysis validates the proposed roles of the active site residues in catalysis. Our structural and functional analyses provide further insight into the enzymatic features of PUMY towards ΨMP.

伪尿嘧啶是一种非典型的 C 核苷,含有尿嘧啶和核糖之间的 C-C 糖苷键。在假尿苷的两步降解过程中,假尿嘧啶-5'-单磷酸糖基化酶(PUMY)负责第二步,催化假尿嘧啶-5'-单磷酸(ΨMP)中的 C-C 糖苷键裂解为尿苷和核糖-5'-磷酸,并通过其他代谢途径循环利用。已有关于大肠杆菌 PUMY 结构特征的报道,但ΨMP 底物特异性的细节尚不清楚。在这里,我们展示了拟南芥 PUMY 在不同连接状态下的三个晶体结构以及ΨMP 降解的动力学分析。结果表明,在 PUMY 家族中保守的 Thr149 和 Asn308 是识别 ΨMP 核碱基的结构决定因素。ΨMP与核糖-5'-磷酸的不同结合模式也表明,ΨMP的核碱基而不是磷酸基决定了底物的结合模式。活性位点从开放到封闭的转变是催化所必需的,这种转变是由活性位点附近的两个α-螺旋(α11 和 α12)介导的。突变分析验证了活性位点残基在催化作用中的作用。我们的结构和功能分析进一步揭示了 PUMY 对 ΨMP 的酶学特征。
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引用次数: 0
Epitranscriptomic regulation in fasting hearts: implications for cardiac health. 空腹心脏的表转录组调控:对心脏健康的影响。
IF 4.1 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-01 Epub Date: 2024-02-07 DOI: 10.1080/15476286.2024.2307732
Daniel Benak, Kristyna Holzerova, Jaroslav Hrdlicka, Frantisek Kolar, Mark Olsen, Mati Karelson, Marketa Hlavackova

Cardiac tolerance to ischaemia can be increased by dietary interventions such as fasting, which is associated with significant changes in myocardial gene expression. Among the possible mechanisms of how gene expression may be altered are epigenetic modifications of RNA - epitranscriptomics. N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) are two of the most prevalent modifications in mRNA. These methylations are reversible and regulated by proteins called writers, erasers, readers, and m6A-repelled proteins. We analysed 33 of these epitranscriptomic regulators in rat hearts after cardioprotective 3-day fasting using RT-qPCR, Western blot, and targeted proteomic analysis. We found that the most of these regulators were changed on mRNA or protein levels in fasting hearts, including up-regulation of both demethylases - FTO and ALKBH5. In accordance, decreased methylation (m6A+m6Am) levels were detected in cardiac total RNA after fasting. We also identified altered methylation levels in Nox4 and Hdac1 transcripts, both of which play a role in the cytoprotective action of ketone bodies produced during fasting. Furthermore, we investigated the impact of inhibiting demethylases ALKBH5 and FTO in adult rat primary cardiomyocytes (AVCMs). Our findings indicate that inhibiting these demethylases reduced the hypoxic tolerance of AVCMs isolated from fasting rats. This study showed that the complex epitranscriptomic machinery around m6A and m6Am modifications is regulated in the fasting hearts and might play an important role in cardiac adaptation to fasting, a well-known cardioprotective intervention.

禁食等饮食干预措施可增强心脏对缺血的耐受性,而禁食与心肌基因表达的显著变化有关。改变基因表达的可能机制包括 RNA 的表观遗传修饰--表转录组学。N6-甲基腺苷(m6A)和 N6,2'-O-二甲基腺苷(m6Am)是 mRNA 中最常见的两种修饰。这些甲基化是可逆的,并由称为写入蛋白、擦除蛋白、读取蛋白和 m6A 清除蛋白的蛋白质调控。我们使用 RT-qPCR、Western 印迹和靶向蛋白质组分析方法分析了大鼠心脏在禁食 3 天后的 33 种表转录调节因子。我们发现,在禁食的心脏中,这些调节因子大多在 mRNA 或蛋白质水平上发生了变化,包括 FTO 和 ALKBH5 这两种去甲基化酶的上调。相应地,禁食后在心脏总核糖核酸中检测到甲基化(m6A+m6Am)水平下降。我们还发现 Nox4 和 Hdac1 转录本中的甲基化水平发生了变化,这两种物质在禁食期间产生的酮体的细胞保护作用中发挥作用。此外,我们还研究了抑制脱甲基酶 ALKBH5 和 FTO 对成年大鼠原代心肌细胞(AVCMs)的影响。我们的研究结果表明,抑制这些去甲基化酶会降低从禁食大鼠中分离出来的原代大鼠心肌细胞的缺氧耐受性。这项研究表明,围绕 m6A 和 m6Am 修饰的复杂表转录组机制在禁食心脏中受到调控,并可能在心脏适应禁食(一种众所周知的心脏保护干预措施)过程中发挥重要作用。
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引用次数: 0
An elusive debate on the evidence for RNA editing in SARS-CoV-2. 关于 SARS-CoV-2 中 RNA 编辑证据的一场难以捉摸的辩论。
IF 4.1 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-01 Epub Date: 2024-03-01 DOI: 10.1080/15476286.2024.2321032
Giorgio Mattiuz, Salvatore Di Giorgio, Silvestro G Conticello
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引用次数: 0
Ordering events in a developing genetic code. 发育中遗传密码的排序事件
IF 4.1 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-01 Epub Date: 2024-01-03 DOI: 10.1080/15476286.2023.2299615
Michael Yarus

Preexisting partial genetic codes can fuse to evolve towards the complete Standard Genetic Code (SGC). Such code fusion provides a path of 'least selection', readily generating precursor codes that resemble the SGC. Consequently, such least selections produce the SGC via minimal, thus rapid, change. Optimal code evolution therefore requires delayed wobble. Early wobble encoding slows code evolution, very specifically diminishing the most likely SGC precursors: near-complete, accurate codes which are the products of code fusions. In contrast: given delayed wobble, the SGC can emerge from a truncation selection/evolutionary radiation based on proficient fused coding.

已有的部分遗传密码可以融合进化成完整的标准遗传密码(SGC)。这种代码融合提供了一种 "最少选择 "的途径,很容易产生与 SGC 相似的前体代码。因此,这种 "最少选择 "可以通过最小的变化,也就是快速变化产生 SGC。因此,最佳的代码进化需要延迟的摇摆。早期摇摆编码会减慢代码进化的速度,特别是会减少最有可能的 SGC 前体:近乎完整、准确的代码,它们是代码融合的产物。与此相反的是:在延迟摇摆的情况下,SGC 可以从基于熟练融合编码的截断选择/进化辐射中产生。
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引用次数: 0
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RNA Biology
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