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Circular RNAs: Non-canonical Observations on Non-canonical RNAs
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Circular RNAs: Non-canonical Observations on Non-canonical RNAs

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 56112

Special Issue Editor

Dr. Simon Conn

E-Mail Website
Guest Editor
Head, Molecular Hallmarks of Cancer Laboratory Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, Australia
Interests: alternative splicing; circular RNAs; cancer; epithelial-mesenchymal transition; plant molecular biology

Special Issue Information

Dear Colleagues,

The existence of circular RNA research among mainstream science can be ascribed to the contemporary synergism of big data and keen attention to detail by a number of research groups worldwide. Since the re-emergence of these alternatively spliced RNA transcripts, seminal advances have been made in understanding their biogenesis, interactome, and functions in diverse fields and myriad human diseases. However, the vast majority of research outputs focus on the ability of the highly stable circRNAs to interact with and impact signaling through microRNAs. This is a likely result of seminal papers in the field ascribing a few remarkable circRNAs as “miRNA sponges”. However, the stoichiometric ratio between the (often lowly expressed) circRNA and its (commonly more abundant) target is rarely in favor of a biologically relevant and functional consequence of these interactions.

It is time for yet another revolution in circRNA research to uncover functions beyond their documented ability to bind miRNAs.

This Special Issue aims to illuminate non-canonical functions for this non-canonical family of RNA molecules. As the first of its kind in the circRNA field, this issue will be widely read and, therefore, submissions are strongly encouraged from all areas on cell biology where circRNAs are emerging as key playmakers – prokaryotic, viral, eukaryotic, animal, and plant.

Assoc. Prof. Dr. Simon Conn
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • circular RNAs
  • cell development
  • cancers
  • alternative splicing
  • transcription
  • bioinformatics

Published Papers (15 papers)

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Editorial

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6 pages, 238 KiB  
Editorial
Circular RNAs: Non-Canonical Observations on Non-Canonical RNAs
by Brett W. Stringer, Laura Gantley and Simon J. Conn
Cells 2023, 12(2), 323; https://doi.org/10.3390/cells12020323 - 14 Jan 2023
Cited by 1 | Viewed by 1422
Abstract
The existence of circular RNA (circRNA) research in mainstream science can be attributed to the contemporary synergism of big data and keen attention to detail by several research groups worldwide. Since the re-emergence of these non-canonical RNA transcripts, seminal advances have been made [...] Read more.
The existence of circular RNA (circRNA) research in mainstream science can be attributed to the contemporary synergism of big data and keen attention to detail by several research groups worldwide. Since the re-emergence of these non-canonical RNA transcripts, seminal advances have been made in understanding their biogenesis, interactome, and functions in diverse fields and a myriad of human diseases. However, most research outputs to date have focused on the ability of highly stable circRNAs to interact with, and impact signalling through, microRNAs. This is likely to be the result of seminal papers in the field ascribing a few remarkable circRNAs as “miRNA sponges”. However, the stoichiometric ratio between the (often-lowly-expressed) circRNA and their (commonly-more-abundant) target is rarely in favour of a biologically relevant and functional consequence of these interactions. It is time for yet another revolution in circRNA research to uncover functions beyond their documented ability to bind miRNAs. This Special Issue aims to highlight non-canonical functions for this non-canonical family of RNA molecules. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)

Research

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17 pages, 5215 KiB  
Article
SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion
by Vanessa M. Conn, Marta Gabryelska, Shashikanth Marri, Brett W. Stringer, Rebecca J. Ormsby, Timothy Penn, Santosh Poonnoose, Ganessan Kichenadasse and Simon J. Conn
Cells 2020, 9(11), 2488; https://doi.org/10.3390/cells9112488 - 16 Nov 2020
Cited by 7 | Viewed by 3264
Abstract
High-throughput RNA sequencing (RNA-seq) and dedicated bioinformatics pipelines have synergized to identify an expansive repertoire of unique circular RNAs (circRNAs), exceeding 100,000 variants. While the vast majority of these circRNAs comprise canonical exonic and intronic sequences, microexons (MEs)—which occur in 30% of functional [...] Read more.
High-throughput RNA sequencing (RNA-seq) and dedicated bioinformatics pipelines have synergized to identify an expansive repertoire of unique circular RNAs (circRNAs), exceeding 100,000 variants. While the vast majority of these circRNAs comprise canonical exonic and intronic sequences, microexons (MEs)—which occur in 30% of functional mRNA transcripts—have been entirely overlooked. CircRNAs which contain these known MEs (ME-circRNAs) could be identified with commonly utilized circRNA prediction pipelines, CIRCexplorer2 and CIRI2, but were not previously recognized as ME-circRNAs. In addition, when employing a bespoke bioinformatics pipeline for identifying RNA chimeras, called Hyb, we could also identify over 2000 ME-circRNAs which contain novel MEs at their backsplice junctions, that are uncalled by either CIRCexplorer2 or CIRI2. Analysis of circRNA-seq datasets from gliomas of varying clinical grades compared with matched control tissue has shown circRNAs have potential as prognostic markers for stratifying tumor from healthy tissue. Furthermore, the abundance of microexon-containing circRNAs (ME-circRNAs) between tumor and normal tissues is correlated with the expression of a splicing associated factor, Serine/arginine repetitive matrix 4 (SRRM4). Overexpressing SRRM4, known for regulating ME inclusion in mRNAs critical for neural differentiation, in human HEK293 cells resulted in the biogenesis of over 2000 novel ME-circRNAs, including ME-circEIF4G3, and changes in the abundance of many canonical circRNAs, including circSETDB2 and circLRBA. This shows SRRM4, in which its expression is correlated with poor prognosis in gliomas, acts as a bona fide circRNA biogenesis factor. Given the known roles of MEs and circRNAs in oncogenesis, the identification of these previously unrecognized ME-circRNAs further increases the complexity and functional purview of this non-coding RNA family. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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19 pages, 3102 KiB  
Article
Circular RNA Encoded Amyloid Beta peptides—A Novel Putative Player in Alzheimer’s Disease
by Dingding Mo, Xinping Li, Carsten A. Raabe, Timofey S. Rozhdestvensky, Boris V. Skryabin and Juergen Brosius
Cells 2020, 9(10), 2196; https://doi.org/10.3390/cells9102196 - 29 Sep 2020
Cited by 32 | Viewed by 4965
Abstract
Alzheimer’s disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case [...] Read more.
Alzheimer’s disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case of sporadic AD, the mechanism of Aβ biogenesis remains elusive. circRNAs are a class of transcripts preferentially expressed in brain. We identified a circRNA harboring the Aβ-coding region of the APP gene termed circAβ-a. This circular RNA was detected in the brains of AD patients and non-dementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circAβ-a is efficiently translated into a novel Aβ-containing Aβ175 polypeptide (19.2 KDa) in both cultured cells and human brain. Furthermore, Aβ175 was shown to be processed into Aβ peptides—a hallmark of AD. In summary, our analysis revealed an alternative pathway of Aβ biogenesis. Consequently, circAβ-a and its corresponding translation product could potentially represent novel therapeutic targets for AD treatment. Importantly, our data point to yet another evolutionary route for potentially increasing proteome complexity by generating additional polypeptide variants using back-splicing of primary transcripts that yield circular RNA templates. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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13 pages, 2282 KiB  
Article
Arabidopsis thaliana cbp80, c2h2, and flk Knockout Mutants Accumulate Increased Amounts of Circular RNAs
by Anna Philips, Katarzyna Nowis, Michal Stelmaszczuk, Jan Podkowiński, Luiza Handschuh, Paulina Jackowiak and Marek Figlerowicz
Cells 2020, 9(9), 1937; https://doi.org/10.3390/cells9091937 - 21 Aug 2020
Cited by 8 | Viewed by 3512
Abstract
Circular RNAs (circRNAs) are the products of the non-canonical splicing of pre-mRNAs. In contrast to humans and animals, our knowledge of the biogenesis and function of circRNAs in plants is very scarce. To identify proteins involved in plant circRNA generation, we characterized the [...] Read more.
Circular RNAs (circRNAs) are the products of the non-canonical splicing of pre-mRNAs. In contrast to humans and animals, our knowledge of the biogenesis and function of circRNAs in plants is very scarce. To identify proteins involved in plant circRNA generation, we characterized the transcriptomes of 18 Arabidopsis thaliana knockout mutants for genes related to splicing. The vast majority (>90%) of circRNAs were formed in more than one variant; only a small fraction of circRNAs was mutant-specific. Five times more circRNA types were identified in cbp80 and three times more in c2h2 mutants than in the wild-type. We also discovered that in cbp80, c2h2 and flk mutants, the accumulation of circRNAs was significantly increased. The increased accumulation of circular transcripts was not accompanied by corresponding changes in the accumulation of linear transcripts. Our results indicate that one of the roles of CBP80, C2H2 and FLK in splicing is to ensure the proper order of the exons. In the absence of one of the above-mentioned factors, the process might be altered, leading to the production of circular transcripts. This suggests that the transition toward circRNA production can be triggered by factors sequestering these proteins. Consequently, the expression of linear transcripts might be regulated through circRNA production. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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18 pages, 3891 KiB  
Article
circRNAome Profiling in Oral Carcinoma Unveils a Novel circFLNB that Mediates Tumour Growth-Regulating Transcriptional Response
by Yi-Tung Chen, Ian Yi-Feng Chang, Chia-Hua Kan, Yu-Hao Liu, Yu-Ping Kuo, Hsin-Hao Tseng, Hsing-Chun Chen, Hsuan Liu, Yu-Sun Chang, Jau-Song Yu, Kai-Ping Chang and Bertrand Chin-Ming Tan
Cells 2020, 9(8), 1868; https://doi.org/10.3390/cells9081868 - 10 Aug 2020
Cited by 2 | Viewed by 2455
Abstract
Deep sequencing technologies have revealed the once uncharted non-coding transcriptome of circular RNAs (circRNAs). Despite the lack of protein-coding potential, these unorthodox yet highly stable RNA species are known to act as critical gene regulatory hubs, particularly in malignancies. However, their mechanistic implications [...] Read more.
Deep sequencing technologies have revealed the once uncharted non-coding transcriptome of circular RNAs (circRNAs). Despite the lack of protein-coding potential, these unorthodox yet highly stable RNA species are known to act as critical gene regulatory hubs, particularly in malignancies. However, their mechanistic implications in tumor outcome and translational potential have not been fully resolved. Using RNA-seq data, we profiled the circRNAomes of tumor specimens derived from oral squamous cell carcinoma (OSCC), which is a prevalently diagnosed cancer with a persistently low survival rate. We further catalogued dysregulated circRNAs in connection with tumorigenic progression. Using comprehensive bioinformatics analyses focused on co-expression maps and miRNA-interaction networks, we delineated the regulatory networks that are centered on circRNAs. Interestingly, we identified a tumor-associated, pro-tumorigenic circRNA, named circFLNB, that was implicated in maintaining several tumor-associated phenotypes in vitro and in vivo. Correspondingly, transcriptome profiling of circFLNB-knockdown cells showed alterations in tumor-related genes. Integrated in silico analyses further deciphered the circFLNB-targeted gene network. Together, our current study demarcates the OSCC-associated circRNAome, and unveils a novel circRNA circuit with functional implication in OSCC progression. These systems-based findings broaden mechanistic understanding of oral malignancies and raise new prospects for translational medicine. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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19 pages, 3107 KiB  
Article
In-Depth Analysis Reveals Production of Circular RNAs from Non-Coding Sequences
by Annie Robic, Julie Demars and Christa Kühn
Cells 2020, 9(8), 1806; https://doi.org/10.3390/cells9081806 - 30 Jul 2020
Cited by 15 | Viewed by 2724
Abstract
The sequencing of total RNA depleted for ribosomal sequences remains the method of choice for the study of circRNAs. Our objective was to characterize non-canonical circRNAs, namely not originating from back splicing and circRNA produced by non-coding genes. To this end, we analyzed [...] Read more.
The sequencing of total RNA depleted for ribosomal sequences remains the method of choice for the study of circRNAs. Our objective was to characterize non-canonical circRNAs, namely not originating from back splicing and circRNA produced by non-coding genes. To this end, we analyzed a dataset from porcine testis known to contain about 100 intron-derived circRNAs. Labelling reads containing a circular junction and originating from back splicing provided information on the very small contribution of long non-coding genes to the production of canonical circRNAs. Analyses of the other reads revealed two origins for non-canonical circRNAs: (1) Intronic sequences for lariat-derived intronic circRNAs and intron circles, (2) Mono-exonic genes (mostly non-coding) for either a new type of circRNA (including only part of the exon: sub-exonic circRNAs) or, even more rarely, mono-exonic canonical circRNAs. The most complex set of sub-exonic circRNAs was produced by RNase_MRP (ribozyme RNA). We specifically investigated the intronic circRNA of ATXN2L, which is probably an independently transcribed sisRNA (stable intronic sequence RNA). We may be witnessing the emergence of a new non-coding gene in the porcine genome. Our results are evidence that most non-canonical circRNAs originate from non-coding sequences. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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26 pages, 4394 KiB  
Article
Deep Characterization of Circular RNAs from Human Cardiovascular Cell Models and Cardiac Tissue
by Tobias Jakobi, Dominik Siede, Jessica Eschenbach, Andreas W. Heumüller, Martin Busch, Rouven Nietsch, Benjamin Meder, Patrick Most, Stefanie Dimmeler, Johannes Backs, Hugo A. Katus and Christoph Dieterich
Cells 2020, 9(7), 1616; https://doi.org/10.3390/cells9071616 - 04 Jul 2020
Cited by 28 | Viewed by 4576
Abstract
For decades, cardiovascular disease (CVD) has been the leading cause of death throughout most developed countries. Several studies relate RNA splicing, and more recently also circular RNAs (circRNAs), to CVD. CircRNAs originate from linear transcripts and have been shown to exhibit tissue-specific expression [...] Read more.
For decades, cardiovascular disease (CVD) has been the leading cause of death throughout most developed countries. Several studies relate RNA splicing, and more recently also circular RNAs (circRNAs), to CVD. CircRNAs originate from linear transcripts and have been shown to exhibit tissue-specific expression profiles. Here, we present an in-depth analysis of sequence, structure, modification, and cardiac circRNA interactions. We used human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), human healthy and diseased (ischemic cardiomyopathy, dilated cardiomyopathy) cardiac tissue, and human umbilical vein endothelial cells (HUVECs) to profile circRNAs. We identified shared circRNAs across all samples, as well as model-specific circRNA signatures. Based on these circRNAs, we identified 63 positionally conserved and expressed circRNAs in human, pig, and mouse hearts. Furthermore, we found that the sequence of circRNAs can deviate from the sequence derived from the genome sequence, an important factor in assessing potential functions. Integration of additional data yielded evidence for m6A-methylation of circRNAs, potentially linked to translation, as well as, circRNAs overlapping with potential Argonaute 2 binding sites, indicating potential association with the RISC complex. Moreover, we describe, for the first time in cardiac model systems, a sub class of circRNAs containing the start codon of their primary transcript (AUG circRNAs) and observe an enrichment for m6A-methylation for AUG circRNAs. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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Review

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19 pages, 1928 KiB  
Review
The Pseudo-Circular Genomes of Flaviviruses: Structures, Mechanisms, and Functions of Circularization
by Louis De Falco, Nelly M. Silva, Nuno C. Santos, Roland G. Huber and Ivo C. Martins
Cells 2021, 10(3), 642; https://doi.org/10.3390/cells10030642 - 13 Mar 2021
Cited by 5 | Viewed by 3152
Abstract
The circularization of viral genomes fulfills various functions, from evading host defense mechanisms to promoting specific replication and translation patterns supporting viral proliferation. Here, we describe the genomic structures and associated host factors important for flaviviruses genome circularization and summarize their functional roles. [...] Read more.
The circularization of viral genomes fulfills various functions, from evading host defense mechanisms to promoting specific replication and translation patterns supporting viral proliferation. Here, we describe the genomic structures and associated host factors important for flaviviruses genome circularization and summarize their functional roles. Flaviviruses are relatively small, single-stranded, positive-sense RNA viruses with genomes of approximately 11 kb in length. These genomes contain motifs at their 5′ and 3′ ends, as well as in other regions, that are involved in circularization. These motifs are highly conserved throughout the Flavivirus genus and occur both in mature virions and within infected cells. We provide an overview of these sequence motifs and RNA structures involved in circularization, describe their linear and circularized structures, and discuss the proteins that interact with these circular structures and that promote and regulate their formation, aiming to clarify the key features of genome circularization and understand how these affect the flaviviruses life cycle. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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14 pages, 2291 KiB  
Review
A Singular and Widespread Group of Mobile Genetic Elements: RNA Circles with Autocatalytic Ribozymes
by Marcos de la Peña, Raquel Ceprián and Amelia Cervera
Cells 2020, 9(12), 2555; https://doi.org/10.3390/cells9122555 - 28 Nov 2020
Cited by 16 | Viewed by 3324
Abstract
Circular DNAs, such as most prokaryotic and phage genomes, are a frequent form of nucleic acids, whereas circular RNAs had been regarded as unusual macromolecules until very recently. The first reported RNA circles were the family of small infectious genomes of viroids and [...] Read more.
Circular DNAs, such as most prokaryotic and phage genomes, are a frequent form of nucleic acids, whereas circular RNAs had been regarded as unusual macromolecules until very recently. The first reported RNA circles were the family of small infectious genomes of viroids and circular RNA (circRNA) satellites of plant viruses, some of which contain small self-cleaving RNA motifs, such as the hammerhead (HHR) and hairpin ribozymes. A similar infectious circRNA, the unique human hepatitis delta virus (HDV), is another viral satellite that also encodes self-cleaving motifs called HDV ribozymes. Very recently, different animals have been reported to contain HDV-like circRNAs with typical HDV ribozymes, but also conserved HHR motifs, as we describe here. On the other hand, eukaryotic and prokaryotic genomes encode sequences able to self-excise as circRNAs, like the autocatalytic Group I and II introns, which are widespread genomic mobile elements. In the 1990s, the first circRNAs encoded in a mammalian genome were anecdotally reported, but their abundance and importance have not been unveiled until recently. These gene-encoded circRNAs are produced by events of alternative splicing in a process generally known as backsplicing. However, we have found a second natural pathway of circRNA expression conserved in numerous plant and animal genomes, which efficiently promotes the accumulation of small non-coding RNA circles through the participation of HHRs. Most of these genome-encoded circRNAs with HHRs are the transposition intermediates of a novel family of non-autonomous retrotransposons called retrozymes, with intriguing potential as new forms of gene regulation. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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15 pages, 883 KiB  
Review
The Biomarker and Therapeutic Potential of Circular Rnas in Schizophrenia
by Artem Nedoluzhko, Natalia Gruzdeva, Fedor Sharko, Sergey Rastorguev, Natalia Zakharova, Georgy Kostyuk and Vadim Ushakov
Cells 2020, 9(10), 2238; https://doi.org/10.3390/cells9102238 - 04 Oct 2020
Cited by 11 | Viewed by 4029
Abstract
Circular RNAs (circRNAs) are endogenous, single-stranded, most frequently non-coding RNA (ncRNA) molecules that play a significant role in gene expression regulation. Circular RNAs can affect microRNA functionality, interact with RNA-binding proteins (RBPs), translate proteins by themselves, and directly or indirectly modulate gene expression [...] Read more.
Circular RNAs (circRNAs) are endogenous, single-stranded, most frequently non-coding RNA (ncRNA) molecules that play a significant role in gene expression regulation. Circular RNAs can affect microRNA functionality, interact with RNA-binding proteins (RBPs), translate proteins by themselves, and directly or indirectly modulate gene expression during different cellular processes. The affected expression of circRNAs, as well as their targets, can trigger a cascade of events in the genetic regulatory network causing pathological conditions. Recent studies have shown that altered circular RNA expression patterns could be used as biomarkers in psychiatric diseases, including schizophrenia (SZ); moreover, circular RNAs together with other cell molecules could provide new insight into mechanisms of this disorder. In this review, we focus on the role of circular RNAs in the pathogenesis of SZ and analyze their biomarker and therapeutic potential in this disorder. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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20 pages, 1172 KiB  
Review
Protein-Related Circular RNAs in Human Pathologies
by Olga Wawrzyniak, Żaneta Zarębska, Konrad Kuczyński, Anna Gotz-Więckowska and Katarzyna Rolle
Cells 2020, 9(8), 1841; https://doi.org/10.3390/cells9081841 - 06 Aug 2020
Cited by 36 | Viewed by 4176
Abstract
Circular RNAs (circRNAs) are a distinct family of RNAs derived from alternative splicing which play a crucial role in regulating gene expression by acting as microRNA (miRNA) and RNA binding protein (RBP) sponges. However, recent studies have also reported the multifunctional potential of [...] Read more.
Circular RNAs (circRNAs) are a distinct family of RNAs derived from alternative splicing which play a crucial role in regulating gene expression by acting as microRNA (miRNA) and RNA binding protein (RBP) sponges. However, recent studies have also reported the multifunctional potential of these particles. Under different conditions, circRNAs not only regulate protein synthesis, destination, and degradation but can serve as protein scaffolds or recruiters and are also able to produce short peptides with active biological functions. circRNAs are under ongoing investigation because of their close association with the development of diseases. Some circRNAs are reportedly expressed in a tissue- and development stage-specific manner. Furthermore, due to other features of circRNAs, including their stability, conservation, and high abundance in bodily fluids, they are believed to be potential biomarkers for various diseases, including cancers. In this review, we focus on providing a summary of the current knowledge on circRNA–protein interactions. We present the properties and functions of circRNAs, the possible mechanisms of their translation abilities, and the emerging functions of circRNA-derived peptides in human pathologies. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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24 pages, 2127 KiB  
Review
The Secret Garden of Neuronal circRNAs
by Silvia Gasparini, Valerio Licursi, Carlo Presutti and Cecilia Mannironi
Cells 2020, 9(8), 1815; https://doi.org/10.3390/cells9081815 - 31 Jul 2020
Cited by 11 | Viewed by 3760
Abstract
High-throughput transcriptomic profiling approaches have revealed that circular RNAs (circRNAs) are important transcriptional gene products, identified across a broad range of organisms throughout the eukaryotic tree of life. In the nervous system, they are particularly abundant, developmentally regulated, region-specific, and enriched in genes [...] Read more.
High-throughput transcriptomic profiling approaches have revealed that circular RNAs (circRNAs) are important transcriptional gene products, identified across a broad range of organisms throughout the eukaryotic tree of life. In the nervous system, they are particularly abundant, developmentally regulated, region-specific, and enriched in genes for neuronal proteins and synaptic factors. These features suggested that circRNAs are key components of an important layer of neuronal gene expression regulation, with known and anticipated functions. Here, we review major recognized aspects of circRNA biogenesis, metabolism and biological activities, examining potential new functions in the context of the nervous system. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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20 pages, 1805 KiB  
Review
Circular RNAs in Sepsis: Biogenesis, Function, and Clinical Significance
by Jesús Beltrán-García, Rebeca Osca-Verdegal, Elena Nacher-Sendra, Federico V. Pallardó and José Luis García-Giménez
Cells 2020, 9(6), 1544; https://doi.org/10.3390/cells9061544 - 25 Jun 2020
Cited by 46 | Viewed by 4457
Abstract
Sepsis is a life-threatening condition that occurs when the body responds to an infection that damages it is own tissues. The major problem in sepsis is rapid, vital status deterioration in patients, which can progress to septic shock with multiple organ failure if [...] Read more.
Sepsis is a life-threatening condition that occurs when the body responds to an infection that damages it is own tissues. The major problem in sepsis is rapid, vital status deterioration in patients, which can progress to septic shock with multiple organ failure if not properly treated. As there are no specific treatments, early diagnosis is mandatory to reduce high mortality. Despite more than 170 different biomarkers being postulated, early sepsis diagnosis and prognosis remain a challenge for clinicians. Recent findings propose that circular RNAs (circRNAs) may play a prominent role in regulating the patients’ immune system against different pathogens, including bacteria and viruses. Mounting evidence also suggests that the misregulation of circRNAs is an early event in a wide range of diseases, including sepsis. Despite circRNA levels being altered in sepsis, the specific mechanisms controlling the dysregulation of these noncoding RNAs are not completely elucidated, although many factors are known to affect circRNA biogenesis. Therefore, there is a need to explore the molecular pathways that lead to this disorder. This review describes the role of this new class of regulatory RNAs in sepsis and the feasibility of using circRNAs as diagnostic biomarkers for sepsis, opening up new avenues for circRNA-based medicine. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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17 pages, 1081 KiB  
Review
Circular RNA in Diseased Heart
by Ying Wang and Bin Liu
Cells 2020, 9(5), 1240; https://doi.org/10.3390/cells9051240 - 17 May 2020
Cited by 33 | Viewed by 4410
Abstract
Heart disease remains the leading cause of death globally and leads to tremendous socio-economic burden. Despite advances in the field of cardiovascular research, novel theranostics are still in urgent need. Remarkable progress has been made in understanding aberrant protein interactions and signaling pathways [...] Read more.
Heart disease remains the leading cause of death globally and leads to tremendous socio-economic burden. Despite advances in the field of cardiovascular research, novel theranostics are still in urgent need. Remarkable progress has been made in understanding aberrant protein interactions and signaling pathways in the diseased heart, but less is known regarding epigenetic regulation. Non-coding RNAs have emerged as important regulators of cardiac function and have been implicated in disease. While significant progress has been made in understanding the roles of microRNAs and long non-coding RNAs, the functional roles of circular RNAs are less explored. Recent studies have provided ample evidence supporting their roles in multiple physiological processes including regulating the function of the heart. Compared with other RNAs, circular RNAs exhibit higher stability and more versatile functional modes: including sponging microRNAs, scaffolding proteins, regulating transcription, and even encoding small regulatory peptides. These characteristics make circular RNAs promising candidates for the development of diagnostic tools and therapies for heart disease. In this review, we will discuss the biogenesis of circular RNAs and provide an update of their functional implications in heart disease, with an emphasis on heart failure and arrhythmias. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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19 pages, 740 KiB  
Review
circRNAs Signature as Potential Diagnostic and Prognostic Biomarker for Diabetes Mellitus and Related Cardiovascular Complications
by Mohamed Zaiou
Cells 2020, 9(3), 659; https://doi.org/10.3390/cells9030659 - 09 Mar 2020
Cited by 66 | Viewed by 4641
Abstract
Circular RNAs (circRNAs) belong to the ever-growing class of naturally occurring noncoding RNAs (ncRNAs) molecules. Unlike linear RNA, circRNAs are covalently closed transcripts mostly generated from precursor-mRNA by a non-canonical event called back-splicing. They are highly stable, evolutionarily conserved, and widely distributed in [...] Read more.
Circular RNAs (circRNAs) belong to the ever-growing class of naturally occurring noncoding RNAs (ncRNAs) molecules. Unlike linear RNA, circRNAs are covalently closed transcripts mostly generated from precursor-mRNA by a non-canonical event called back-splicing. They are highly stable, evolutionarily conserved, and widely distributed in eukaryotes. Some circRNAs are believed to fulfill a variety of functions inside the cell mainly by acting as microRNAs (miRNAs) or RNA-binding proteins (RBPs) sponges. Furthermore, mounting evidence suggests that the misregulation of circRNAs is among the first alterations in various metabolic disorders including obesity, hypertension, and cardiovascular diseases. More recent research has revealed that circRNAs also play a substantial role in the pathogenesis of diabetes mellitus (DM) and related vascular complications. These findings have added a new layer of complexity to our understanding of DM and underscored the need to reexamine the molecular pathways that lead to this disorder in the context of epigenetics and circRNA regulatory mechanisms. Here, I review current knowledge about circRNAs dysregulation in diabetes and describe their potential role as innovative biomarkers to predict diabetes-related cardiovascular (CV) events. Finally, I discuss some of the actual limitations to the promise of these RNA transcripts as emerging therapeutics and provide recommendations for future research on circRNA-based medicine. Full article
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
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