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      Circular RNAs—The Road Less Traveled

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          Abstract

          Circular RNAs are the most recent addition in the non-coding RNA family, which has started to gain recognition after a decade of obscurity. The first couple of reports that emerged at the beginning of this decade and the amount of evidence that has accumulated thereafter has, however, encouraged RNA researchers to navigate further in the quest for the exploration of circular RNAs. The joining of 5′ and 3′ ends of RNA molecules through backsplicing forms circular RNAs during co-transcriptional or post-transcriptional processes. These molecules are capable of effectively sponging microRNAs, thereby regulating the cellular processes, as evidenced by numerous animal and plant systems. Preliminary studies have shown that circular RNA has an imperative role in transcriptional regulation and protein translation, and it also has significant therapeutic potential. The high stability of circular RNA is rendered by its closed ends; they are nevertheless prone to degradation by circulating endonucleases in serum or exosomes or by microRNA-mediated cleavage due to their high complementarity. However, the identification of circular RNAs involves diverse methodologies and the delineation of its possible role and mechanism in the regulation of cellular and molecular architecture has provided a new direction for the continuous research into circular RNA. In this review, we discuss the possible mechanism of circular RNA biogenesis, its structure, properties, degradation, and the growing amount of evidence regarding the detection methods and its role in animal and plant systems.

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          CIRI: an efficient and unbiased algorithm for de novo circular RNA identification

          Recent studies reveal that circular RNAs (circRNAs) are a novel class of abundant, stable and ubiquitous noncoding RNA molecules in animals. Comprehensive detection of circRNAs from high-throughput transcriptome data is an initial and crucial step to study their biogenesis and function. Here, we present a novel chiastic clipping signal-based algorithm, CIRI, to unbiasedly and accurately detect circRNAs from transcriptome data by employing multiple filtration strategies. By applying CIRI to ENCODE RNA-seq data, we for the first time identify and experimentally validate the prevalence of intronic/intergenic circRNAs as well as fragments specific to them in the human transcriptome. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0571-3) contains supplementary material, which is available to authorized users.
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            Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation.

            Circularization was recently recognized to broadly expand transcriptome complexity. Here, we exploit massive Drosophila total RNA-sequencing data, >5 billion paired-end reads from >100 libraries covering diverse developmental stages, tissues, and cultured cells, to rigorously annotate >2,500 fruit fly circular RNAs. These mostly derive from back-splicing of protein-coding genes and lack poly(A) tails, and the circularization of hundreds of genes is conserved across multiple Drosophila species. We elucidate structural and sequence properties of Drosophila circular RNAs, which exhibit commonalities and distinctions from mammalian circles. Notably, Drosophila circular RNAs harbor >1,000 well-conserved canonical miRNA seed matches, especially within coding regions, and coding conserved miRNA sites reside preferentially within circularized exons. Finally, we analyze the developmental and tissue specificity of circular RNAs and note their preferred derivation from neural genes and enhanced accumulation in neural tissues. Interestingly, circular isoforms increase substantially relative to linear isoforms during CNS aging and constitute an aging biomarker. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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              Specific effects of microRNAs on the plant transcriptome.

              Most plant microRNAs (miRNAs) have perfect or near-perfect complementarity with their targets. This is consistent with their primary mode of action being cleavage of target mRNAs, similar to that induced by perfectly complementary small interfering RNAs (siRNAs). However, there are natural targets with up to five mismatches. Furthermore, artificial siRNAs can have substantial effects on so-called off-targets, to which they have only limited complementarity. By analyzing the transcriptome of plants overexpressing different miRNAs, we have deduced a set of empirical parameters for target recognition. Compared to artificial siRNAs, authentic plant miRNAs appear to have much higher specificity, which may reflect their coevolution with the remainder of the transcriptome. We also demonstrate that miR172, previously thought to act primarily by translational repression, can efficiently guide mRNA cleavage, although the effects on steady-state levels of target transcripts are obscured by strong feedback regulation. This finding unifies the view of plant miRNA action.
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                Author and article information

                Contributors
                Journal
                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                2296-889X
                10 January 2020
                2019
                : 6
                : 146
                Affiliations
                [1] 1Department of Plant Biotechnology, School of Biotechnology, Madurai Kamaraj University , Madurai, India
                [2] 2Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University , Madurai, India
                Author notes

                Edited by: Amaresh Chandra Panda, Institute of Life Sciences (ILS), India

                Reviewed by: Kotb Abdelmohsen, National Institute on Aging (NIA), United States; Alfredo Berzal-Herranz, Instituto de Parasitología y Biomedicina López-Neyra (IPBLN), Spain

                *Correspondence: Sankar Natesan sankar.biotech@ 123456mkuniversity.org

                This article was submitted to Protein and RNA Networks, a section of the journal Frontiers in Molecular Biosciences

                †These authors have contributed equally to this work

                Article
                10.3389/fmolb.2019.00146
                6965350
                31998746
                5f7d36be-d098-4657-a44e-4bef93060206
                Copyright © 2020 Guria, Sharma, Natesan and Pandi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 September 2019
                : 03 December 2019
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 151, Pages: 20, Words: 16277
                Funding
                Funded by: Science and Engineering Research Board 10.13039/501100001843
                Award ID: EEQ/2018/000067
                Categories
                Molecular Biosciences
                Review

                circrna,biogenesis,long non-coding rna,mirna sponging,backsplicing

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