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Dai, Chenyue, Bing Liu, Shaolei Li, Yang Hong, Jiahui Si, Ying Xiong, Nan Wu, and Yuanyuan Ma. "Construction of a circRNA-miRNA-mRNA Regulated Pathway Involved in EGFR-TKI Lung Adenocarcinoma Resistance." Technology in Cancer Research & Treatment 20 (January 2021): 153303382110568. http://dx.doi.org/10.1177/15330338211056809.
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Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors are widely used for lung epidermal growth factor receptor-positive lung adenocarcinomas, but acquired resistance is inevitable. Although non-coding RNAs, such as circular RNA and microRNA, are known to play vital roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance, comprehensive analysis is lacking. Thus, this study aimed to explore the circular RNA-microRNA-messenger RNA regulatory network involved in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. Methods: To identify differentially expressed genes between the epidermal growth factor receptor-tyrosine kinase inhibitor sensitive cell line PC9 and resistant cell line PC9/ epidermal growth factor receptor-tyrosine kinase inhibitor resistance(PC9/ER), circular RNA, microRNA and messenger RNA microarrays were performed. Candidates were then identified to construct a circular RNA-microRNA-messenger RNA network using bioinformatics. Additionally, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to evaluate the network messenger RNA, setting up a protein-protein interaction network for hub-gene identification. Afterwards, RNA immunoprecipitation was performed to enrich microRNA, and quantitative real-time PCR was used to estimated gene expression levels. Results: In total, 603, 377, and 1863 differentially expressed circular RNA, microRNA, messenger RNAs, respectively, were identified using microarray analysis, constructing a circular RNA-microRNA-messenger RNA network containing 18 circular RNAs, 17 microRNAs and 175 messenger RNAs. Moreover, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the most enriched biological process terms and pathways were related to epidermal growth factor receptor-tyrosine kinase inhibitor resistance, including Wnt and Hippo signaling pathways. Based on the competing endogenous RNA and protein-protein interaction network, circ-0007312 was showed to interact with miR-764 and both circ-0003748 and circ-0001398 were shown to interact with miR-628; both these microRNAs targeted MAPK1. Furthermore, circ-0007312, circ-0003748, circ-0001398, and MAPK1 were up-regulated, whereas miR-764 and miR-628 were downregulated in PC9/ER cells as compared to parental PC9 cells. We also found that circ-0007312 and miR-764 were positively expressed in plasma. Conclusions: Our original study associated with mechanism of target therapy in lung cancer provided a systematic and comprehensive regulation of circular RNA, microRNA and messenger RNA in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. It was found that circ-0007312- miR-764-MAPK1, circ-0003748-miR-628-MAPK1, and circ-0001398-miR-628-MAPK1 axis may play key roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance.
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Peng, Ziqi, Boyang Xu, and Feng Jin. "Circular RNA hsa_circ_0000376 Participates in Tumorigenesis of Breast Cancer by Targeting miR-1285-3p." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382092847. http://dx.doi.org/10.1177/1533033820928471.
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This study was designed to identify novel circular RNAs and the related regulatory axis to provide research targets for the diagnosis and treatment of breast cancer. The circular RNA expression microarray “GSE101123” related to breast cancer was downloaded from the Gene Expression Omnibus database. The differentially expressed circular RNAs between tumor and normal samples were screened using Limma package. The targeted microRNAs of the differentially expressed circular RNAs and the targeted messenger RNAs of the microRNAs were predicted using miRanda and miRWalk, respectively, and a circular RNAs–microRNAs–messenger RNAs network was constructed. Then, functional enrichment analysis, protein–protein interaction network construction, and drug–gene interaction analysis were conducted for the messenger RNAs. A total of 11 differentially expressed circular RNAs were identified between the breast cancer and normal samples, of which 3 were upregulated, while 8 were downregulated. The circular RNA–microRNA–messenger RNA network contained 1 circular RNA (hsa_circ_0000376), 2 microRNAs (miR-1285-3p and miR-1286), and 353 messenger RNAs. The protein–protein interaction network contained 150 nodes and 240 interactions. The hub genes in the protein–protein interaction network were all targeted messenger RNAs of miR-1285-3p that were significantly enriched in the ubiquitin–proteasome system, apoptosis, cell cycle arrest–related pathways, and cancer-related pathways involving SMAD specific E3 ubiquitin protein ligase 1, β-transducin repeat containing E3 ubiquitin protein ligase, tumor protein P53 among others. Twenty-two drugs were predicted to target 4 messenger RNAs, including tumor protein P53. A novel circular RNA, hsa_circ_0000376, was identified in breast cancer that may act as a sponge targeting miR-1285-3p expression which through its target genes, SMURF1, BTRC, and TP53, may further regulate tumorigenesis.
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Begliarzade, S. A., R. I. Tamrazov, E. R. Musaev, and C. Wang. "Circular RNA Expression Profile in Cervical Cancer and Construction of the Circular RNA‑MicroRNA‑Messenger RNA Regulatory Network." Creative surgery and oncology 14, no. 2 (July 5, 2024): 116–26. http://dx.doi.org/10.24060/2076-3093-2024-14-2-116-126.
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Introduction. Cervical cancer (CC) remains the most common cancer in women worldwide. However, effective and specific biomarkers for the diagnosis and prognosis of cervical cancer are yet to be found. In recent years, the potential of circular RNAs (circRNAs) as new diagnostic, prognostic and therapeutic tools has received much attention. The current study involved an in-depth bioinformatics research to explore the circRNA-microRNA (miRNA)-messenger RNA (mRNA) regulatory network in order to identify important molecular processes and biological pathways supposedly associated with CC. Materials and methods. The study collected data on the expression of circRNA (GSE102686), miRNA (GSE30656) and mRNA of target genes (GSE9750), based on the Gene Expression Omnibus (GEO) database, in squamous cell carcinoma of the cervix samples and normal squamous epithelium of the cervix, dividing them into study and control groups. Protein-protein interaction (PPI), Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to further understand the function of circRNAs for their target genes. Results. A total of 105 differentially expressed circular RNAs (DECs), 144 differentially expressed microRNAs (DEMs), and 539 differentially expressed target genes (DEGs) were identified for cervical cancer. Concurrently, functional enrichment analysis of GO and KEGG pathways was performed for DEGs. Subsequently, searching databases for circRNA, miRNA and mRNA target genes, as well as PPI network analysis and functional enrichment revealed 3 DECs with significantly high expression levels (hsa_circ_0000745, hsa_circ_0084927 and hsa_circ_0002762), 6 DEMs with reduced expression levels (hsa -miR-145, hsa-miR-876-3p, hsa-miR-1229, hsa-miR-182, hsa-miR-520h and hsa-miR-1252) and 9 key genes such as ANGPT2, COL11A1, MEST, KIF20A, CLN6, FNDC3B, USP18, DLGAP5 and CXCL9, suggesting a potentially significant role in cervical cancer. Conclusion.Understanding the circRNA-miRNA-mRNA regulatory network is of great importance for evaluating the oncogenesis of CC, as well as discoverying new circRNAs as the main regulatory molecules in this network. This is considered to be a new direction in the diagnosis and targeted therapy of cervical cancer.
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Xia, Bing, Tao Hong, Xin He, Xinlan Hu, and Yongbo Gao. "A circular RNA derived from MMP9 facilitates oral squamous cell carcinoma metastasis through regulation of MMP9 mRNA stability." Cell Transplantation 28, no. 12 (September 11, 2019): 1614–23. http://dx.doi.org/10.1177/0963689719875409.
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Emerging evidence demonstrates that dysregulation of circular RNA is linked to tumorigenesis and aggressive progression. However, its role in oral squamous cell carcinoma remains largely uncharacterized. In this study, we identified a novel metastasis-associated circular RNA, circular matrix metalloproteinase 9 (hsa_circ_0001162, a circular RNA derived from matrix metalloproteinase 9), which was remarkably upregulated in oral squamous cell carcinoma and positively correlated with matrix metalloproteinase 9 expression. Patients with high circular matrix metalloproteinase 9 expression were prone to lymph node metastasis and an advanced TNM stage. Importantly, circular matrix metalloproteinase 9 was identified as an efficacious diagnostic and prognostic biomarker for oral squamous cell carcinoma patients. Functional experiments showed that depletion of circular matrix metalloproteinase 9 weakened the migratory and invasive capabilities of oral squamous cell carcinoma cells in vitro as well as inhibited lung metastasis in vivo. Regarding the mechanism, circular matrix metalloproteinase 9 could simultaneously interact with AUF1 and miR-149 to block the inhibitory effect of AUF1 and miR-149 on matrix metalloproteinase 9 3′-untranslated region, resulting in enhanced matrix metalloproteinase 9 messenger RNA stability, thereby facilitating oral squamous cell carcinoma metastasis. Collectively, our data indicate that circular matrix metalloproteinase 9 acts as a metastasis-promoting gene in oral squamous cell carcinoma through regulating the messenger RNA stability of its parental gene. Therapeutic targeting of circular matrix metalloproteinase 9 may be a promising treatment intervention for metastatic oral squamous cell carcinoma patients.
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Liu, Tao, Guoru Zhang, Yaling Wang, Mingyue Rao, Yang Zhang, Anjun Guo, Mei Wang, and Cheng-I. Cheng. "Identification of Circular RNA-MicroRNA-Messenger RNA Regulatory Network in Atrial Fibrillation by Integrated Analysis." BioMed Research International 2020 (September 29, 2020): 1–13. http://dx.doi.org/10.1155/2020/8037273.
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Background. Circular RNA (circRNA) is a noncoding RNA that forms a closed-loop structure, and its abnormal expression may cause disease. We aimed to find potential network for circRNA-related competitive endogenous RNA (ceRNA) in atrial fibrillation (AF). Methods. The circRNA, miRNA, and mRNA expression profiles in the heart tissue from AF patients were retrieved from the Gene Expression Omnibus database and analyzed comprehensively. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were identified, followed by the establishment of DEcircRNA-DEmiRNA-DEmRNA regulatory network. Functional annotation analysis of host gene of DEcircRNAs and DEmRNAs in ceRNA regulatory network was performed. In vitro experiment and electronic validation were used to validate the expression of DEcircRNAs, DEmiRNAs, and DEmRNAs. Results. A total of 1611 DEcircRNAs, 51 DEmiRNAs, and 1250 DEmRNAs were identified in AF. The DEcircRNA-DEmiRNA-DEmRNA network contained 62 circRNAs, 14 miRNAs, and 728 mRNAs. Among which, two ceRNA regulatory pairs of hsa-circRNA-100053-hsa-miR-455-5p-TRPV1 and hsa-circRNA-005843-hsa-miR-188-5p-SPON1 were identified. In addition, six miRNA-mRNA regulatory pairs including hsa-miR-34c-5p-INMT, hsa-miR-1253-DDIT4L, hsa-miR-508-5p-SMOC2, hsa-miR-943-ACTA1, hsa-miR-338-3p-WIPI1, and hsa-miR-199a-3p-RAP1GAP2 were also obtained. MTOR was a significantly enriched signaling pathway of host gene of DEcircRNAs. In addition, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy were remarkably enriched signaling pathways of DEmRNAs in DEcircRNA-DEmiRNA-DEmRNA regulatory network. The expression validation of hsa-circRNA-402565, hsa-miR-34c-5p, hsa-miR-188-5p, SPON1, DDIT4L, SMOC2, and WIPI1 was consistent with the integrated analysis. Conclusion. We speculated that hsa-circRNA-100053-hsa-miR-455-5p-TRPV1 and hsa-circRNA-005843-hsa-miR-188-5p-SPON1 interaction pairs may be involved in AF.
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Sun, Xiangjun, Xinfeng Ge, Zhiyong Xu, and Dongfeng Chen. "Identification of circular RNA–microRNA–messenger RNA regulatory network in hepatocellular carcinoma by integrated analysis." Journal of Gastroenterology and Hepatology 35, no. 1 (July 18, 2019): 157–64. http://dx.doi.org/10.1111/jgh.14762.
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Rostain, William, Shensi Shen, Teresa Cordero, Guillermo Rodrigo, and Alfonso Jaramillo. "Engineering a Circular Riboregulator in Escherichia coli." BioDesign Research 2020 (September 14, 2020): 1–9. http://dx.doi.org/10.34133/2020/1916789.
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RNAs of different shapes and sizes, natural or synthetic, can regulate gene expression in prokaryotes and eukaryotes. Circular RNAs have recently appeared to be more widespread than previously thought, but their role in prokaryotes remains elusive. Here, by inserting a riboregulatory sequence within a group I permuted intron-exon ribozyme, we created a small noncoding RNA that self-splices to produce a circular riboregulator in Escherichia coli. We showed that the resulting riboregulator can trans-activate gene expression by interacting with a cis-repressed messenger RNA. We characterized the system with a fluorescent reporter and with an antibiotic resistance marker, and we modeled this novel posttranscriptional mechanism. This first reported example of a circular RNA regulating gene expression in E. coli adds to an increasing repertoire of RNA synthetic biology parts, and it highlights that topological molecules can play a role in the case of prokaryotic regulation.
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Song, Yan, Ning Hu, Xiaowei Song, and Juhong Yang. "Hsa_Circ_0007841 Enhances Multiple Myeloma Chemotherapy Resistance Through Upregulating ABCG2." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382092837. http://dx.doi.org/10.1177/1533033820928371.
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The current researches have reported that circular RNA is an important regulatory factor in the progression of various human disease. However, the function and mechanism of most circular RNAs remain unknown in cancers including multiple myeloma. Our study has confirmed that hsa_circ_0007841 is up regulated in U266 doxorubicin resistant cells (U266R) and 8226 doxorubicin resistant cells (8226R) compared to U266 parent cells (U266P) and 8226 parent cells (8226P). Silence of hsa_circ_0007841 in U266R and 8226R could reduce the half-maximal inhibitory concentration which indicated reduction in chemoresistance. In doxorubicin resistant cells, the messenger RNA and protein level of ATP-binding cassette transporters G2 increased. Silence of hsa_circ_0007841 in drug resistant cells could decrease both the messenger RNA and protein levels of ATP-binding cassette transporters G2; reexpression of hsa_circ_0007841 could block the reduction. However, overexpression of hsa_circ_0007841 could effectively upregulate the ATP-binding cassette transporters G2 messenger RNA and protein level. Inhibition of ATP-binding cassette transporters G2 could block hsa_circ_0007841 overexpression induced chemoresistance in U266P and 8226P cells. What’s more, inhibition of ATP-binding cassette transporters G2 could reduce differences of half-maximal inhibitory concentration between parent cell lines and drug-resistant cell lines. Our data collectively suggest a new model in which hsa_circ_0007841 promotes acquired chemotherapy resistance by upregulating ATP-binding cassette transporters G2 providing a novel molecular basis of chemotherapy in multiple myeloma cancer.
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Zhou, Wenshuo, Linglei Jiang, Shimiao Liao, Feifei Wu, Guohuan Yang, Li Hou, Lan Liu, Xinping Pan, William Jia, and Yuntao Zhang. "Vaccines’ New Era-RNA Vaccine." Viruses 15, no. 8 (August 18, 2023): 1760. http://dx.doi.org/10.3390/v15081760.
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RNA vaccines, including conventional messenger RNA (mRNA) vaccines, circular RNA (circRNA) vaccines, and self-amplifying RNA (saRNA) vaccines, have ushered in a promising future and revolutionized vaccine development. The success of mRNA vaccines in combating the COVID-19 pandemic caused by the SARS-CoV-2 virus that emerged in 2019 has highlighted the potential of RNA vaccines. These vaccines possess several advantages, such as high efficacy, adaptability, simplicity in antigen design, and the ability to induce both humoral and cellular immunity. They also offer rapid and cost-effective manufacturing, flexibility to target emerging or mutant pathogens and a potential approach for clearing immunotolerant microbes by targeting bacterial or parasitic survival mechanisms. The self-adjuvant effect of mRNA-lipid nanoparticle (LNP) formulations or circular RNA further enhances the potential of RNA vaccines. However, some challenges need to be addressed. These include the technology’s immaturity, high research expenses, limited duration of antibody response, mRNA instability, low efficiency of circRNA cyclization, and the production of double-stranded RNA as a side product. These factors hinder the widespread adoption and utilization of RNA vaccines, particularly in developing countries. This review provides a comprehensive overview of mRNA, circRNA, and saRNA vaccines for infectious diseases while also discussing their development, current applications, and challenges.
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Rybak-Wolf, Agnieszka, and Mireya Plass. "RNA Dynamics in Alzheimer’s Disease." Molecules 26, no. 17 (August 24, 2021): 5113. http://dx.doi.org/10.3390/molecules26175113.
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Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance of specific RNA species are linked to the pathology of AD.
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Aquilina-Reid, Chiara, Samuel Brennan, Ashton Curry-Hyde, Guus M. Teunisse, and Michael Janitz. "Circular RNA Expression and Interaction Patterns Are Perturbed in Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 23, no. 23 (November 24, 2022): 14665. http://dx.doi.org/10.3390/ijms232314665.
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Circular RNAs (circRNAs) are a type of long noncoding RNA that are highly abundant and highly conserved throughout evolution and exhibit differential expression patterns in various tissue types in multiple diseases, including amyotrophic lateral sclerosis (ALS). The most well-known function of circRNAs is their ability to act as microRNA (miRNA) sponges. This entails circRNA binding to miRNA, which would otherwise target and degrade messenger RNA, thus affecting gene expression. This study analyzed ALS patient samples from three spinal cord regions to investigate circular transcriptome perturbation and circular RNA–microRNA–mRNA interactions. Using stringent statistical parameters, we identified 92 differentially expressed circRNAs across the spinal cord tissues with the aim of identifying specific circRNAs with biomarker potential. We also found evidence for differential expression of 37 linear RNAs possibly due to miRNA sequestration by circRNAs, thus revealing their potential as novel biomarkers and therapeutic candidates for ALS.
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Gao, Mengjia, Jingxin Xin, Xiaoling Li, Ling Gao, Shanshan Shao, and Meng Zhao. "Differential Expression Profiles of mRNA and Noncoding RNA and Analysis of Competitive Endogenous RNA Regulatory Networks in Nonalcoholic Steatohepatitis." Gastroenterology Research and Practice 2022 (July 7, 2022): 1–13. http://dx.doi.org/10.1155/2022/3200932.
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Nonalcoholic steatohepatitis (NASH) is a liver disease caused by multiple factors, and there is no approved pharmacotherapy. The pathogenesis of NASH remains underexplored. In this study, differentially expressed circular RNAs (circRNAs) were obtained by analyzing NASH-related circRNA datasets, and then, corresponding target microRNAs (miRNAs) and messenger RNAs (mRNAs) were predicted to construct a circRNA–miRNA–mRNA regulatory network. On this basis, a total of 38 circRNAs, 7 miRNAs, and 10 mRNAs were screened out. The present study reveals novel circRNA biomarkers of NASH and reports a potential competing endogenous RNA (ceRNA) regulatory network that might provide insights for further investigation into the underlying pathogenesis of NASH.
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Ward, Zoe, Sebastian Schmeier, John Pearson, Vicky A. Cameron, Chris M. Frampton, Richard W. Troughton, Rob N. Doughty, A. Mark Richards, and Anna P. Pilbrow. "Identifying Candidate Circulating RNA Markers for Coronary Artery Disease by Deep RNA-Sequencing in Human Plasma." Cells 11, no. 20 (October 11, 2022): 3191. http://dx.doi.org/10.3390/cells11203191.
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Advances in RNA sequencing (RNA-Seq) have facilitated transcriptomic analysis of plasma for the discovery of new diagnostic and prognostic markers for disease. We aimed to develop a short-read RNA-Seq protocol to detect mRNAs, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in plasma for the discovery of novel markers for coronary artery disease (CAD) and heart failure (HF). Circulating cell-free RNA from 59 patients with stable CAD (half of whom developed HF within 3 years) and 30 controls was sequenced to a median depth of 108 paired reads per sample. We identified fragments from 3986 messenger RNAs (mRNAs), 164 long non-coding RNAs (lncRNAs), 405 putative novel lncRNAs and 227 circular RNAs in plasma. Circulating levels of 160 mRNAs, 10 lncRNAs and 2 putative novel lncRNAs were altered in patients compared with controls (absolute fold change >1.2, p < 0.01 adjusted for multiple comparisons). The most differentially abundant transcripts were enriched in mRNAs encoded by the mitochondrial genome. We did not detect any differences in the plasma RNA profile between patients who developed HF compared with those who did not. In summary, we show that mRNAs, lncRNAs and circular RNAs can be reliably detected in plasma by deep RNA-Seq. Multiple coding and non-coding transcripts were altered in association with CAD, including several mitochondrial mRNAs, which may indicate underlying myocardial ischaemia and oxidative stress. If validated, circulating levels of these transcripts could potentially be used to help identify asymptomatic individuals with established CAD prior to an acute coronary event.
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Kabzinski, Jacek, Aleksandra Kucharska-Lusina, and Ireneusz Majsterek. "RNA-Based Liquid Biopsy in Head and Neck Cancer." Cells 12, no. 14 (July 23, 2023): 1916. http://dx.doi.org/10.3390/cells12141916.
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Head and neck cancer (HNC) is a prevalent and diverse group of malignancies with substantial morbidity and mortality rates. Early detection and monitoring of HNC are crucial for improving patient outcomes. Liquid biopsy, a non-invasive diagnostic approach, has emerged as a promising tool for cancer detection and monitoring. In this article, we review the application of RNA-based liquid biopsy in HNC. Various types of RNA, including messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA (lncRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), circular RNA (circRNA) and PIWI-interacting RNA (piRNA), are explored as potential biomarkers in HNC liquid-based diagnostics. The roles of RNAs in HNC diagnosis, metastasis, tumor resistance to radio and chemotherapy, and overall prognosis are discussed. RNA-based liquid biopsy holds great promise for the early detection, prognosis, and personalized treatment of HNC. Further research and validation are necessary to translate these findings into clinical practice and improve patient outcomes.
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Li, Yongwen, Ruifeng Shi, Guangsheng Zhu, Chen Chen, Hua Huang, Min Gao, Songlin Xu, et al. "Construction of a circular RNA – microRNA –messenger RNA regulatory network of hsa_circ_0043256 in lung cancer by integrated analysis." Thoracic Cancer 13, no. 1 (November 21, 2021): 61–75. http://dx.doi.org/10.1111/1759-7714.14226.
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Zhu, Zirui, Rui Huang, and Baojun Huang. "Predicting functional circular RNA-based competitive endogenous RNA network in gastric carcinoma using novel bioinformatics analysis." Experimental Biology and Medicine 247, no. 2 (October 7, 2021): 131–44. http://dx.doi.org/10.1177/15353702211048757.
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Gastric cancer (GC) remains one of the most prevalent types of malignancies worldwide, and also one of the most reported lethal tumor-related diseases. Circular RNAs (circRNAs) have been certified to be trapped in multiple aspects of GC pathogenesis. Yet, the mechanism of this regulation is mostly undefined. This research is designed to discover the vital circRNA-microRNA (miRNA)-messenger RNA (mRNA) regulatory network in GC. Expression profiles with diverse levels including circRNAs, miRNAs, and mRNAs were all determined using microarray public datasets from Gene Expression Ominous (GEO). The differential circRNAs expressions were recognized against the published robust rank aggregation algorithm. Besides, a circRNA-based competitive endogenous RNA (ceRNA) interaction network was visualized via Cytoscape software (version 3.8.0). Functional and pathway enrichment analysis associated with differentially expressed targeted mRNAs were conducted using Cytoscape and an online bioinformatics database. Furthermore, an interconnected protein–protein interaction association network which consisted of 51 mRNAs was predicted, and hub genes were screened using STRING and CytoHubba. Then, several hub genes were chosen to explore their expression associated with survival rate and clinical stage in GEPIA and Kaplan-Meier Plotter databases. Finally, a carefully designed circRNA-related ceRNA regulatory subnetwork including four circRNAs, six miRNAs, and eight key hub genes was structured using the online bioinformatics tool.
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Owens, Robert A., Kimberly B. Tech, Jonathan Y. Shao, Teruo Sano, and C. Jacyn Baker. "Global Analysis of Tomato Gene Expression During Potato spindle tuber viroid Infection Reveals a Complex Array of Changes Affecting Hormone Signaling." Molecular Plant-Microbe Interactions® 25, no. 4 (April 2012): 582–98. http://dx.doi.org/10.1094/mpmi-09-11-0258.
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Viroids like Potato spindle tuber viroid (PSTVd) are the smallest known agents of infectious disease—small, highly structured, circular RNA molecules that lack detectable messenger RNA activity, yet are able to replicate autonomously in susceptible plant species. To better understand the possible role of RNA silencing in disease induction, a combination of microarray analysis and large-scale RNA sequence analysis was used to compare changes in tomato gene expression and microRNA levels associated with PSTVd infection in two tomato cultivars plus a third transformed line expressing small PSTVd small interfering RNAs in the absence of viroid replication. Changes in messenger (m)RNA levels for the sensitive cultivar ‘Rutgers’ were extensive, involving more than half of the approximately 10,000 genes present on the array. Chloroplast biogenesis was down-regulated in both sensitive and tolerant cultivars, and effects on mRNAs encoding enzymes involved in the biosynthesis of gibberellin and other hormones were accompanied by numerous changes affecting their respective signaling pathways. In the dwarf cultivar ‘MicroTom’, a marked upregulation of genes involved in response to stress and other stimuli was observed only when exogenous brassinosteroid was applied to infected plants, thereby providing the first evidence for the involvement of brassinosteroid-mediated signaling in viroid disease induction.
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Harland, R., and L. Misher. "Stability of RNA in developing Xenopus embryos and identification of a destabilizing sequence in TFIIIA messenger RNA." Development 102, no. 4 (April 1, 1988): 837–52. http://dx.doi.org/10.1242/dev.102.4.837.
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Synthetic capped RNA transcripts injected into fertilized eggs of Xenopus laevis have a half-life of 3–4 h. Addition of a long (approximately 200 nucleotide) poly(A) tail increases the half-life to 6–8 h which approaches the half-life of natural polyadenylated globin RNA injected into embryos. Since exonucleolytic action alone could account for the degradation of RNA, we tested whether circular RNA is stable after injection and find that circles are exceptionally stable (half-life greater than 40 h). After the midblastula transition, polyadenylated chloramphenicol transferase (CAT) mRNAs transcribed from injected plasmids have a half-life of 2.5 h. Insertion of a 1000 nucleotide 3′ untranslated region from the Xhox-36 gene into the transcripts does not affect the half-life. In contrast to the finding that internal sequences do not affect stability, we find that sequences from the TFIIIA message reduce the half-life of CAT mRNA from 2.5 h to less than 30 min. We conclude that most RNAs are degraded exonucleolytically from the 3′ end, but specialized internal sequences can greatly destabilize the RNA, possibly by acting as a site for an endonuclease.
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Gomes, Clarissa Pedrosa da Costa, Blanche Schroen, Gabriela M. Kuster, Emma L. Robinson, Kerrie Ford, Iain B. Squire, Stephane Heymans, Fabio Martelli, Costanza Emanueli, and Yvan Devaux. "Regulatory RNAs in Heart Failure." Circulation 141, no. 4 (January 28, 2020): 313–28. http://dx.doi.org/10.1161/circulationaha.119.042474.
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Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.
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Sen, Rituparno, Suman Ghosal, Shaoli Das, Subrata Balti, and Jayprokas Chakrabarti. "Competing Endogenous RNA: The Key to Posttranscriptional Regulation." Scientific World Journal 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/896206.
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Competing endogenous RNA, ceRNA, vie with messenger RNAs (mRNAs) for microRNAs (miRNAs) with shared miRNAs responses elements (MREs) and act as modulator of miRNA by influencing the available level of miRNA. It has recently been discovered that, apart from protein-coding ceRNAs, pseudogenes, long noncoding RNAs (lncRNAs), and circular RNAs act as miRNA “sponges” by sharing common MRE, inhibiting normal miRNA targeting activity on mRNA. These MRE sharing elements form the posttranscriptional ceRNA network to regulate mRNA expression. ceRNAs are widely implicated in many biological processes. Recent studies have identified ceRNAs associated with a number of diseases including cancer. This brief review focuses on the molecular mechanism of ceRNA as part of the complex post-transcriptional regulatory circuit in cell and the impact of ceRNAs in development and disease.
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Gu, Rui, Xiaodong Li, Xiaowei Yan, Zhen Feng, and Aixin Hu. "Circular RNA circ_0032462 Enhances Osteosarcoma Cell Progression by Promoting KIF3B Expression." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382094321. http://dx.doi.org/10.1177/1533033820943217.
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Circular RNAs are a recently discovered subclass of endogenous noncoding RNAs that have been confirmed to play an important role in various pathophysiological processes. However, the underlying function of circular RNAs in osteosarcoma still remains unclear. We aimed to comprehend the function of circ_0032462 in osteosarcoma, as it has been predicted to be highly expressed in osteosarcoma cells. Using real-time polymerase chain reaction, we verified the elevated expression of circ_0032462 in osteosarcoma cells than normal cells. Functional validation experiments revealed that circ_0032462 overexpression promoted proliferation, migration, and invasion in osteosarcoma cells, whereas circ_0032462 silencing was observed to inhibit cancer cell progression (proliferation, migration, and invasion). Furthermore, we found that circ_0032462 upregulated the messenger RNA and protein expression level of kinesin family member 3B. In addition, kinesin family member 3B inhibition was found to inhibit circ_0032462-induced enhanced osteosarcoma cell progression. circ_0032462 overexpression was observed to reverse circ_0032462 silencing-induced inhibitory effect on osteosarcoma cell progression. Overall, our research revealed the function of circ_0032462 in osteosarcoma progression, which might serve as a novel chemotherapeutic target for osteosarcoma.
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Yeh, Shih-Chia, Faith J. F. Cheong, and Yvonne Tay. "Circular RNAs And Untranslated Regions in Acute Myeloid Leukemia." International Journal of Molecular Sciences 24, no. 4 (February 6, 2023): 3215. http://dx.doi.org/10.3390/ijms24043215.
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Before the advent of next-generation sequencing, research on acute myeloid leukemia (AML) mostly centered on protein-coding genes. In recent years, breakthroughs in RNA sequencing technologies and whole transcriptome analysis have led to the discovery that approximately 97.5% of the human genome is transcribed into non-coding RNAs (ncRNAs). This paradigm shift has led to an explosion of research interest in different classes of non-coding RNAs, such as circular RNAs (circRNAs) as well as non-coding untranslated regions (UTRs) of protein-coding messenger RNAs. The critical roles of circRNAs and UTRs in AML pathogenesis have become increasingly apparent. In this review, we discuss the cellular mechanisms of circRNAs and summarize recent studies that reveal their biological roles in AML. Furthermore, we also review the contribution of 3′UTRs to disease progression. Finally, we discuss the potential of circRNAs and 3′UTRs as new biomarkers for disease stratification and/or the prediction of treatment response and targets for the development of RNA-directed therapeutic applications.
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Vučković, Ana, Christoph Freyer, Anna Wredenberg, and Hauke S. Hillen. "The molecular machinery for maturation of primary mtDNA transcripts." Human Molecular Genetics 33, R1 (May 22, 2024): R19—R25. http://dx.doi.org/10.1093/hmg/ddae023.
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Abstract Human mitochondria harbour a circular, polyploid genome (mtDNA) encoding 11 messenger RNAs (mRNAs), two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Mitochondrial transcription produces long, polycistronic transcripts that span almost the entire length of the genome, and hence contain all three types of RNAs. The primary transcripts then undergo a number of processing and maturation steps, which constitute key regulatory points of mitochondrial gene expression. The first step of mitochondrial RNA processing consists of the separation of primary transcripts into individual, functional RNA molecules and can occur by two distinct pathways. Both are carried out by dedicated molecular machineries that substantially differ from RNA processing enzymes found elsewhere. As a result, the underlying molecular mechanisms remain poorly understood. Over the last years, genetic, biochemical and structural studies have identified key players involved in both RNA processing pathways and provided the first insights into the underlying mechanisms. Here, we review our current understanding of RNA processing in mammalian mitochondria and provide an outlook on open questions in the field.
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Yukseloglu, Emel. "RNA-Approached technology applications in forensic genetics." Novel Forensic Research 1, no. 1 (2022): 10. http://dx.doi.org/10.5455/nofor.2022.06.01.
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Ribonucleic acid (RNA) is a nucleic acid which is structurally different from DNA. DNA is the most used and approved nucleic acid in routine applications in forensic caseworks. In this article, giving an information about which RNA types are chosen for which forensic applications is aimed. RNA technologies are developing in the concept of forensic genetics and they can be adapted into routine case works in the case of well conditions are supplied. Both coding and non-coding RNAs are investigated for forensic purposes and most examined ones are messenger RNAs, and microRNAs. There are some researches on circular RNAs and piwi-interacting RNAs but they are in low number when compared with first two RNA types. Forensic studies based on RNA technologies are body fluid identification, post mortem interval determination, determination of stain age, estimation of an individual’s age and sex, identification of organ tissues, wound age estimation, and determination of drug abuse. Lastly, different RNA based technologies can be used in these studies and some of them are micro-array, Nano-String technology, real time PCR, end point PCR, high resolution melt (HRM) analysis and next generation sequencing (NGS) technology.
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Huang, Rongrong, Yuan Zhang, Ying Bai, Bing Han, Minzi Ju, Biling Chen, Li Yang, et al. "N6-Methyladenosine Modification of Fatty Acid Amide Hydrolase Messenger RNA in Circular RNA STAG1–Regulated Astrocyte Dysfunction and Depressive-like Behaviors." Biological Psychiatry 88, no. 5 (September 2020): 392–404. http://dx.doi.org/10.1016/j.biopsych.2020.02.018.
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Ren, Yi, Thamizhanban Manoharan, Beijia Liu, Cyrus Zai Ming Cheng, Bei En Siew, Wai-Kit Cheong, Kai Yin Lee, et al. "Circular RNA as a source of neoantigens for cancer vaccines." Journal for ImmunoTherapy of Cancer 12, no. 3 (March 2024): e008402. http://dx.doi.org/10.1136/jitc-2023-008402.
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BackgroundThe effectiveness of somatic neoantigen-based immunotherapy is often hindered by the limited number of mutations in tumors with low to moderate mutation burden. Focusing on microsatellite-stable colorectal cancer (CRC), this study investigates the potential of tumor-associated circular RNAs (circRNAs) as an alternative source of neoepitopes in CRC.MethodsTumor-associated circRNAs in CRC were identified using the MiOncoCirc database and ribo-depletion RNA sequencing of paired clinical normal and tumor samples. Candidate circRNA expression was validated by quantitative real-time PCR (RT-qPCR) using divergent primers. TransCirc database was used for translation prediction. Human leukocyte antigen binding affinity of open reading frames from potentially translatable circRNA was predicted using pVACtools. Strong binders from messenger RNA-encoded proteins were excluded using BlastP. The immunogenicity of the candidate antigens was functionally validated through stimulation of naïve CD8+T cells against the predicted neoepitopes and subsequent analysis of the T cells through enzyme-linked immunospot (ELISpot) assay, intracellular cytokine staining (ICS) and granzyme B (GZMB) reporter. The cytotoxicity of T cells trained with antigen peptides was further tested using patient-derived organoids.ResultsWe identified a neoepitope from circRAPGEF5 that is upregulated in CRC tumor samples from MiOncoCirc database, and two neoepitopes from circMYH9, which is upregulated across various tumor samples from our matched clinical samples. The translation potential of candidate peptides was supported by Clinical Proteomic Tumor Analysis Consortium database using PepQuery. The candidate peptides elicited antigen-specific T cells response and expansion, evidenced by various assays including ELISpot, ICS and GZMB reporter. Furthermore, T cells trained with circMYH9 peptides were able to specifically target and eliminate tumor-derived organoids but not match normal organoids. This observation underscores the potential of circRNAs as a source of immunogenic neoantigens. Lastly, circMYH9 was enriched in the liquid biopsies of patients with CRC, thus enabling a detection-to-vaccination treatment strategy for patients with CRC.ConclusionsOur findings underscore the feasibility of tumor-associated circRNAs as an alternative source of neoantigens for cancer vaccines targeting tumors with moderate mutation levels.
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Zhang, Yingjie, Chenyang Huang, Mengran Zhao, Guangyu Li, Zeyin Wu, Jie Zhang, and Lijiao Zhang. "Whole-Transcriptome Sequencing Reveals That mRNA and ncRNA Levels Correlate with Pleurotus cornucopiae Color Formation." Horticulturae 10, no. 1 (January 7, 2024): 60. http://dx.doi.org/10.3390/horticulturae10010060.
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Pleurotus cornucopiae cap color is an important commercial trait. The roles of non-coding RNA molecules (ncRNAs) in fungal fruiting body color formation are unclear. Whole-transcriptome analyses were performed, identifying messenger RNA (mRNA) and ncRNA (including long stranded non-coding RNA (lncRNA), micro RNA-like (milRNA), and circular RNA (circRNA)) molecules in three P. cornucopiae strains with different cap colors (grayish-black, grayish-white, and white), to investigate their roles in cap color formation. Differentially expressed mRNAs (n = 3604), lncRNAs (n = 520), milRNAs (n = 56), and circRNAs (n = 20) were identified among the three different color strains. Differentially expressed mRNAs and ncRNAs target genes were mainly involved in tyrosine, arachidonic acid, and histidine metabolism, plus other pathways potentially important in color formation. A competitive endogenous RNA (ceRNA) network and three mRNA and ncRNA co-expression networks were constructed, revealing relationships contributing to cap color formation, involving genes with roles in protein phosphorylation, and phenylalanine, tyrosine, and tryptophan biosynthesis. qRT-PCR analysis confirmed that mRNA and ncRNA levels were related to P. cornucopiae color. These regulatory networks may be crucial in P. cornucopiae color formation. Our data provide a new perspective to support further study of the mechanisms underlying P. cornucopiae color formation.
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Wu, Yueh-Lin, Hsiao-Fen Li, Hsi-Hsien Chen, and Heng Lin. "Emergent Roles of Circular RNAs in Metabolism and Metabolic Disorders." International Journal of Molecular Sciences 23, no. 3 (January 18, 2022): 1032. http://dx.doi.org/10.3390/ijms23031032.
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Circular RNAs (circRNAs) are an emerging group of long non-coding RNAs (lncRNAs) and have attracted attention again according to the progress in high-throughput sequencing in recent years. circRNAs are genome transcripts produced from pre-messenger (m)RNA regions in a specific process called “back-splicing,” which forms covalently closed continuous loops. Due to their lack of a 5’ cap and 3’ poly-adenylated tails, circRNAs are remarkably more stable than linear RNAs. Functionally, circRNAs can endogenously sponge to microRNAs, interact with RNA-binding proteins (RBPs), or translate themselves. Moreover, circRNAs can be expressed in cell type- or tissue-specific expression patterns. Therefore, they are proposed to play essential roles in fine-tuning our body’s homeostasis by regulating transcription and translation processes. Indeed, there has been accumulating emergent evidence showing that dysregulation of circRNAs can lead to metabolic disorders. This study explored the current knowledge of circRNAs that regulate molecular processes associated with glucose and lipid homeostasis and related pathogeneses of metabolic disorders. We also suggest the potential role of circRNAs as disease biomarkers and therapeutic targets.
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Filippenkov, Ivan B., Vasily V. Stavchansky, Alina E. Denisova, Liya V. Valieva, Julia A. Remizova, Ivan V. Mozgovoy, Elizaveta I. Zaytceva, Leonid V. Gubsky, Svetlana A. Limborska, and Lyudmila V. Dergunova. "Genome-Wide RNA-Sequencing Reveals Massive Circular RNA Expression Changes of the Neurotransmission Genes in the Rat Brain after Ischemia–Reperfusion." Genes 12, no. 12 (November 24, 2021): 1870. http://dx.doi.org/10.3390/genes12121870.
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Ischemic brain stroke is one of the most serious and socially significant diseases. In addition to messenger RNAs (mRNAs), encoding protein, the study of regulatory RNAs in ischemic has exceptional importance for the development of new strategies for neuroprotection. Circular RNAs (circRNAs) have a closed structure, predominantly brain-specific expression, and remain highly promising targets of research. They can interact with microRNAs (miRNAs), diminish their activity and thereby inhibit miRNA-mediated repression of mRNA. Genome-wide RNA-Seq analysis of the subcortical structures of the rat brain containing an ischemic damage focus and penumbra area revealed 395 circRNAs changed their expression significantly at 24 h after transient middle cerebral artery occlusion model (tMCAO) conditions. Furthermore, functional annotation revealed their association with neuroactive signaling pathways. It was found that about a third of the differentially expressed circRNAs (DECs) originate from genes whose mRNA levels also changed at 24 h after tMCAO. The other DECs originate from genes encoding non-regulated mRNAs under tMCAO conditions. In addition, bioinformatic analysis predicted a circRNA–miRNA–mRNA network which was associated with the neurotransmission signaling regulation. Our results show that such circRNAs can persist as potential miRNA sponges for the protection of mRNAs of neurotransmitter genes. The results expanded our views about the neurotransmission regulation in the rat brain after ischemia–reperfusion with circRNA action.
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Papaioannou, Dimitrios, Stefano Volinia, Deedra Nicolet, Michał Świerniak, Andreas Petri, Krzysztof Mrózek, Marius Bill, et al. "Clinical and functional significance of circular RNAs in cytogenetically normal AML." Blood Advances 4, no. 2 (January 16, 2020): 239–51. http://dx.doi.org/10.1182/bloodadvances.2019000568.
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Abstract Circular RNAs (circRNAs) are noncoding RNA molecules that display a perturbed arrangement of exons, called backsplicing. To examine the prognostic and biologic significance of circRNA expression in cytogenetically normal acute myeloid leukemia (CN-AML), we conducted whole-transcriptome profiling in 365 younger adults (age 18-60 years) with CN-AML. We applied a novel pipeline, called Massive Scan for circRNA, to identify and quantify circRNA expression. We validated the high sensitivity and specificity of our pipeline by performing RNase R treatment and RNA sequencing in samples of AML patients and cell lines. Unsupervised clustering analyses identified 3 distinct circRNA expression–based clusters with different frequencies of clinical and molecular features. After dividing our cohort into training and validation data sets, we identified 4 circRNAs (circCFLAR, circKLHL8, circSMC1A, and circFCHO2) that were prognostic in both data sets; high expression of each prognostic circRNA was associated with longer disease-free, overall, and event-free survival. In multivariable analyses, high circKLHL8 and high circFCHO2 expression were independently associated with better clinical outcome of CN-AML patients, after adjusting for other covariates. To examine the biologic relevance of circRNA expression, we performed knockdown screening experiments in a subset of prognostic and gene mutation–related candidate circRNAs. We identified circFBXW7, but not its linear messenger RNA, as a regulator of the proliferative capacity of AML blasts. In summary, our findings underscore the molecular associations, prognostic significance, and functional relevance of circRNA expression in CN-AML.
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Zhu, Weihua, Yuanting Zhang, Qianqian Zhou, Cheng Zhen, Herong Huang, and Xiaoying Liu. "Identification and Comprehensive Analysis of circRNA-miRNA-mRNA Regulatory Networks in A2780 Cells Treated with Resveratrol." Genes 15, no. 7 (July 22, 2024): 965. http://dx.doi.org/10.3390/genes15070965.
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Ovarian cancer (OC) is one of the most commonplace gynecological malignancies. This study explored the effects of resveratrol (RES) on OC cell proliferation and apoptosis. Proliferation activity was measured for A2780 cells treated with RES for 24 h and 48 h at concentrations of 0, 10, 25, 50, 75, 100, 150, 200, and 300 μM. RNA sequencing (RNA-seq) was performed to analyze the circular RNA (circRNA), microRNA (miRNA), and messenger RNA (mRNA) expression spectrum. The differentially expressed genes included 460 circRNAs, 1988 miRNAs, and 1671 mRNAs, and they were subjected to analyses including Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome enrichment. We selected signaling pathways enriched in the cell processes by mRNA KEGG, comprehensively analyzed the circRNA-miRNA-mRNA regulatory network, and verified several miRNAs expressed in the regulatory network diagram using the quantitative real-time polymerase chain reaction. The data showed that the cell proliferation of A2780 cells treated with RES for 24 h or 48 h decreased with increasing concentrations of RES. The circRNA-miRNA-mRNA regulatory network that we constructed provides new insights into the ability of RES to inhibit cell proliferation and promote apoptosis in A2780 cells.
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He, Ningning, Yuxiao Sun, Mengmeng Yang, Qianying Lu, Jinhan Wang, Changyan Xiao, Yan Wang, et al. "Analysis of Circular RNA Expression Profile in HEK 293T Cells Exposed to Ionizing Radiation." Dose-Response 17, no. 2 (April 1, 2019): 155932581983779. http://dx.doi.org/10.1177/1559325819837795.
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Radiation therapy is one of the most common cancer treatments. It is important to understand how cells respond to ionizing radiation (IR) to improve therapeutic efficacy. Circular RNAs (circRNAs) recently have been found to regulate a variety of cellular processes. However, it is poorly defined that their expression pattern and their identity in cells following IR exposure. Here, we performed high-throughput sequencing and comprehensive analysis of circRNA expression in human embryonic kidney (HEK) 293T cells before and after irradiation. We identified totally 5592 circRNAs and discovered 1038 new circRNAs. We found 158 circRNAs with significantly differential expression after IR exposure. Among them, there were 61 upregulated and 97 downregulated circRNAs. Using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and circRNA-microRNA-messenger RNA network analyses, we found the differentially expressed circRNAs might be involved in the signal pathways of oxidative phosphorylation, epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, and mammalian target of rapamycin (mTOR) signaling.
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Urdánoz-Casado, Amaya, Javier Sánchez-Ruiz de Gordoa, Maitane Robles, Blanca Acha, Miren Roldan, María Victoria Zelaya, Idoia Blanco-Luquin, and Maite Mendioroz. "Gender-Dependent Deregulation of Linear and Circular RNA Variants of HOMER1 in the Entorhinal Cortex of Alzheimer’s Disease." International Journal of Molecular Sciences 22, no. 17 (August 26, 2021): 9205. http://dx.doi.org/10.3390/ijms22179205.
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The HOMER1 gene is involved in synaptic plasticity, learning and memory. Recent studies show that circular RNA derived from HOMER1 (circHOMER1) expression is altered in some Alzheimer’s disease (AD) brain regions. In addition, HOMER1 messenger (mRNA) levels have been associated with β-Amyloid (Aβ) deposits in brain cortical regions. Our aim was to measure the expression levels of HOMER1 circRNAs and their linear forms in the human AD entorhinal cortex. First, we showed downregulation of HOMER1B/C and HOMER1A mRNA and hsa_circ_0006916 and hsa_circ_0073127 levels in AD female cases compared to controls by RT-qPCR. A positive correlation was observed between HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073128 with HOMER1B/C protein only in females. Global average area of Aβ deposits in entorhinal cortex samples was negatively correlated with HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073127 in both genders. Furthermore, no differences in DNA methylation were found in two regions of HOMER1 promoter between AD cases and controls. To sum up, we demonstrate that linear and circular RNA variants of HOMER1 are downregulated in the entorhinal cortex of female patients with AD. These results add to the notion that HOMER1 and its circular forms could be playing a female-specific role in the pathogenesis of AD.
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Ravnik-Glavač, Metka, and Damjan Glavač. "Circulating RNAs as Potential Biomarkers in Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 21, no. 5 (March 3, 2020): 1714. http://dx.doi.org/10.3390/ijms21051714.
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Amyotrophic lateral sclerosis (ALS) is a complex multi-system neurodegenerative disorder with currently limited diagnostic and no therapeutic options. Despite the intense efforts no clinically applicable biomarkers for ALS are yet established. Most current research is thus focused, in particular, in identifying potential non-invasive circulating biomarkers for more rapid and accurate diagnosis and monitoring of the disease. In this review, we have focused on messenger RNA (mRNA), non-coding RNAs (lncRNAs), micro RNAs (miRNAs) and circular RNA (circRNAs) as potential biomarkers for ALS in peripheral blood serum, plasma and cells. The most promising miRNAs include miR-206, miR-133b, miR-27a, mi-338-3p, miR-183, miR-451, let-7 and miR-125b. To test clinical potential of this miRNA panel, a useful approach may be to perform such analysis on larger multi-center scale using similar experimental design. However, other types of RNAs (lncRNAs, circRNAs and mRNAs) that, together with miRNAs, represent RNA networks, have not been yet extensively studied in blood samples of patients with ALS. Additional research has to be done in order to find robust circulating biomarkers and therapeutic targets that will distinguish key RNA interactions in specific ALS-types to facilitate diagnosis, predict progression and design therapy.
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del Solar, Gloria, Rafael Giraldo, María Jesús Ruiz-Echevarría, Manuel Espinosa, and Ramón Díaz-Orejas. "Replication and Control of Circular Bacterial Plasmids." Microbiology and Molecular Biology Reviews 62, no. 2 (June 1, 1998): 434–64. http://dx.doi.org/10.1128/mmbr.62.2.434-464.1998.
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SUMMARY An essential feature of bacterial plasmids is their ability to replicate as autonomous genetic elements in a controlled way within the host. Therefore, they can be used to explore the mechanisms involved in DNA replication and to analyze the different strategies that couple DNA replication to other critical events in the cell cycle. In this review, we focus on replication and its control in circular plasmids. Plasmid replication can be conveniently divided into three stages: initiation, elongation, and termination. The inability of DNA polymerases to initiate de novo replication makes necessary the independent generation of a primer. This is solved, in circular plasmids, by two main strategies: (i) opening of the strands followed by RNA priming (theta and strand displacement replication) or (ii) cleavage of one of the DNA strands to generate a 3′-OH end (rolling-circle replication). Initiation is catalyzed most frequently by one or a few plasmid-encoded initiation proteins that recognize plasmid-specific DNA sequences and determine the point from which replication starts (the origin of replication). In some cases, these proteins also participate directly in the generation of the primer. These initiators can also play the role of pilot proteins that guide the assembly of the host replisome at the plasmid origin. Elongation of plasmid replication is carried out basically by DNA polymerase III holoenzyme (and, in some cases, by DNA polymerase I at an early stage), with the participation of other host proteins that form the replisome. Termination of replication has specific requirements and implications for reinitiation, studies of which have started. The initiation stage plays an additional role: it is the stage at which mechanisms controlling replication operate. The objective of this control is to maintain a fixed concentration of plasmid molecules in a growing bacterial population (duplication of the plasmid pool paced with duplication of the bacterial population). The molecules involved directly in this control can be (i) RNA (antisense RNA), (ii) DNA sequences (iterons), or (iii) antisense RNA and proteins acting in concert. The control elements maintain an average frequency of one plasmid replication per plasmid copy per cell cycle and can “sense” and correct deviations from this average. Most of the current knowledge on plasmid replication and its control is based on the results of analyses performed with pure cultures under steady-state growth conditions. This knowledge sets important parameters needed to understand the maintenance of these genetic elements in mixed populations and under environmental conditions.
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Pisanu, Claudia, and Alessio Squassina. "RNA Biomarkers in Bipolar Disorder and Response to Mood Stabilizers." International Journal of Molecular Sciences 24, no. 12 (June 13, 2023): 10067. http://dx.doi.org/10.3390/ijms241210067.
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Bipolar disorder (BD) is a severe chronic disorder that represents one of the main causes of disability among young people. To date, no reliable biomarkers are available to inform the diagnosis of BD or clinical response to pharmacological treatment. Studies focused on coding and noncoding transcripts may provide information complementary to genome-wide association studies, allowing to correlate the dynamic evolution of different types of RNAs based on specific cell types and developmental stage with disease development or clinical course. In this narrative review, we summarize findings from human studies that evaluated the potential utility of messenger RNAs and noncoding transcripts, such as microRNAs, circular RNAs and long noncoding RNAs, as peripheral markers of BD and/or response to lithium and other mood stabilizers. The majority of available studies investigated specific targets or pathways, with large heterogeneity in the included type of cells or biofluids. However, a growing number of studies are using hypothesis-free designs, with some studies also integrating data on coding and noncoding RNAs measured in the same participants. Finally, studies conducted in neurons derived from induced-pluripotent stem cells or in brain organoids provide promising preliminary findings supporting the power and utility of these cellular models to investigate the molecular determinants of BD and clinical response.
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Miladi, Milad, Martin Raden, Sven Diederichs, and Rolf Backofen. "MutaRNA: analysis and visualization of mutation-induced changes in RNA structure." Nucleic Acids Research 48, W1 (May 11, 2020): W287—W291. http://dx.doi.org/10.1093/nar/gkaa331.
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Abstract RNA molecules fold into complex structures as a result of intramolecular interactions between their nucleotides. The function of many non-coding RNAs and some cis-regulatory elements of messenger RNAs highly depends on their fold. Single-nucleotide variants (SNVs) and other types of mutations can disrupt the native function of an RNA element by altering its base pairing pattern. Identifying the effect of a mutation on an RNA’s structure is, therefore, a crucial step in evaluating the impact of mutations on the post-transcriptional regulation and function of RNAs within the cell. Even though a single nucleotide variation can have striking impacts on the structure formation, interpreting and comparing the impact usually needs expertise and meticulous efforts. Here, we present MutaRNA, a web server for visualization and interpretation of mutation-induced changes on the RNA structure in an intuitive and integrative fashion. To this end, probabilities of base pairing and position-wise unpaired probabilities of wildtype and mutated RNA sequences are computed and compared. Differential heatmap-like dot plot representations in combination with circular plots and arc diagrams help to identify local structure abberations, which are otherwise hidden in standard outputs. Eventually, MutaRNA provides a comprehensive and comparative overview of the mutation-induced changes in base pairing potentials and accessibility. The MutaRNA web server is freely available at http://rna.informatik.uni-freiburg.de/MutaRNA.
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Lu, Jianan, Yujie Luo, Shuhao Mei, Yuanjian Fang, Jianmin Zhang, and Sheng Chen. "The Effect of Melatonin Modulation of Non-coding RNAs on Central Nervous System Disorders: An Updated Review." Current Neuropharmacology 19, no. 1 (December 31, 2020): 3–23. http://dx.doi.org/10.2174/1570159x18666200503024700.
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: Melatonin is a hormone produced in and secreted by the pineal gland. Besides its role in regulating circadian rhythms, melatonin has a wide range of protective functions in the central nervous system (CNS) disorders. The mechanisms underlying this protective function are associated with the regulatory effects of melatonin on related genes and proteins. In addition to messenger ribonucleic acid (RNA) that can be translated into protein, an increasing number of non-coding RNAs in the human body are proven to participate in many diseases. This review discusses the current progress of research on the effects of melatonin modulation of non-coding RNAs (ncRNAs), including microRNA, long ncRNA, and circular RNA. The role of melatonin in regulating common pathological mechanisms through these ncRNAs is also summarized. Furthermore, the ncRNAs, currently shown to be involved in melatonin signaling in CNS diseases, are discussed. The information compiled in this review will open new avenues for future research into melatonin mechanisms and provide a further understanding of ncRNAs in the CNS.
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Lai, Hongyan, Yuchen Li, Hena Zhang, Jia Hu, Jiatao Liao, Ying Su, Qin Li, et al. "exoRBase 2.0: an atlas of mRNA, lncRNA and circRNA in extracellular vesicles from human biofluids." Nucleic Acids Research 50, no. D1 (November 19, 2021): D118—D128. http://dx.doi.org/10.1093/nar/gkab1085.
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Abstract Extracellular vesicles (EVs) are small membranous vesicles that contain an abundant cargo of different RNA species with specialized functions and clinical implications. Here, we introduce an updated online database (http://www.exoRBase.org), exoRBase 2.0, which is a repository of EV long RNAs (termed exLRs) derived from RNA-seq data analyses of diverse human body fluids. In exoRBase 2.0, the number of exLRs has increased to 19 643 messenger RNAs (mRNAs), 15 645 long non-coding RNAs (lncRNAs) and 79 084 circular RNAs (circRNAs) obtained from ∼1000 human blood, urine, cerebrospinal fluid (CSF) and bile samples. Importantly, exoRBase 2.0 not only integrates and compares exLR expression profiles but also visualizes the pathway-level functional changes and the heterogeneity of origins of circulating EVs in the context of different physiological and pathological conditions. Our database provides an attractive platform for the identification of novel exLR signatures from human biofluids that will aid in the discovery of new circulating biomarkers to improve disease diagnosis and therapy.
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Vashchenko, Vladimir I., Alexey B. Chuklovin, and Petr D. Shabanov. "Circular RNAs in eukaryotic cells: origin, characteristics, mechanisms of molecular functioning in human malignant diseases." Reviews on Clinical Pharmacology and Drug Therapy 20, no. 4 (March 6, 2023): 335–84. http://dx.doi.org/10.17816/rcf204335-384.
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Circular RNAs (circRNAs) are an evolutionarily conserved novel class of non-coding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome, originally believed to be aberrant RNA splicing by-products with limited functionality.
However, recent advances in highthroughput genomic technology have allowed circRNAs to be characterized in detail and revealed their important functions in controlling various biological and molecular processes, the most essential being gene regulation. Due to structural stability, high expression, availability of microRNA (miRNA) binding sites and tissue-specific expression, circRNAs have become hot topic of research in RNA 2 biology. Unlike linear RNAs, circRNAs are produced differentially by backsplicing exons or lariat introns from a pre-messenger RNA (mRNA) forming covalently closed loop-like molecules missing 3' poly-(A) tail or 5' cap structures, thus rendering them resistant to exonuclease-mediated degradation.
Previous studies have revealed multiple roles of circRNAs as sponges for miRNA and RNA-binding proteins (RBP), as well as regulators of transcription, translation, and splicing events. Recent advances in the field suggest that the circRNAs are involved in many human disorders, including cancer and neurodegenerative disorders such as Alzheimers and Parkinsons disease, due to their aberrant expression in different pathological conditions. The circRNAs are stable in cells, owing to their circular structure. Participation of circRNAs in programmed cellular destruction by autophagy is discussed in details. The autophagy is a catabolic process which promotes decomposition and recycling of harmful or redundant biological macromolecules and initiates destruction of ageing cells. Processes how circRNAs influence a course of a disease, including an autophagy are in detail discussed, specifying that it joins at the beginning and upon development of various illnesses, and it can influence drug resistance (for example, antitumor efficiency of Cisplatin).
The functional versatility exhibited by circRNAs enables them to serve as potential diagnostic or predictive biomarkers for various diseases. This review discusses the properties, characterization, profiling, and the diverse molecular actions of circRNAs and their usage as potential therapeutic targets in different human malignancies.
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Gao, Zheng-Rong, Qiong Liu, Jie Zhao, Ya-Qiong Zhao, Li Tan, Shao-Hui Zhang, Ying-Hui Zhou, Yun Chen, Yue Guo, and Yun-Zhi Feng. "A comprehensive analysis of the circRNA–miRNA–mRNA network in osteocyte-like cell associated with Mycobacterium leprae infection." PLOS Neglected Tropical Diseases 16, no. 5 (May 2, 2022): e0010379. http://dx.doi.org/10.1371/journal.pntd.0010379.
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Background Bone formation and loss are the characteristic clinical manifestations of leprosy, but the mechanisms underlying the bone remodeling with Mycobacterium leprae (M. leprae) infection are unclear. Methodology/Principal findings Osteocytes may have a role through regulating the differentiation of osteogenic lineages. To investigate osteocyte-related mechanisms in leprosy, we treated osteocyte-like cell with N-glycosylated muramyl dipeptide (N.g MDP). RNA-seq analysis showed 724 differentially expressed messenger RNAs (mRNAs) and 724 differentially expressed circular RNA (circRNAs). Of these, we filtered through eight osteogenic-related differentially expressed genes, according to the characteristic of competing endogenous RNA, PubMed databases, and bioinformatic analysis, including TargetScan, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes. Based on these results, we built a circRNA–microRNA (miRNA)–mRNA triple network. Quantitative reverse-transcription polymerase chain reaction and western blots analyses confirmed decreased Clock expression in osteocyte-like cell, while increased in bone mesenchymal stem cells (BMSCs), implicating a crucial factor in osteogenic differentiation. Immunohistochemistry showed obviously increased expression of CLOCK protein in BMSCs and osteoblasts in N.g MDP–treated mice, but decreased expression in osteocytes. Conclusions/Significance This analytical method provided a basis for the relationship between N.g MDP and remodeling in osteocytes, and the circRNA–miRNA–mRNA triple network may offer a new target for leprosy therapeutics.
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Miklavčič, Rok, Polona Megušar, Špela Meta Kodermac, Blaž Bakalar, Darko Dolenc, Rok Sekirnik, Aleš Štrancar, and Urh Černigoj. "High Recovery Chromatographic Purification of mRNA at Room Temperature and Neutral pH." International Journal of Molecular Sciences 24, no. 18 (September 19, 2023): 14267. http://dx.doi.org/10.3390/ijms241814267.
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Messenger RNA (mRNA) is becoming an increasingly important therapeutic modality due to its potential for fast development and platform production. New emerging RNA modalities, such as circular RNA, drive the need for the development of non-affinity purification approaches. Recently, the highly efficient chromatographic purification of mRNA was demonstrated with multimodal monolithic chromatography media (CIM® PrimaS), where efficient mRNA elution was achieved with an ascending pH gradient approach at pH 10.5. Here, we report that a newly developed chromatographic material enables the elution of mRNA at neutral pH and room temperature. This material demonstrates weak anion-exchanging properties and an isoelectric point of 5.3. It enables the baseline separation of mRNA (at least up to 10,000 nucleotides (nt) in size) from parental plasmid DNA (regardless of isoform composition) with both a NaCl gradient and ascending pH gradient approach, while mRNA elution is achieved in a pH range of 5–7. In addition, the basic structure of the novel material is a chromatographic monolith, enabling convection-assisted mass transfer of large RNA molecules to and from the active surface. This facilitates the elution of mRNA in 3–7 column volumes with more than 80% elution recovery and uncompromised integrity. This is demonstrated by the purification of a model mRNA (size 995 nt) from an in vitro transcription reaction mixture. The purified mRNA is stable for at least 34 days, stored in purified H2O at room temperature.
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Chen, Hong, Tao Wang, Zhiyou Gong, Hui Lu, Yong Chen, Fei Deng, and Wanjun Ren. "Low Light Conditions Alter Genome-Wide Profiles of Circular RNAs in Rice Grains during Grain Filling." Plants 11, no. 9 (May 9, 2022): 1272. http://dx.doi.org/10.3390/plants11091272.
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In animals and plants, circRNAs regulate gene expression and act as sponges that inhibit the activity of microRNAs. This study aimed to determine how specific circRNAs are expressed in rice grains at different stages of grain filling, under normal and low light conditions. We extracted total RNA from rice grains under low and sufficient light conditions. Deep sequencing was performed using circRNA libraries, and bioinformatics tools were used to identify the circRNAs. In addition, we analyzed targeted messenger RNA functions using two databases to predict the processes involved in rice grain development, and we conducted real-time PCR on 15 of the circRNAs as well as Sanger sequencing. During the grain development process, 8015 candidate circRNAs were isolated, among which the number of known circRNAs was 1661. We also found that the number of circRNAs changed with the time of development. Among them, six circRNAs acted as sponges that targeted more than two microRNAs at different stages of development, and these circRNAs showed a regulatory pattern consistent with the transcriptome sequencing results. More circRNA diversity was found under low light treatment compared to normal light. These findings reveal a possible link between circRNA regulation and the expression of the functional genes associated with photosignal-mediated rice grain development.
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An, Xiaopeng, Yue Zhang, Fu Li, Zhanhang Wang, Shaohua Yang, and Binyun Cao. "Whole Transcriptome Analysis: Implication to Estrous Cycle Regulation." Biology 10, no. 6 (May 25, 2021): 464. http://dx.doi.org/10.3390/biology10060464.
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Estrous cycle is one of the placental mammal characteristics after sexual maturity, including estrus stage (ES) and diestrus stage (DS). Estrous cycle is important in female physiology and its disorder may lead to diseases, such as polycystic ovary syndrome, ovarian carcinoma, anxiety, and epilepsy. In the latest years, effects of non-coding RNAs and messenger RNA (mRNA) on estrous cycle have started to arouse much concern, however, a whole transcriptome analysis among non-coding RNAs and mRNA has not been reported. Here, we report a whole transcriptome analysis of goat ovary in estrus and diestrus periods. Estrus synchronization was conducted to induce the estrus phase and on day 32, the goats shifted into the diestrus stage. The ovary RNA of estrus and diestrus stages was respectively collected to perform RNA-sequencing. Then, the circular RNA (circRNA), microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA databases of goat ovary were acquired, and the differential expressions between estrus and diestrus stages were screened to construct circRNA-miRNA-mRNA/lncRNA and lncRNA-miRNA/mRNA networks, thus providing potential pathways that are involved in the regulation of estrous cycle. Differentially expressed mRNAs, such as MMP9, TIMP1, 3BHSD, and PTGIS, and differentially expressed miRNAs that play key roles in the regulation of estrous cycle, such as miR-21-3p, miR-202-3p, and miR-223-3p, were extracted from the network. Our data provided the miRNA, circRNA, lncRNA, and mRNA databases of goat ovary and each differentially expressed profile between ES and DS. Networks among differentially expressed miRNAs, circRNAs, lncRNAs, and mRNAs were constructed to provide valuable resources for the study of estrous cycle and related diseases.
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Tan, Lulin, Zhaojun Chen, MingDe Teng, Bin Chen, and Houqiang Xu. "Genome-wide analysis of mRNAs, lncRNAs, and circRNAs during intramuscular adipogenesis in Chinese Guizhou Congjiang pigs." PLOS ONE 17, no. 1 (January 25, 2022): e0261293. http://dx.doi.org/10.1371/journal.pone.0261293.
Full textAbstract:
Intramuscular fat content is an important determinant of meat quality, and preadipocyte differentiation plays a critical role in intramuscular fat deposition in pigs. However, many types of RNA differentiation, including messenger RNA (mRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) remain unreported despite their crucial roles in regulating adipogenesis. Chinese Guizhou Congjiang pigs are raised in the Guizhou province of China for their high-quality meat. Therefore, it is important for breeders to explore the mechanisms of proliferation and differentiation of intramuscular adipocytes from the longissimus dorsi muscle of these pigs. In the present study, a transcriptome analysis of intramuscular preadipocytes from Chinese Guizhou Congjiang pigs, including analyses of mRNAs, lncRNAs, and circRNAs at days 0 (D0), 4 (D4), and 8 (D8) was performed. A total of 1,538, 639, and 445 differentially expressed (DE) mRNAs, 479, 192, and 126 DE lncRNAs, and 360, 439, and 304 DE circRNAs were detected between D4 and D0, D8 and D0, and D8 and D4, respectively. Functional analyses identified many significantly enriched RNAs related to lipid deposition, cell differentiation, metabolism processes, and obesity-related diseases, biological processes, and pathways. We identified two lncRNAs (TCONS_00012086 and TCONS_00007245) closely related to fat deposition according to their target genes and tissue expression profiles. Subcellular distribution analysis using quantitative real-time PCR (qRT-PCR) revealed that both TCONS_00012086 and TCONS_00007245 are cytoplasmic lncRNAs. These data provide a genome-wide resource for mRNAs, lncRNAs, and circRNAs potentially involved in Chinese Guizhou Congjiang pig fat metabolism, thus improving our understanding of their function in adipogenesis.
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Delgado, Sonia, Ángel E. Martínez de Alba, Carmen Hernández, and Ricardo Flores. "A Short Double-Stranded RNA Motif of Peach Latent Mosaic Viroid Contains the Initiation and the Self-Cleavage Sites of Both Polarity Strands." Journal of Virology 79, no. 20 (October 15, 2005): 12934–43. http://dx.doi.org/10.1128/jvi.79.20.12934-12943.2005.
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ABSTRACT The transcription initiation sites of viroid RNAs, despite their relevance for replication and in vivo folding, are poorly characterized. Here we have examined this question for Peach latent mosaic viroid (PLMVd), which belongs to the family of chloroplastic viroids with hammerhead ribozymes (Avsunviroidae), by adapting an RNA ligase-mediated rapid amplification of cDNA ends methodology developed for mapping the genuine capped 5′ termini of eukaryotic messenger RNAs. To this aim, the characteristic free 5′-triphosphate group of chloroplastic primary transcripts from PLMVd-infected young fruits was previously capped in vitro with GTP and guanylyltransferase. PLMVd plus and minus initiation sites map at similar double-stranded motifs of 6 to 7 bp that also contain the conserved GUC triplet preceding the self-cleavage site in both polarity strands. Within the branched secondary structures predicted for the two PLMVd strands, this motif is located at the base of a similar long hairpin that presumably contains the promoters for a chloroplastic RNA polymerase. The transcription templates could be the circular viroid RNAs or their most abundant linear counterparts, assuming the involvement of an RNA polymerase able to jump over template discontinuities. Both PLMVd initiation sites were confirmed by applying the same methodology to two purified PLMVd subgenomic RNAs and by primer extension, and they therefore likely reflect the in vivo situation. The location of the PLMVd initiation sites provides a mechanistic view into how the nascent strands may fold and self-cleave during transcription. The approach described here may be extended to other chloroplastic RNA replicons and transcripts accumulating at low levels.
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Withers, Johanna B., Vanessa Mondol, Paulina Pawlica, Nicolle A. Rosa-Mercado, Kazimierz T. Tycowski, Salehe Ghasempur, Seyed F. Torabi, and Joan A. Steitz. "Idiosyncrasies of Viral Noncoding RNAs Provide Insights into Host Cell Biology." Annual Review of Virology 6, no. 1 (September 29, 2019): 297–317. http://dx.doi.org/10.1146/annurev-virology-092818-015811.
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Like their host cells, many viruses express noncoding RNAs (ncRNAs). Despite the technical challenge of ascribing function to ncRNAs, diverse biological roles for virally expressed ncRNAs have been described, including regulation of viral replication, modulation of host gene expression, host immune evasion, cellular survival, and cellular transformation. Insights into conserved interactions between viral ncRNAs and host cell machinery frequently lead to novel findings concerning host cell biology. In this review, we discuss the functions and biogenesis of ncRNAs produced by animal viruses. Specifically, we describe noncanonical pathways of microRNA (miRNA) biogenesis and novel mechanisms used by viruses to manipulate miRNA and messenger RNA stability. We also highlight recent advances in understanding the function of viral long ncRNAs and circular RNAs.
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Chen, Robert, Sean K. Wang, Julia A. Belk, Laura Amaya, Zhijian Li, Angel Cardenas, Brian T. Abe, Chun-Kan Chen, Paul A. Wender, and Howard Y. Chang. "Engineering circular RNA for enhanced protein production." Nature Biotechnology, July 18, 2022. http://dx.doi.org/10.1038/s41587-022-01393-0.
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AbstractCircular RNAs (circRNAs) are stable and prevalent RNAs in eukaryotic cells that arise from back-splicing. Synthetic circRNAs and some endogenous circRNAs can encode proteins, raising the promise of circRNA as a platform for gene expression. In this study, we developed a systematic approach for rapid assembly and testing of features that affect protein production from synthetic circRNAs. To maximize circRNA translation, we optimized five elements: vector topology, 5′ and 3′ untranslated regions, internal ribosome entry sites and synthetic aptamers recruiting translation initiation machinery. Together, these design principles improve circRNA protein yields by several hundred-fold, provide increased translation over messenger RNA in vitro, provide more durable translation in vivo and are generalizable across multiple transgenes.
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D’Anna, Luisa, Aurane Froux, Aurianne Rainot, Angelo Spinello, Ugo Perricone, Florent Barbault, Stéphanie Grandemange, Giampaolo Barone, Alessio Terenzi, and Antonio Monari. "Resolving the Structure of a Guanine Quadruplex in TMPRSS2 Messenger RNA by Circular Dichroism and Molecular Modeling." Chemistry – A European Journal, October 4, 2024. http://dx.doi.org/10.1002/chem.202403572.
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The presence of a guanine quadruplex in the opening reading frame of the messenger RNA coding for the transmembrane serine protease 2 (TMPRSS2) may pave the way to original anticancer and host‐oriented antiviral strategy. Indeed, TMPRSS2 in addition to being overexpressed in different cancer types, is also related to the infection of respiratory viruses, including SARS‐CoV‐2, by promoting the cellular and viral membrane fusion through its proteolytic activity. The design of selective ligands targeting TMPRSS2 messenger RNA requires a detailed knowledge, at atomic level, of its structure. Therefore, we have used an original experimental‐computational protocol to predict the first resolved structure of the parallel guanine quadruplex secondary structure in the RNA of TMPRSS2, which shows a rigid core flanked by a flexible loop. This represents the first atomic scale structure of the guanine quadruplex structure present in TMPRSS2 messenger RNA.
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Mishra, Rajakishore. "Bio-genesis and deregulation of circular ribonucleic acid and their role in human cancer." Applied Biology & Chemistry Journal, December 27, 2020, 83–94. http://dx.doi.org/10.52679/tabcj.2020.0010.
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RiboNucleic Acid (RNA) occupies the center position in the central dogma of molecular biology. These are the nucleotide with a ribose sugar and are found either in linear or circular form. The linear RNAs are of different types and include ribosomal RNA (rRNA), messenger RNA (mRNA), transfer RNA (t-RNA), small nuclear (snRNA) RNA, and very small/micro RNA (microRNAs). The circular (circRNA) RNA is a group of noncoding RNA, stable molecules, established recently and linked with the regulation of different genes, RNAs including microRNAs. The current understanding of these molecules suggests that these circRNAs are fairly conserved and show tissue-specific expression patterns. These molecules are connected with different pathogenic conditions and associated with verities of diseases, including cancer. CircRNAs are thus contributing to tumorigenesis, and these molecules show the potential to become future predictive biomarkers for diagnosis, prognosis and even can be targeted in personalized therapy. Hence, these bio-molecules will get exposed frequently, and their new cellular role will emerge, soon. This review outlines the current trend, limitations, and future potential of circRNA in cancer research.