scholarly journals Reduced RNA editing in the failing human heart mediates alternative circular RNA splicing

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
K Kokot ◽  
J Kneuer ◽  
D John ◽  
M Moebius-Winkler ◽  
M Mueller ◽  
...  
Keyword(s):  
Rna Editing ◽  
Rna Splicing ◽  
Human Heart ◽  
Rna Stability ◽  
Circular Rna ◽  
Major Type ◽  
Circular Rnas ◽  
Protein Coding ◽  
Alu Elements ◽  
Alternative Mrna Splicing

Abstract Background and purpose Post-transcriptional RNA editing is an important mechanism in the development of human diseases. RNA editing can affect RNA stability and alternative splicing. The aim of our study was to characterize RNA editing and its impact on alternative RNA splicing in the healthy and failing human heart. Methods and results Human heart samples of heart failure (HF) patients (n=20) and controls (n=10) were analyzed using RNA sequencing with subsequent analysis of RNA editing. We identified adenosine-to-inosine (A-to-I) editing as the major form of RNA editing in human hearts, being reduced in HF patients. Consistently, we found the editing enzyme ADAR2 reduced in HF patients. A-to-I RNA editing predominantly occurred in intronic regions of protein-coding genes, specifically in repetitive, primate-specific Alu elements which can affect RNA splicing. Indeed, we found 173 circular RNAs (circRNAs) regulated by alternative mRNA splicing in the failing heart. Loss of ADAR2 led to reduced RNA editing concomitant with an increase of circRNA, while overexpression reduced circRNA expression and enhanced RNA editing. Conclusion A-to-I editing is the major type of RNA editing in the human heart, being reduced in HF. We demonstrate a primate-specific alternative RNA splicing mechanism mediated by RNA editing in human hearts. The findings may be relevant to diseases with reduced RNA editing such as cancer, neurological and cardiac diseases. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals CircITCH: A Circular RNA With Eminent Roles in the Carcinogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Soudeh Ghafouri-Fard ◽  
Tayyebeh Khoshbakht ◽  
Mohammad Taheri ◽  
Elena Jamali
Keyword(s):  
Tumor Suppressor ◽  
Circular Rna ◽  
Circular Rnas ◽  
Protein Coding ◽  
Comprehensive Review ◽  
Ubiquitin Protein Ligase ◽  
Single Study ◽  
Non Coding Rnas

Circular RNAs (circRNAs) are a group of long non-coding RNAs with enclosed structure generated by back-splicing events. Numerous members of these transcripts have been shown to affect carcinogenesis. Circular RNA itchy E3 ubiquitin protein ligase (circITCH) is a circRNA created from back splicing events in ITCH gene, a protein coding gene on 20q11.22 region. ITCH has a role as a catalyzer for ubiquitination through both proteolytic and non-proteolytic routes. CircITCH is involved in the pathetiology of cancers through regulation of the linear isoform as well as serving as sponge for several microRNAs, namely miR-17, miR-224, miR-214, miR-93-5p, miR-22, miR-7, miR-106a, miR-10a, miR-145, miR-421, miR-224-5p, miR-197 and miR-199a-5p. CircITCH is also involved in the modulation of Wnt/β-catenin and PTEN/PI3K/AKT pathways. Except from a single study in osteosarcoma, circITCH has been found to exert tumor suppressor role in diverse cancers. In the present manuscript, we provided a comprehensive review of investigations that reported function of circITCH in the carcinogenesis.

scholarly journals The Regulatory Activity of Noncoding RNAs in ILCs

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2742
Author(s):  
Alessio Grimaldi ◽  
Giuseppe Pietropaolo ◽  
Helena Stabile ◽  
Andrea Kosta ◽  
Cristina Capuano ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Rna Stability ◽  
Lymphoid Cells ◽  
Circular Rnas ◽  
Transcriptional Networks ◽  
Regulatory Activity ◽  
Protein Coding ◽  
Host Protection ◽  
Microbial Infections ◽  
And Function

Innate lymphoid cells (ILCs) are innate lymphocytes playing essential functions in protection against microbial infections and participate in both homeostatic and pathological contexts, including tissue remodeling, cancer, and inflammatory disorders. A number of lineage-defining transcription factors concur to establish transcriptional networks which determine the identity and the activity of the distinct ILC subsets. However, the contribution of other regulatory molecules in controlling ILC development and function is also recently emerging. In this regard, noncoding RNA (ncRNAs) represent key elements of the complex regulatory network of ILC biology and host protection. ncRNAs mostly lack protein-coding potential, but they are endowed with a relevant regulatory activity in immune and nonimmune cells because of their ability to control chromatin structure, RNA stability, and/or protein synthesis. Herein, we summarize recent studies describing how distinct types of ncRNAs, mainly microRNAs, long ncRNAs, and circular RNAs, act in the context of ILC biology. In particular, we comment on how ncRNAs can exert key effects in ILCs by controlling gene expression in a cell- or state-specific manner and how this tunes distinct functional outputs in ILCs.

scholarly journals Comparative Analysis of the Circular Transcriptome in Muscle, Liver, and Testis in Three Livestock Species

2021 ◽  
Vol 12 ◽  
Author(s):  
Annie Robic ◽  
Chloé Cerutti ◽  
Christa Kühn ◽  
Thomas Faraut
Keyword(s):  
Mitochondrial Protein ◽  
Relative Weight ◽  
Circular Rna ◽  
Farm Animals ◽  
Circular Rnas ◽  
Transcription Level ◽  
Protein Coding ◽  
Comparative Analyses ◽  
Protein Coding Genes ◽  
Genomic Regions

Circular RNAs have been observed in a large number of species and tissues and are now recognized as a clear component of the transcriptome. Our study takes advantage of functional datasets produced within the FAANG consortium to investigate the pervasiveness of circular RNA transcription in farm animals. We describe here the circular transcriptional landscape in pig, sheep and bovine testicular, muscular and liver tissues using total 66 RNA-seq datasets. After an exhaustive detection of circular RNAs, we propose an annotation of exonic, intronic and sub-exonic circRNAs and comparative analyses of circRNA content to evaluate the variability between individuals, tissues and species. Despite technical bias due to the various origins of the datasets, we were able to characterize some features (i) (ruminant) liver contains more exonic circRNAs than muscle (ii) in testis, the number of exonic circRNAs seems associated with the sexual maturity of the animal. (iii) a particular class of circRNAs, sub-exonic circRNAs, are produced by a large variety of multi-exonic genes (protein-coding genes, long non-coding RNAs and pseudogenes) and mono-exonic genes (protein-coding genes from mitochondrial genome and small non-coding genes). Moreover, for multi-exonic genes there seems to be a relationship between the sub-exonic circRNAs transcription level and the linear transcription level. Finally, sub-exonic circRNAs produced by mono-exonic genes (mitochondrial protein-coding genes, ribozyme, and sno) exhibit a particular behavior. Caution has to be taken regarding the interpretation of the unannotated circRNA proportion in a given tissue/species: clusters of circRNAs without annotation were characterized in genomic regions with annotation and/or assembly problems of the respective animal genomes. This study highlights the importance of improving genome annotation to better consider candidate circRNAs and to better understand the circular transcriptome. Furthermore, it emphasizes the need for considering the relative “weight” of circRNAs/parent genes for comparative analyses of several circular transcriptomes. Although there are points of agreement in the circular transcriptome of the same tissue in two species, it will be not possible to do without the characterization of it in both species.

scholarly journals Closing the circle: current state and perspectives of circular RNA databases

2020 ◽  
Author(s):  
Marieke Vromman ◽  
Jo Vandesompele ◽  
Pieter-Jan Volders
Keyword(s):  
Splice Junction ◽  
Circular Rna ◽  
Circular Rnas ◽  
Working Mechanism ◽  
Comprehensive Overview ◽  
Specific Expression ◽  
Protein Coding ◽  
Rna Molecules ◽  
Current State ◽  
Coding Potential

Abstract Circular RNAs (circRNAs) are covalently closed RNA molecules that have been linked to various diseases, including cancer. However, a precise function and working mechanism are lacking for the larger majority. Following many different experimental and computational approaches to identify circRNAs, multiple circRNA databases were developed as well. Unfortunately, there are several major issues with the current circRNA databases, which substantially hamper progression in the field. First, as the overlap in content is limited, a true reference set of circRNAs is lacking. This results from the low abundance and highly specific expression of circRNAs, and varying sequencing methods, data-analysis pipelines, and circRNA detection tools. A second major issue is the use of ambiguous nomenclature. Thus, redundant or even conflicting names for circRNAs across different databases contribute to the reproducibility crisis. Third, circRNA databases, in essence, rely on the position of the circRNA back-splice junction, whereas alternative splicing could result in circRNAs with different length and sequence. To uniquely identify a circRNA molecule, the full circular sequence is required. Fourth, circRNA databases annotate circRNAs’ microRNA binding and protein-coding potential, but these annotations are generally based on presumed circRNA sequences. Finally, several databases are not regularly updated, contain incomplete data or suffer from connectivity issues. In this review, we present a comprehensive overview of the current circRNA databases and their content, features, and usability. In addition to discussing the current issues regarding circRNA databases, we come with important suggestions to streamline further research in this growing field.

scholarly journals An improved method for circular RNA purification using RNase R that efficiently removes linear RNAs containing G-quadruplexes or structured 3′ ends

2019 ◽  
Vol 47 (16) ◽  
pp. 8755-8769 ◽  
Author(s):  
Mei-Sheng Xiao ◽  
Jeremy E Wilusz
Keyword(s):  
Circular Rna ◽  
The Body ◽  
Circular Rnas ◽  
Rna Structures ◽  
Rnase R ◽  
Protein Coding ◽  
Histone Mrnas ◽  
Rna Purification ◽  
G Quadruplex ◽  
Covalently Linked

AbstractThousands of eukaryotic protein-coding genes generate circular RNAs that have covalently linked ends and are resistant to degradation by exonucleases. To prove their circularity as well as biochemically enrich these transcripts, it has become standard in the field to use the 3′-5′ exonuclease RNase R. Here, we demonstrate that standard protocols involving RNase R can fail to digest >20% of all highly expressed linear RNAs, but these shortcomings can largely be overcome. RNAs with highly structured 3′ ends, including snRNAs and histone mRNAs, are naturally resistant to RNase R, but can be efficiently degraded once a poly(A) tail has been added to their ends. In addition, RNase R stalls in the body of many polyadenylated mRNAs, especially at G-rich sequences that have been previously annotated as G-quadruplex (G4) structures. Upon replacing K+ (which stabilizes G4s) with Li+ in the reaction buffer, we find that RNase R is now able to proceed through these sequences and fully degrade the mRNAs in their entirety. In total, our results provide important improvements to the current methods used to isolate circular RNAs as well as a way to reveal RNA structures that may naturally inhibit degradation by cellular exonucleases.

scholarly journals Circular and long non-coding RNAs and their role in ophthalmologic diseases

2018 ◽  
Author(s):  
Olga Wawrzyniak ◽  
Żaneta Zarębska ◽  
Katarzyna Rolle ◽  
Anna Gotz-Więckowska
Keyword(s):  
Current Knowledge ◽  
Critical Role ◽  
Circular Rna ◽  
Age Related Macular Degeneration ◽  
Circular Rnas ◽  
Protein Coding ◽  
Rna Molecules ◽  
Age Related ◽  
Non Coding Rnas ◽  
Transcriptional Gene Regulation

Long non-coding RNAs are >200-nucleotide-long RNA molecules which lack or have limited protein-coding potential. They can regulate protein formation through several different mechanisms. Similarly, circular RNAs are reported to play a critical role in post-transcriptional gene regulation. Changes in the expression pattern of these molecules are known to underlie various diseases, including cancer, cardiovascular, neurological and immunological disorders (Rinn & Chang, 2012; Sun & Kraus, 2015). Recent studies suggest that they are differentially expressed both in healthy ocular tissues as well as in eye pathologies, such as neovascularization, proliferative vitreoretinopathy, glaucoma, cataract, ocular malignancy or even strabismus (Li et al., 2016). Aetiology of ocular diseases is multifactorial and combines genetic and environmental factors, including epigenetic and non-coding RNAs. In addition, disorders like diabetic retinopathy or age-related macular degeneration lack biomarkers for early detection as well as effective treatment methods that would allow controlling the disease progression at its early stages. The newly discovered non-coding RNAs seem to be the ideal candidates for novel molecular markers and therapeutic strategies. In this review, we summarized the current knowledge about gene expression regulators – long non-coding and circular RNA molecules in eye diseases.

scholarly journals SpliceV: Analysis and publication quality printing of linear and circular RNA splicing, expression and regulation

2019 ◽  
Author(s):  
Nathan Ungerleider ◽  
Erik Flemington
Keyword(s):  
Rna Splicing ◽  
Rna Binding ◽  
Circular Rna ◽  
Rapid Expansion ◽  
Circular Rnas ◽  
Analysis Tool ◽  
Transcript Processing ◽  
Alternatively Spliced ◽  
The Impact ◽  
Publication Quality

AbstractIn eukaryotes, most genes code for multiple transcript isoforms that are generated through the complex and tightly regulated process of RNA splicing. Despite arising from identical precursor transcripts, alternatively spliced RNAs can have dramatically different functions. Transcriptome complexity is elevated further by the production of circular RNAs (circRNAs), another class of mature RNA that results from the splicing of a downstream splice donor to an upstream splice acceptor. While there has been a rapid expansion of circRNA catalogs in the last few years through the utilization of next generation sequencing approaches, our understanding of the mechanisms and regulation of circular RNA biogenesis, the impact that circRNA generation has on parental transcript processing, and the functions carried out by circular RNAs remains limited. Here, we present a visualization and analysis tool, SpliceV, that rapidly plots all relevant forward-and back-splice data, with exon and single nucleotide level coverage information from RNA-seq experiments in a publication quality format. SpliceV also integrates analysis features that assist investigations into splicing regulation and transcript functions through the display of predicted RNA binding protein sites and the configuration of repetitive elements along the primary transcript. SpliceV is compatible with both Python 2.7 and 3+, and is distributed under the GNU Public License. The source code is freely available for download at https://github.com/flemingtonlab/SpliceV and can be installed from PyPI using pip.

scholarly journals The majority of A-to-I RNA editing is not required for mammalian homeostasis

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Alistair M. Chalk ◽  
Scott Taylor ◽  
Jacki E. Heraud-Farlow ◽  
Carl R. Walkley
Keyword(s):  
Rna Editing ◽  
Rna Splicing ◽  
Significant Proportion ◽  
Small Subset ◽  
Protein Coding ◽  
Site Preferences ◽  
Dependent Protein ◽  
Immune Sensing ◽  
Innate Immune Sensing

Abstract Background Adenosine-to-inosine (A-to-I) RNA editing, mediated by ADAR1 and ADAR2, occurs at tens of thousands to millions of sites across mammalian transcriptomes. A-to-I editing can change the protein coding potential of a transcript and alter RNA splicing, miRNA biology, RNA secondary structure and formation of other RNA species. In vivo, the editing-dependent protein recoding of GRIA2 is the essential function of ADAR2, while ADAR1 editing prevents innate immune sensing of endogenous RNAs by MDA5 in both human and mouse. However, a significant proportion of A-to-I editing sites can be edited by both ADAR1 and ADAR2, particularly within the brain where both are highly expressed. The physiological function(s) of these shared sites, including those evolutionarily conserved, is largely unknown. Results To generate completely A-to-I editing-deficient mammals, we crossed the viable rescued ADAR1-editing-deficient animals (Adar1E861A/E861AIfih1−/−) with rescued ADAR2-deficient (Adarb1−/−Gria2R/R) animals. Unexpectedly, the global absence of editing was well tolerated. Adar1E861A/E861AIfih1−/−Adarb1−/−Gria2R/R were recovered at Mendelian ratios and age normally. Detailed transcriptome analysis demonstrated that editing was absent in the brains of the compound mutants and that ADAR1 and ADAR2 have similar editing site preferences and patterns. Conclusions We conclude that ADAR1 and ADAR2 are non-redundant and do not compensate for each other’s essential functions in vivo. Physiologically essential A-to-I editing comprises a small subset of the editome, and the majority of editing is dispensable for mammalian homeostasis. Moreover, in vivo biologically essential protein recoding mediated by A-to-I editing is an exception in mammals.

A Novel Circular RNA circPLCE1 Facilitates the Malignant Progression of Colorectal Cancer by Repressing the SRSF2-dependent PLCE1 pre-RNA Splicing

2021 ◽  
Author(s):  
Zhi-Lei Chen ◽  
Hong-Yu Chen ◽  
Lei Yang ◽  
Xiang-Nan Li ◽  
Zhenjun Wang
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Rna Splicing ◽  
Ectopic Expression ◽  
Circular Rna ◽  
Malignant Progression ◽  
Circular Rnas ◽  
Normal Tissues

Abstract Background: Studies have demonstrated that circular RNAs (circRNAs) play important roles in various types of cancer; however, the mechanisms of circRNAs located in the nucleus have rarely been explored. Here, we reported a novel circular RNA circPLCE1 facilitates the malignant progression of colorectal cancer (CRC) via repression of SRSF2-dependent PLCE1 pre-RNA splicing. Methods: qRT-PCR was used to determine the expression of circPLCE1 in CRC tissues and cells. CCK-8, transwell and flow cytometric assays were used to assess the role of circPLCE1 in CRC cell proliferation, migration and apoptosis, respectively. Animal study was carried to test the role of circPLCE1 in vivo. Further, catRAPID and RPISeq were applied to predict the possible binding protein of circPLCE1. RNA fractionation and RIP assays were used to confirm the RNA-protein interaction. Results: In this study, we found that circPLCE1 was significantly downregulated in CRC tissues compared with adjacent normal tissues. However, circPLCE1 knockdown suppresses CRC cell proliferation, migration, invasion and increased apoptosis. Nude mice experiments showed that ectopic expression of circPLCE1 dramatically increased tumor growth in vivo. Mechanically, circPLCE1 directly binding to SRSF2 protein, repressing SRSF2-dependent PLCE1 pre-RNA splicing, resulting in the progression of CRC. Individually mutating the binding sites of circPLCE1 derepressed the production of PLCE1 mRNA. Conclusions: Our studies revealed a novel molecular mechanism in the regulation of PLCE1 and implicated a new function of circular RNA, supporting the pursuit of circPLCE1 as a potential tool for future CRC treatment.

scholarly journals Role of Circular RNA in Kidney-Related Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin-Tian Chen ◽  
Zhong-Wei Li ◽  
Xue Zhao ◽  
Min-Le Li ◽  
Ping-Fu Hou ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Circular Rna ◽  
Public Health Issue ◽  
Circular Rnas ◽  
Biological Functions ◽  
Acid Base Balance ◽  
Base Balance

The kidney is vital in maintaining fluid, electrolyte, and acid–base balance. Kidney-related diseases, which are an increasing public health issue, can happen to people of any age and at any time. Circular RNAs (circRNAs) are endogenous RNA that are produced by selective RNA splicing and are involved in progression of various diseases. Studies have shown that various kidney diseases, including renal cell carcinoma, acute kidney injury, and chronic kidney disease, are linked to circRNAs. This review outlines the characteristics and biological functions of circRNAs and discusses specific studies that provide insights into the function and potential of circRNAs for application in the diagnosis and treatment of kidney-related diseases.

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