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      Functional Role of circRNAs in the Regulation of Fetal Development, Muscle Development, and Lactation in Livestock

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          Abstract

          circRNAs are a class of endogenous noncoding RNA molecules with closed loop structures. They are mainly responsible for regulating gene expression in eukaryotic cells. With the emergence of high-throughput RNA sequencing (RNA-Seq) and new types of bioinformatics tools, thousands of circRNAs have been discovered, making circRNA one of the research hotspots. Recent studies have shown that circRNAs play an important regulatory role in the growth, reproduction, and formation of livestock products. They can not only regulate mammalian fetal growth and development but also have important regulatory effects on livestock muscle development and lactation. In this review, we briefly introduce the putative biogenic pathways and regulatory functions of circRNA and highlight our understanding of circRNA and its latest advances in fetal development, muscle development, and lactation biogenesis as well as expression in livestock. This review will provide a theoretical basis for the research and development of related industries.

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          Most cited references86

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          Circular RNAs are a large class of animal RNAs with regulatory potency.

          Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
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            Natural RNA circles function as efficient microRNA sponges.

            MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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              circRNA biogenesis competes with pre-mRNA splicing.

              Circular RNAs (circRNAs) are widely expressed noncoding RNAs. However, their biogenesis and possible functions are poorly understood. Here, by studying circRNAs that we identified in neuronal tissues, we provide evidence that animal circRNAs are generated cotranscriptionally and that their production rate is mainly determined by intronic sequences. We demonstrate that circularization and splicing compete against each other. These mechanisms are tissue specific and conserved in animals. Interestingly, we observed that the second exon of the splicing factor muscleblind (MBL/MBNL1) is circularized in flies and humans. This circRNA (circMbl) and its flanking introns contain conserved muscleblind binding sites, which are strongly and specifically bound by MBL. Modulation of MBL levels strongly affects circMbl biosynthesis, and this effect is dependent on the MBL binding sites. Together, our data suggest that circRNAs can function in gene regulation by competing with linear splicing. Furthermore, we identified muscleblind as a factor involved in circRNA biogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2021
                19 February 2021
                : 2021
                : 5383210
                Affiliations
                1Laboratory for Bio-Feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing, China
                2The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan
                Author notes

                Academic Editor: Hamid Mukhtar

                Author information
                https://orcid.org/0000-0001-5173-589X
                https://orcid.org/0000-0001-6992-1447
                https://orcid.org/0000-0003-2172-6006
                https://orcid.org/0000-0003-2983-2268
                https://orcid.org/0000-0001-7355-3050
                https://orcid.org/0000-0002-5104-8106
                Article
                10.1155/2021/5383210
                7914090
                33688493
                cec1d164-1b42-46ee-bba4-b3aceaad309e
                Copyright © 2021 Tianle He et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 February 2020
                : 23 January 2021
                : 5 February 2021
                Funding
                Funded by: Chongqing Innovation Funding Projects for Returned Scholars
                Award ID: cx2019093
                Funded by: China Association for Science and Technology
                Award ID: [2019]293-98
                Funded by: Special Funding for Postdoctoral Research Projects in Chongqing
                Award ID: XMT 2081061
                Funded by: National Science Foundation for Post-Doctoral Scientists of China
                Award ID: 2018M640895
                Funded by: National Key Research and Development Plan of China
                Award ID: 2018YFD0501004
                Funded by: National Natural Science Foundation of China
                Award ID: 31902167
                Funded by: Natural Science Foundation of Chongqing
                Award ID: cstc2019jcyj-msxmX0524
                Categories
                Review Article

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