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RNA Regulatory Networks at the Crossroad of Human Diseases 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 26145

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Special Issue Editor

Prof. Nicoletta Potenza

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Guest Editor

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania “L. Vanvitelli”, Via Vivaldi, 43-81100 Caserta, Italy
Interests: microRNAs; lncRNA; non-coding RNA; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second volume of our previous Special Issue "RNA Regulatory Networks at the Crossroad of Human Diseases". Exploration of the transcriptome space has turned the spotlight on the dark side of the RNA planet, non-coding RNAs (ncRNAs), previously overlooked by conventional protein-coding studies. It has become increasingly clear that ncRNAs constitute the largest class of RNA transcripts, resulting from pervasive transcription of the genome, of which only 1–2% code for proteins. ncRNAs comprise different RNA species, which can be broadly categorized into short ncRNAs, including microRNAs (miRNA), and long ncRNAs (lncRNAs), such as lincRNA, antisense RNAs, pseudogenes and circular RNAs. We are now in an exciting era, which is unveiling the previously unappreciated regulatory power of all these RNA species and their functional interactions. Various studies have demonstrated that ncRNAs engage in competitive regulatory interactions, known as competing endogenous RNA (ceRNA) networks, ceRNET, whereby miRNAs and lncRNAs modulate each other, since miRNAs can regulate the expression of lncRNAs, which in turn regulate miRNAs by competing with the binding to mRNA targets. In this scenario, coding transcripts themselves could have a regulatory power beyond their coding potential, when they compete for binding to shared miRNAs.

Untangling such RNA-based networks is now outlining their relevant role in a wide range of biological pathways; the unbalancing of any network component can act as a driving force for human diseases, as demonstrated for various cancer types. ceRNET research is still in its infancy, but could fulfill the promise to gain a deeper insight into molecular mechanisms underlying human diseases, and probably of the identification of new biomarkers and therapeutic targets.

This special issue welcomes original research manuscripts, unraveling novel RNA regulatory networks and their impact on human diseases, possible rules for ncRNA structure-function relationships, or reporting innovative methodological approaches, including new bioinformatics tools; critical review manuscripts with a perspective vision setting the stage for future research are also especially welcome.

Prof. Nicoletta Potenza
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Non-coding RNA
microRNA
piRNA
lncRNA
circRNA
disease pathogenesis
developmental defects
cancer

Published Papers (10 papers)

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Research

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15 pages, 788 KiB

Open AccessArticle

circRNA from APP Gene Changes in Alzheimer’s Disease Human Brain

by Amaya Urdánoz-Casado, Javier Sánchez-Ruiz de Gordoa, Maitane Robles, Miren Roldan, Mónica Macías Conde, Blanca Acha, Idoia Blanco-Luquin and Maite Mendioroz

Int. J. Mol. Sci. 2023, 24(5), 4308; https://doi.org/10.3390/ijms24054308 - 21 Feb 2023

Cited by 4 | Viewed by 1554

Abstract

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Amyloid precursor protein (APP) is the precursor of Aβ peptides, and its role in AD has been widely investigated. Recently, it has been reported that a circular RNA (circRNA) originated from APP gene can serve as a template for Aβ synthesis, postulating it as an alternative pathway for the Aβ biogenesis. Moreover, circRNAs play important roles in brain development and in neurological diseases. Therefore, our aim was to study the expression of a circAPP (hsa_circ_0007556) and its linear cognate in AD human entorhinal cortex, a brain region most vulnerable to AD pathology. First, we confirmed the presence of circAPP (hsa_circ_0007556) in human entorhinal cortex samples using RT-PCR and Sanger sequencing of PCR products. Next, a 0.49-fold decrease in circAPP (hsa_circ_0007556) levels was observed in entorhinal cortex of AD cases compared to controls (p-value < 0.05) by qPCR. In contrast, APP mRNA expression did not show changes in the entorhinal cortex between AD cases and controls (Fold-change = 1.06; p-value = 0.81). A negative correlation was found between Aβ deposits and circAPP (hsa_circ_0007556) and APP expression levels (Rho Spearman = −0.56, p-value < 0.001 and Rho Spearman = −0.44, p-values < 0.001, respectively). Finally, by using bioinformatics tools, 17 miRNAs were predicted to bind circAPP (hsa_circ_0007556), and the functional analysis predicted that they were involved in some pathways, such as the Wnt-signaling pathway (p = 3.32 × 10⁻⁶). Long-term potentiation (p = 2.86 × 10⁻⁵), among others, is known to be altered in AD. To sum up, we show that circAPP (hsa_circ_0007556) is deregulated in the entorhinal cortex of AD patients. These results add to the notion that circAPP (hsa_circ_0007556) could be playing a role in the pathogenesis of AD disease. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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19 pages, 2508 KiB

Open AccessArticle

MicroRNAs Expression in Response to rhNGF in Epithelial Corneal Cells: Focus on Neurotrophin Signaling Pathway

by Chiara Compagnoni, Veronica Zelli, Andrea Bianchi, Antinisca Di Marco, Roberta Capelli, Davide Vecchiotti, Laura Brandolini, Anna Maria Cimini, Francesca Zazzeroni, Marcello Allegretti, Edoardo Alesse and Alessandra Tessitore

Int. J. Mol. Sci. 2022, 23(7), 3597; https://doi.org/10.3390/ijms23073597 - 25 Mar 2022

Cited by 2 | Viewed by 2361

Abstract

Purpose. Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombinant human NGF (rhNGF) was approved for neurotrophic keratitis therapy. However, NGF-induced molecular responses in cornea are still largely unknown. We analyzed microRNAs expression in human epithelial corneal cells after time-dependent rhNGF treatment. Methods. Nearly 700 microRNAs were analyzed by qRT-PCR. MicroRNAs showing significant expression differences were examined by DIANA-miRpath v.3.0 to identify target genes and pathways. Immunoblots were performed to preliminarily assess the strength of the in silico results. Results. Twenty-one microRNAs (miR-26a-1-3p, miR-30d-3p, miR-27b-5p, miR-146a-5p, miR-362-5p, mir-550a-5p, mir-34a-3p, mir-1227-3p, mir-27a-5p, mir-222-5p, mir-151a-5p, miR-449a, let7c-5p, miR-337-5p, mir-29b-3p, miR-200b-3p, miR-141-3p, miR-671-3p, miR-324-5p, mir-411-3p, and mir-425-3p) were significantly regulated in response to rhNGF. In silico analysis evidenced interesting target genes and pathways, including that of neurotrophin, when analyzed in depth. Almost 80 unique target genes (e.g., PI3K, AKT, MAPK, KRAS, BRAF, RhoA, Cdc42, Rac1, Bax, Bcl2, FasL) were identified as being among those most involved in neurotrophin signaling and in controlling cell proliferation, growth, and apoptosis. AKT and RhoA immunoblots demonstrated congruence with microRNA expression, providing preliminary validation of in silico data. Conclusions. MicroRNA levels in response to rhNGF were for the first time analyzed in corneal cells. Novel insights about microRNAs, target genes, pathways modulation, and possible biological responses were provided. Importantly, given the putative role of microRNAs as biomarkers or therapeutic targets, our results make available data which might be potentially exploitable for clinical applications. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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21 pages, 2545 KiB

Open AccessArticle

MicroRNA-mRNA Regulatory Network Mediates Activation of mTOR and VEGF Signaling in African American Prostate Cancer

by Himali Gujrati, Siyoung Ha, Azah Mohamed and Bi-Dar Wang

Int. J. Mol. Sci. 2022, 23(6), 2926; https://doi.org/10.3390/ijms23062926 - 08 Mar 2022

Cited by 10 | Viewed by 2371

Abstract

African American (AA) men exhibit 1.6-fold higher prostate cancer (PCa) incidence and 2.4-fold higher mortality rates compared to European American (EA) men. In addition to socioeconomic factors, emerging evidence suggests that intrinsic biological differences may explain part of PCa disparities. In this study, we applied microRNA (miRNA)-driven bioinformatics to evaluate whether differential miRNA-mRNA regulatory networks play a role in promoting the AA PCa disparities. 10 differentially expressed miRNAs were imported to mirPath V.3 algorithm, leading to identification of 58 signaling pathways differentially regulated in AA PCa versus EA PCa. Among these pathways, we particularly focused on mTOR and VEGF signaling, where we identified 5 reciprocal miRNA-mRNA pairings: miR-34a-5p/HIF1A, miR-34a-5p/PIK3CB, miR-34a-5p/IGFBP2, miR-99b-5p/MTOR and miR-96-5p/MAPKAPK2 in AA PCa versus EA PCa. RT-qPCR validation confirmed that miR-34a-5p, miR-99b-5p and MAPKAPK2 were downregulated, while miR-96-5p, IGFBP2, HIF1A, PIK3CB and MTOR were upregulated in AA PCa versus EA PCa cells. Transfection of miRNA mimics/antagomir followed by RT-qPCR and Western blot analysis further verified that IGFBP2, HIF1A and PIK3CB are negatively regulated by miR-34a-5p, whereas MTOR and MAPKAPK2 are negatively regulated by miR-99b-5p and miR-96-5p, respectively, at mRNA and protein levels. Targeting reciprocal pairings by miR-34a-5p mimic, miR-99b-5p mimic or miR-96-5p antagomir downregulates HIF1α, PI3Kβ, mTOR, IGFBP2 but upregulates MAPKAPK2, subsequently reducing cell proliferation and sensitizing docetaxel-induced cytotoxicity in PCa cells. These results suggest that miRNA-mRNA regulatory network plays a critical role in AA PCa disparities, and targeting these core miRNA-mRNA pairings may reduce PCa aggressiveness and overcome the chemoresistance in AA patients. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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14 pages, 2105 KiB

Open AccessArticle

CircRNAs as Potential Blood Biomarkers and Key Elements in Regulatory Networks in Gastric Cancer

by Laís Reis-das-Mercês, Tatiana Vinasco-Sandoval, Rafael Pompeu, Aline Cruz Ramos, Ana K. M. Anaissi, Samia Demachki, Paulo Pimentel de Assumpção, Amanda F. Vidal, Ândrea Ribeiro-dos-Santos and Leandro Magalhães

Int. J. Mol. Sci. 2022, 23(2), 650; https://doi.org/10.3390/ijms23020650 - 07 Jan 2022

Cited by 15 | Viewed by 2204

Abstract

Gastric cancer (GC) is the fifth most common type of cancer and the third leading cause of cancer death in the world. It is a disease that encompasses a variety of molecular alterations, including in non-coding RNAs such as circular RNAs (circRNAs). In the present study, we investigated hsa_circ_0000211, hsa_circ_0000284, hsa_circ_0000524, hsa_circ_0001136 and hsa_circ_0004771 expression profiles using RT-qPCR in 71 gastric tissue samples from GC patients (tumor and tumor-adjacent samples) and volunteers without cancer. In order to investigate the suitability of circRNAs as minimally invasive biomarkers, we also evaluated their expression profile through RT-qPCR in peripheral blood samples from patients with and without GC (n = 41). We also investigated the predicted interactions between circRNA-miRNA-mRNA and circRNA-RBP using the KEGG and Reactome databases. Overall, our results showed that hsa_circ_0000211, hsa_circ_0000284 and hsa_circ_0004771 presented equivalent expression profiles when analyzed by different methods (RNA-Seq and RT-qPCR) and different types of samples (tissue and blood). Further, functional enrichment results identified important signaling pathways related to GC. Thus, our data support the consideration of circRNAs as new, minimally invasive biomarkers capable of aiding in the diagnosis of GC and with great potential to be applied in clinical practice. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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15 pages, 2162 KiB

Open AccessArticle

Gender-Dependent Deregulation of Linear and Circular RNA Variants of HOMER1 in the Entorhinal Cortex of Alzheimer’s Disease

by Amaya Urdánoz-Casado, Javier Sánchez-Ruiz de Gordoa, Maitane Robles, Blanca Acha, Miren Roldan, María Victoria Zelaya, Idoia Blanco-Luquin and Maite Mendioroz

Int. J. Mol. Sci. 2021, 22(17), 9205; https://doi.org/10.3390/ijms22179205 - 26 Aug 2021

Cited by 14 | Viewed by 2664

Abstract

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. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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14 pages, 736 KiB

Open AccessArticle

Can miRNA Indicate Risk of Illness after Continuous Exposure to M. tuberculosis?

by Cleonardo Augusto Silva, Arthur Ribeiro-dos-Santos, Wanderson Gonçalves Gonçalves, Pablo Pinto, Rafael Pompeu Pantoja, Tatiana Vinasco-Sandoval, André Maurício Ribeiro-dos-Santos, Mara Helena Hutz, Amanda Ferreira Vidal, Gilderlanio Santana Araújo, Ândrea Ribeiro-dos-Santos and Sidney Santos

Int. J. Mol. Sci. 2021, 22(7), 3674; https://doi.org/10.3390/ijms22073674 - 01 Apr 2021

Cited by 7 | Viewed by 2329

Abstract

The role of regulatory elements such as small ncRNAs and their mechanisms are poorly understood in infectious diseases. Tuberculosis is one of the oldest infectious diseases of humans and it is still a challenge to prevent and treat. Control of the infection, as well as its diagnosis, are still complex and current treatments used are linked to several side effects. This study aimed to identify possible biomarkers for tuberculosis by applying NGS techniques to obtain global miRNA expression profiles from 22 blood samples of infected patients with tuberculosis (n = 9), their respective healthy physicians (n = 6) and external healthy individuals as controls (n = 7). Samples were run through a pipeline consisting of differential expression, target genes, gene set enrichment and miRNA–gene network analyses. We observed 153 altered miRNAs, among which only three DEmiRNAs (hsa-let-7g-5p, hsa-miR-486-3p and hsa-miR-4732-5p) were found between the investigated patients and their respective physicians. These DEmiRNAs are suggested to play an important role in granuloma regulation and their immune physiopathology. Our results indicate that miRNAs may be involved in immune modulation by regulating gene expression in cells of the immune system. Our findings encourage the application of miRNAs as potential biomarkers for tuberculosis. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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Review

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30 pages, 2304 KiB

Open AccessReview

Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers

by Ba Da Yun, Ye Ji Choi, Seung Wan Son, Gabriel Adelman Cipolla, Fernanda Costa Brandão Berti, Danielle Malheiros, Tae-Jin Oh, Hyo Jeong Kuh, Soo Young Choi and Jong Kook Park

Int. J. Mol. Sci. 2022, 23(2), 930; https://doi.org/10.3390/ijms23020930 - 15 Jan 2022

Cited by 8 | Viewed by 2598

Abstract

Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell–cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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26 pages, 2973 KiB

Open AccessReview

The lncRNAs at X Chromosome Inactivation Center: Not Just a Matter of Sex Dosage Compensation

by Chiara Siniscalchi, Armando Di Palo, Aniello Russo and Nicoletta Potenza

Int. J. Mol. Sci. 2022, 23(2), 611; https://doi.org/10.3390/ijms23020611 - 06 Jan 2022

Cited by 14 | Viewed by 3201

Abstract

Non-coding RNAs (ncRNAs) constitute the majority of the transcriptome, as the result of pervasive transcription of the mammalian genome. Different RNA species, such as lncRNAs, miRNAs, circRNA, mRNAs, engage in regulatory networks based on their reciprocal interactions, often in a competitive manner, in a way denominated “competing endogenous RNA (ceRNA) networks” (“ceRNET”): miRNAs and other ncRNAs modulate each other, since miRNAs can regulate the expression of lncRNAs, which in turn regulate miRNAs, titrating their availability and thus competing with the binding to other RNA targets. The unbalancing of any network component can derail the entire regulatory circuit acting as a driving force for human diseases, thus assigning “new” functions to “old” molecules. This is the case of XIST, the lncRNA characterized in the early 1990s and well known as the essential molecule for X chromosome inactivation in mammalian females, thus preventing an imbalance of X-linked gene expression between females and males. Currently, literature concerning XIST biology is becoming dominated by miRNA associations and they are also gaining prominence for other lncRNAs produced by the X-inactivation center. This review discusses the available literature to explore possible novel functions related to ceRNA activity of lncRNAs produced by the X-inactivation center, beyond their role in dosage compensation, with prospective implications for emerging gender-biased functions and pathological mechanisms. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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18 pages, 698 KiB

Open AccessReview

Regulatory Potential of Competing Endogenous RNAs in Myotonic Dystrophies

by Edyta Koscianska, Emilia Kozlowska and Agnieszka Fiszer

Int. J. Mol. Sci. 2021, 22(11), 6089; https://doi.org/10.3390/ijms22116089 - 04 Jun 2021

Cited by 6 | Viewed by 2606

Abstract

Non-coding RNAs (ncRNAs) have been reported to be implicated in cell fate determination and various human diseases. All ncRNA molecules are emerging as key regulators of diverse cellular processes; however, little is known about the regulatory interaction among these various classes of RNAs. It has been proposed that the large-scale regulatory network across the whole transcriptome is mediated by competing endogenous RNA (ceRNA) activity attributed to both protein-coding and ncRNAs. ceRNAs are considered to be natural sponges of miRNAs that can influence the expression and availability of multiple miRNAs and, consequently, the global mRNA and protein levels. In this review, we summarize the current understanding of the role of ncRNAs in two neuromuscular diseases, myotonic dystrophy type 1 and 2 (DM1 and DM2), and the involvement of expanded CUG and CCUG repeat-containing transcripts in miRNA-mediated RNA crosstalk. More specifically, we discuss the possibility that long repeat tracts present in mutant transcripts can be potent miRNA sponges and may affect ceRNA crosstalk in these diseases. Moreover, we highlight practical information related to innovative disease modelling and studying RNA regulatory networks in cells. Extending knowledge of gene regulation by ncRNAs, and of complex regulatory ceRNA networks in DM1 and DM2, will help to address many questions pertinent to pathogenesis and treatment of these disorders; it may also help to better understand general rules of gene expression and to discover new rules of gene control. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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18 pages, 2624 KiB

Open AccessReview

Information Encoded by the Flavivirus Genomes beyond the Nucleotide Sequence

by Sara Ramos-Lorente, Cristina Romero-López and Alfredo Berzal-Herranz

Int. J. Mol. Sci. 2021, 22(7), 3738; https://doi.org/10.3390/ijms22073738 - 03 Apr 2021

Cited by 10 | Viewed by 2839

Abstract

The genus Flavivirus comprises numerous, small, single positive-stranded RNA viruses, many of which are important human pathogens. To store all the information required for their successful propagation, flaviviruses use discrete structural genomic RNA elements to code for functional information by the establishment of dynamic networks of long-range RNA–RNA interactions that promote specific folding. These structural elements behave as true cis-acting, non-coding RNAs (ncRNAs) and have essential regulatory roles in the viral cycle. These include the control of the formation of subgenomic RNAs, known as sfRNAs, via the prevention of the complete degradation of the RNA genome. These sfRNAs are important in ensuring viral fitness. This work summarizes our current knowledge of the functions performed by the genome conformations and the role of RNA–RNA interactions in these functions. It also reviews the role of RNA structure in the production of sfRNAs across the genus Flavivirus, and their existence in related viruses. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 2.0)

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