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RNA Regulatory Networks 2.0
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RNA Regulatory Networks 2.0

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 (15 November 2022) | Viewed by 29862

Special Issue Editors

Prof. Dr. Francisco J. Enguita

E-Mail Website
Guest Editor
Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal
Interests: non-coding RNAs; cardiovascular diseases; infectious diseases; cell-to-cell communication; circulating RNAs; biomarkers
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. John Mattick

grade E-Mail Website
Guest Editor
School of Biotechnology and Biomolecular Sciences, Room 220C, Level 2, Biological Sciences Building (North), UNSW Sydney, NSW 2052, Australia
Interests: RNA biology; human genome; plasticity; regulatory RNA; gene expression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The centrality of RNA in the flow of information from the genome is the basis of the classical dogma of cell biology. However, the rules and roles governing RNA functions have been dramatically expanded during the last two decades with the discovery of the pervasive transcription of eukaryotic genomes and the growing appreciation of noncoding RNA as a plastic and versatile molecule that carries out a myriad of functions ranging from enzymatic catalysis to scaffolding of protein complexes, nucleation of subcellular domains, and the dynamic organization of chromatin.

The fact that noncoding RNAs (ncRNAs) are prevalent in the transcriptomes of humans and other complex organisms suggests that a second tier of genetic output has evolved in these organisms to enable the integration and coordination of sophisticated suites of gene expression required for differentiation and development, which may be perturbed in cancer and neurological disorders, among others. Moreover, the expansion of the complement of ncRNAs in higher organisms suggests that the evolution of complexity may not have been simply dependent on an expanded repertoire of proteins and protein isoforms but on a (much) larger set of genomic design instructions embedded in trans-acting RNAs, which drive the epigenetic trajectories of development and can respond to internal and external cues through RNA editing and modification.

This Special Issue will welcome scientific contributions and critical reviews analyzing the role and biological functions of RNA-centered regulatory networks in the context of development, brain function, cell physiology, and human disease. 

Prof. Dr. Francisco J. Enguita
Prof. Dr. John Mattick
Guest Editors

Manuscript Submission Information

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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

  • RNA-based regulation
  • Noncoding RNAs
  • RNA editing
  • Cell-to-cell communication
  • Metabolic disease
  • RNA structure
  • Genome dynamics
  • RNA structure-function relationships
  • Methods for functional RNA studies

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Published Papers (21 papers)

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Editorial

Jump to: Research, Review

4 pages, 219 KiB  
Editorial
RNA Regulatory Networks 2.0
by Francisco J. Enguita, Ana Lúcia Leitão and John S. Mattick
Int. J. Mol. Sci. 2023, 24(10), 9001; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24109001 - 19 May 2023
Viewed by 1010
Abstract
The central role of RNA molecules in cell biology has been an expanding subject of study since the proposal of the “RNA world” hypothesis 60 years ago [...] Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)

Research

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19 pages, 27734 KiB  
Article
Interaction of SARS-CoV-2 Nucleocapsid Protein and Human RNA Helicases DDX1 and DDX3X Modulates Their Activities on Double-Stranded RNA
by Camilla Lodola, Massimiliano Secchi, Virginia Sinigiani, Antonella De Palma, Rossana Rossi, Davide Perico, Pier Luigi Mauri and Giovanni Maga
Int. J. Mol. Sci. 2023, 24(6), 5784; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065784 - 17 Mar 2023
Cited by 1 | Viewed by 2090
Abstract
The nucleocapsid protein Np of SARS-CoV-2 is involved in the replication, transcription, and packaging of the viral genome, but it also plays a role in the modulation of the host cell innate immunity and inflammation response. Ectopic expression of Np alone was able [...] Read more.
The nucleocapsid protein Np of SARS-CoV-2 is involved in the replication, transcription, and packaging of the viral genome, but it also plays a role in the modulation of the host cell innate immunity and inflammation response. Ectopic expression of Np alone was able to induce significant changes in the proteome of human cells. The cellular RNA helicase DDX1 was among the proteins whose levels were increased by Np expression. DDX1 and its related helicase DDX3X were found to physically interact with Np and to increase 2- to 4-fold its affinity for double-stranded RNA in a helicase-independent manner. Conversely, Np inhibited the RNA helicase activity of both proteins. These functional interactions among Np and DDX1 and DDX3X highlight novel possible roles played by these host RNA helicases in the viral life cycle. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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9 pages, 551 KiB  
Article
Variability of Human rDNA and Transcription Activity of the Ribosomal Genes
by Nikola Chmúrčiaková, Evgeny Smirnov, Jaroslav Kurfürst, František Liška and Dušan Cmarko
Int. J. Mol. Sci. 2022, 23(23), 15195; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315195 - 02 Dec 2022
Cited by 2 | Viewed by 1420
Abstract
Human ribosomal DNA is represented by hundreds of repeats in each cell. Every repeat consists of two parts: a 13 kb long 47S DNA with genes encoding 18S, 5.8S, and 28S RNAs of ribosomal particles, and a 30 kb long intergenic spacer (IGS). [...] Read more.
Human ribosomal DNA is represented by hundreds of repeats in each cell. Every repeat consists of two parts: a 13 kb long 47S DNA with genes encoding 18S, 5.8S, and 28S RNAs of ribosomal particles, and a 30 kb long intergenic spacer (IGS). Remarkably, transcription does not take place in all the repeats. The transcriptionally silent genes are characterized by the epigenetic marks of the inactive chromatin, including DNA hypermethylation of the promoter and adjacent areas. However, it is still unknown what causes the differentiation of the genes into active and silent. In this study, we examine whether this differentiation is related to the nucleotide sequence of IGS. We isolated ribosomal DNA from the nucleoli of human-derived HT1080 cells, and separated methylated and non-methylated DNA by chromatin immunoprecipitation. Then, we used PCR to amplify a 2 kb long region upstream of the transcription start and sequenced the product. We found that six SNVs and a series of short deletions in a region of simple repeats correlated with the DNA methylation status. These data indicate that variability of IGS sequence may initiate silencing of the ribosomal genes. Our study also suggests a number of pathways to this silencing that involve micro-RNAs and/or non-canonical DNA structures. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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12 pages, 1754 KiB  
Article
The Role of the Exonic lncRNA PRKDC-210 in Transcription Regulation
by Junling Mo, Guangyao Fan, Toshifumi Tsukahara and Matomo Sakari
Int. J. Mol. Sci. 2022, 23(22), 13783; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213783 - 09 Nov 2022
Cited by 1 | Viewed by 1430
Abstract
In recent years, long noncoding RNAs (lncRNAs) have received increasing attention and have been reported to be associated with various genetic abnormalities. However, the functions of many lncRNAs, including those of long exonic noncoding RNAs (lencRNAs), have not yet been elucidated. Here, we [...] Read more.
In recent years, long noncoding RNAs (lncRNAs) have received increasing attention and have been reported to be associated with various genetic abnormalities. However, the functions of many lncRNAs, including those of long exonic noncoding RNAs (lencRNAs), have not yet been elucidated. Here, we used a novel tethering luciferase assay to analyze the transcriptional regulatory functions of five lencRNAs that are upregulated in cancer. We found that the lencRNA PRKDC-210 interacts with MED12, a component of the CDK8 complex, to regulate the transcription of several genes. The transcriptional activation ability of PRKDC-210 was abolished in siRNA-treated CDK8-depleted cells. We also confirmed the enrichment of PRKDC-210 on RNA polymerase II. RNA-seq analysis of cells in which PRKDC-210 or PRKDC mRNA was knocked down using antisense oligonucleotides revealed that PRKDC-210 can affect the expression levels of genes related to fatty acid metabolism. Finally, we used a ChIRP assay to examine PRKDC-210-enriched sites in the genome. Overall, our findings demonstrate that the lencRNA PRKDC-210 promotes transcription through the CDK8 complex pathway at the transcription initiation site. We propose that PRKDC-210 can affect the transcription of adjacent genes after its transcription and splicing. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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24 pages, 12031 KiB  
Article
The Impact of the Anticoagulant Type in Blood Collection Tubes on Circulating Extracellular Plasma MicroRNA Profiles Revealed by Small RNA Sequencing
by Andrey V. Zhelankin, Liliia N. Iulmetova and Elena I. Sharova
Int. J. Mol. Sci. 2022, 23(18), 10340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810340 - 07 Sep 2022
Cited by 4 | Viewed by 3582
Abstract
Pre-analytical factors have a significant influence on circulating microRNA (miRNA) profiling. The aim of this study was a comprehensive assessment of the impact of the anticoagulant type in blood collection tubes on circulating plasma miRNA profiles using small RNA sequencing. Blood from ten [...] Read more.
Pre-analytical factors have a significant influence on circulating microRNA (miRNA) profiling. The aim of this study was a comprehensive assessment of the impact of the anticoagulant type in blood collection tubes on circulating plasma miRNA profiles using small RNA sequencing. Blood from ten healthy participants (five males and five females from 25 to 40 years old) was taken in collection tubes with four different anticoagulants: acid citrate dextrose (ACD-B), sodium citrate, citrate-theophylline-adenosine-dipyridamole (CTAD) and dipotassium-ethylenediaminetetraacetic acid (K2 EDTA). Platelet-free plasma samples were obtained by double centrifugation. EDTA plasma samples had elevated levels of hemolysis compared to samples obtained using other anticoagulants. Small RNA was extracted from plasma samples and small RNA sequencing was performed on the Illumina NextSeq 500 system. A total of 30 samples had been successfully sequenced starting from ~1 M reads mapped to miRNAs, allowing us to analyze their diversity and isoform content. The principal component analysis showed that the EDTA samples have distinct circulating plasma miRNA profiles compared to samples obtained using other anticoagulants. We selected 50 miRNA species that were differentially expressed between the sample groups based on the type of anticoagulant. We found that the EDTA samples had elevated levels of miRNAs which are abundant in red blood cells (RBC) and associated with hemolysis, while the levels of some platelet-specific miRNAs in these samples were lowered. The ratio between RBC-derived and platelet-derived miRNAs differed between the EDTA samples and other sample groups, which was validated by quantitative PCR. This study provides full plasma miRNA profiles of 10 healthy adults, compares them with previous studies and shows that the profile of circulating miRNAs in the EDTA plasma samples is altered primarily due to an increased level of hemolysis. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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16 pages, 2576 KiB  
Article
Unraveling Membrane Perturbations Caused by the Bacterial Riboregulator Hfq
by Florian Turbant, Jehan Waeytens, Camille Campidelli, Marianne Bombled, Denis Martinez, Axelle Grélard, Birgit Habenstein, Vincent Raussens, Marisela Velez, Frank Wien and Véronique Arluison
Int. J. Mol. Sci. 2022, 23(15), 8739; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158739 - 05 Aug 2022
Cited by 7 | Viewed by 2007
Abstract
Hfq is a pleiotropic regulator that mediates several aspects of bacterial RNA metabolism. The protein notably regulates translation efficiency and RNA decay in Gram-negative bacteria, usually via its interaction with small regulatory RNAs. Previously, we showed that the Hfq C-terminal region forms an [...] Read more.
Hfq is a pleiotropic regulator that mediates several aspects of bacterial RNA metabolism. The protein notably regulates translation efficiency and RNA decay in Gram-negative bacteria, usually via its interaction with small regulatory RNAs. Previously, we showed that the Hfq C-terminal region forms an amyloid-like structure and that these fibrils interact with membranes. The immediate consequence of this interaction is a disruption of the membrane, but the effect on Hfq structure was unknown. To investigate details of the mechanism of interaction, the present work uses different in vitro biophysical approaches. We show that the Hfq C-terminal region influences membrane integrity and, conversely, that the membrane specifically affects the amyloid assembly. The reported effect of this bacterial master regulator on membrane integrity is discussed in light of the possible consequence on small regulatory RNA-based regulation. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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12 pages, 1419 KiB  
Article
G-Quadruplex Regulation of VEGFA mRNA Translation by RBM4
by Kangkang Niu, Xiaojuan Zhang, Qisheng Song and Qili Feng
Int. J. Mol. Sci. 2022, 23(2), 743; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020743 - 11 Jan 2022
Cited by 8 | Viewed by 2040
Abstract
In eukaryotes, mRNAs translation is mainly mediated in a cap-dependent or cap-independent manner. The latter is primarily initiated at the internal ribosome entry site (IRES) in the 5′-UTR of mRNAs. It has been reported that the G-quadruplex structure (G4) in the IRES elements [...] Read more.
In eukaryotes, mRNAs translation is mainly mediated in a cap-dependent or cap-independent manner. The latter is primarily initiated at the internal ribosome entry site (IRES) in the 5′-UTR of mRNAs. It has been reported that the G-quadruplex structure (G4) in the IRES elements could regulate the IRES activity. We previously confirmed RBM4 (also known as LARK) as a G4-binding protein in human. In this study, to investigate whether RBM4 is involved in the regulation of the IRES activity by binding with the G4 structure within the IRES element, the IRES-A element in the 5′-UTR of vascular endothelial growth factor A (VEGFA) was constructed into a dicistronic reporter vector, psiCHECK2, and the effect of RBM4 on the IRES activity was tested in 293T cells. The results showed that the IRES insertion significantly increased the FLuc expression activity, indicating that this G4-containing IRES was active in 293T cells. When the G4 structure in the IRES was disrupted by base mutation, the IRES activity was significantly decreased. The IRES activity was notably increased when the cells were treated with G4 stabilizer PDS. EMSA results showed that RBM4 specifically bound the G4 structure in the IRES element. The knockdown of RBM4 substantially reduced the IRES activity, whereas over-expressing RBM4 increased the IRES activity. Taking all results together, we demonstrated that RBM4 promoted the mRNA translation of VEGFA gene by binding to the G4 structure in the IRES. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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23 pages, 4221 KiB  
Article
Identification of Abundant and Functional dodecaRNAs (doRNAs) Derived from Ribosomal RNA
by Marine Lambert, Abderrahim Benmoussa, Idrissa Diallo, Katheryn Ouellet-Boutin, Véronique Dorval, Nathalie Majeau, Charles Joly-Beauparlant, Arnaud Droit, Alain Bergeron, Bernard Têtu, Yves Fradet, Frédéric Pouliot and Patrick Provost
Int. J. Mol. Sci. 2021, 22(18), 9757; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189757 - 09 Sep 2021
Cited by 7 | Viewed by 5951
Abstract
Using a modified RNA-sequencing (RNA-seq) approach, we discovered a new family of unusually short RNAs mapping to ribosomal RNA 5.8S, which we named dodecaRNAs (doRNAs), according to the number of core nucleotides (12 nt) their members contain. Using a new quantitative detection method [...] Read more.
Using a modified RNA-sequencing (RNA-seq) approach, we discovered a new family of unusually short RNAs mapping to ribosomal RNA 5.8S, which we named dodecaRNAs (doRNAs), according to the number of core nucleotides (12 nt) their members contain. Using a new quantitative detection method that we developed, we confirmed our RNA-seq data and determined that the minimal core doRNA sequence and its 13-nt variant C-doRNA (doRNA with a 5′ Cytosine) are the two most abundant doRNAs, which, together, may outnumber microRNAs. The C-doRNA/doRNA ratio is stable within species but differed between species. doRNA and C-doRNA are mainly cytoplasmic and interact with heterogeneous nuclear ribonucleoproteins (hnRNP) A0, A1 and A2B1, but not Argonaute 2. Reporter gene activity assays suggest that C-doRNA may function as a regulator of Annexin II receptor (AXIIR) expression. doRNAs are differentially expressed in prostate cancer cells/tissues and may control cell migration. These findings suggest that unusually short RNAs may be more abundant and important than previously thought. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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20 pages, 3352 KiB  
Article
Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In Vitro
by Anna Fefilova, Pavel Melnikov, Tatiana Prikazchikova, Tatiana Abakumova, Ilya Kurochkin, Pavel V. Mazin, Rustam Ziganshin, Olga Sergeeva and Timofei S. Zatsepin
Int. J. Mol. Sci. 2020, 21(16), 5605; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165605 - 05 Aug 2020
Cited by 7 | Viewed by 3123
Abstract
The coupling of alternative splicing with the nonsense-mediated decay (NMD) pathway maintains quality control of the transcriptome in eukaryotes by eliminating transcripts with premature termination codons (PTC) and fine-tunes gene expression. Long noncoding RNA (lncRNA) can regulate multiple cellular processes, including alternative splicing. [...] Read more.
The coupling of alternative splicing with the nonsense-mediated decay (NMD) pathway maintains quality control of the transcriptome in eukaryotes by eliminating transcripts with premature termination codons (PTC) and fine-tunes gene expression. Long noncoding RNA (lncRNA) can regulate multiple cellular processes, including alternative splicing. Previously, murine Morrbid (myeloid RNA repressor of Bcl2l11 induced death) lncRNA was described as a locus-specific controller of the lifespan of short-living myeloid cells via transcription regulation of the apoptosis-related Bcl2l11 protein. Here, we report that murine Morrbid lncRNA in hepatocytes participates in the regulation of proto-oncogene NRAS (neuroblastoma RAS viral oncogene homolog) splicing, including the formation of the isoform with PTC. We observed a significant increase of the NRAS isoform with PTC in hepatocytes with depleted Morrbid lncRNA. We demonstrated that the NRAS isoform with PTC is degraded via the NMD pathway. This transcript is presented almost only in the nucleus and has a half-life ~four times lower than other NRAS transcripts. Additionally, in UPF1 knockdown hepatocytes (the key NMD factor), we observed a significant increase of the NRAS isoform with PTC. By a modified capture hybridization (CHART) analysis of the protein targets, we uncovered interactions of Morrbid lncRNA with the SFPQ (splicing factor proline and glutamine rich)-NONO (non-POU domain-containing octamer-binding protein) splicing complex. Finally, we propose the regulation mechanism of NRAS splicing in murine hepatocytes by alternative splicing coupled with the NMD pathway with the input of Morrbid lncRNA. Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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20 pages, 3863 KiB  
Article
mRNA with Mammalian Codon Bias Accumulates in Yeast Mutants with Constitutive Stress Granules
by Natalia V. Kozlova, Chantal Pichon and A. Rachid Rahmouni
Int. J. Mol. Sci. 2020, 21(4), 1234; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041234 - 12 Feb 2020
Cited by 3 | Viewed by 3241
Abstract
Stress granules and P bodies are cytoplasmic structures assembled in response to various stress factors and represent sites of temporary storage or decay of mRNAs. Depending on the source of stress, the formation of these structures may be driven by distinct mechanisms, but [...] Read more.
Stress granules and P bodies are cytoplasmic structures assembled in response to various stress factors and represent sites of temporary storage or decay of mRNAs. Depending on the source of stress, the formation of these structures may be driven by distinct mechanisms, but several stresses have been shown to stabilize mRNAs via inhibition of deadenylation. A recent study identified yeast gene deletion mutants with constitutive stress granules and elevated P bodies; however, the mechanisms which trigger its formation remain poorly understood. Here, we investigate the possibility of accumulating mRNA with mammalian codon bias, which we termed the model RNA, in these mutants. We found that the model RNA accumulates in dcp2 and xrn1 mutants and in four mutants with constitutive stress granules overlapping with P bodies. However, in eight other mutants with constitutive stress granules, the model RNA is downregulated, or its steady state levels vary. We further suggest that the accumulation of the model RNA is linked to its protection from the main mRNA surveillance path. However, there is no obvious targeting of the model RNA to stress granules or P bodies. Thus, accumulation of the model RNA and formation of constitutive stress granules occur independently and only some paths inducing formation of constitutive stress granules will stabilize mRNA as well. Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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18 pages, 4215 KiB  
Article
Characterization of a G-Quadruplex Structure in Pre-miRNA-1229 and in Its Alzheimer’s Disease-Associated Variant rs2291418: Implications for miRNA-1229 Maturation
by Joshua A. Imperatore, McKenna L. Then, Keefe B. McDougal and Mihaela Rita Mihailescu
Int. J. Mol. Sci. 2020, 21(3), 767; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030767 - 24 Jan 2020
Cited by 29 | Viewed by 4554
Abstract
Alzheimer’s disease (AD), the most common age-related neurodegenerative disease, is associated with various forms of cognitive and functional impairment that worsen with disease progression. AD is typically characterized as a protein misfolding disease, in which abnormal plaques form due to accumulation of tau [...] Read more.
Alzheimer’s disease (AD), the most common age-related neurodegenerative disease, is associated with various forms of cognitive and functional impairment that worsen with disease progression. AD is typically characterized as a protein misfolding disease, in which abnormal plaques form due to accumulation of tau and β-amyloid (Aβ) proteins. An assortment of proteins is responsible for the processing and trafficking of Aβ, including sortilin-related receptor 1 (SORL1). Recently, a genome-wide association study of microRNA-related variants found that a single nucleotide polymorphism (SNP) rs2291418 within premature microRNA-1229 (pre-miRNA-1229) is significantly associated with AD. Moreover, the levels of the mature miRNA-1229-3p, which has been shown to regulate the SORL1 translation, are increased in the rs2291418 pre-miRNA-1229 variant. In this study we used various biophysical techniques to show that pre-miRNA-1229 forms a G-quadruplex secondary structure that coexists in equilibrium with the canonical hairpin structure, potentially controlling the production of the mature miR-1229-3p, and furthermore, that the AD-associated SNP rs2291418 pre-miR-1229 changes the equilibrium between these structures. Thus, the G-quadruplex structure we identified within pre-miRNA-1229 could potentially act as a novel therapeutic target in AD. Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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15 pages, 22343 KiB  
Article
Integrative Analyses of mRNA Expression Profile Reveal the Involvement of IGF2BP1 in Chicken Adipogenesis
by Jiahui Chen, Xueyi Ren, Limin Li, Shiyi Lu, Tian Chen, Liangtian Tan, Manqing Liu, Qingbin Luo, Shaodong Liang, Qinghua Nie, Xiquan Zhang and Wen Luo
Int. J. Mol. Sci. 2019, 20(12), 2923; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20122923 - 14 Jun 2019
Cited by 31 | Viewed by 3714
Abstract
Excessive abdominal fat deposition is an issue with general concern in broiler production, especially for Chinese native chicken breeds. A high-fat diet (HFD) can induce body weight gained and excessive fat deposition, and genes and pathways participate in fat metabolism and adipogenesis would [...] Read more.
Excessive abdominal fat deposition is an issue with general concern in broiler production, especially for Chinese native chicken breeds. A high-fat diet (HFD) can induce body weight gained and excessive fat deposition, and genes and pathways participate in fat metabolism and adipogenesis would be influenced by HFD. In order to reveal the main genes and pathways involved in chicken abdominal fat deposition, we used HFD and normal diet (ND) to feed a Chinese native chicken breed, respectively. Results showed that HFD can increase abdominal fat deposition and induce adipocyte hypertrophy. Additionally, we used RNA-sequencing to identify the differentially expressed genes (DEGs) between HFD and ND chickens in liver and abdominal fat. By analyzed these DEGs, we found that the many DEGs were enriched in fat metabolism related pathways, such as peroxisome proliferator-activated receptor (PPAR) signaling, fat digestion and absorption, extracellular matrix (ECM)-receptor interaction, and steroid hormone biosynthesis. Notably, the expression of insulin-like growth factor II mRNA binding protein 1 (IGF2BP1), which is a binding protein of IGF2 mRNA, was found to be induced in liver and abdominal fat by HFD. Ectopic expression of IGF2BP1 in chicken liver-related cell line Leghorn strain M chicken hepatoma (LMH) cell revealed that IGF2BP1 can regulate the expression of genes associated with fatty acid metabolism. In chicken preadipocytes (ICP cell line), we found that IGF2BP1 can promote adipocyte proliferation and differentiation, and the lipid droplet content would be increased by overexpression of IGF2BP1. Taken together, this study provides new insights into understanding the genes and pathways involved in abdominal fat deposition of Chinese native broiler, and IGF2BP1 is an important candidate gene for the study of fat metabolism and adipogenesis in chicken. Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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12 pages, 3577 KiB  
Article
The Possible Role of Complete Loss of Myostatin in Limiting Excessive Proliferation of Muscle Cells (C2C12) via Activation of MicroRNAs
by Peixuan Huang, Daxin Pang, Kankan Wang, Aishi Xu, Chaogang Yao, Mengjing Li, Wenni You, Qiushuang Wang and Hao Yu
Int. J. Mol. Sci. 2019, 20(3), 643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030643 - 02 Feb 2019
Cited by 9 | Viewed by 3900
Abstract
Myostatin (MSTN) is a member of the TGF-β superfamily that negatively regulates skeletal muscle growth and differentiation. However, the mechanism by which complete MSTN deletion limits excessive proliferation of muscle cells remains unclear. In this study, we knocked out MSTN in mouse myoblast [...] Read more.
Myostatin (MSTN) is a member of the TGF-β superfamily that negatively regulates skeletal muscle growth and differentiation. However, the mechanism by which complete MSTN deletion limits excessive proliferation of muscle cells remains unclear. In this study, we knocked out MSTN in mouse myoblast lines using a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9) system and sequenced the mRNA and miRNA transcriptomes. The results show that complete loss of MSTN upregulates seven miRNAs targeting an interaction network composed of 28 downregulated genes, including TGFB1, FOS and RB1. These genes are closely associated with tumorigenesis and cell proliferation. Our study suggests that complete loss of MSTN may limit excessive cell proliferation via activation of miRNAs. These data will contribute to the treatment of rhabdomyosarcoma (RMS). Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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Review

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34 pages, 1082 KiB  
Review
Modopathies Caused by Mutations in Genes Encoding for Mitochondrial RNA Modifying Enzymes: Molecular Mechanisms and Yeast Disease Models
by Martina Magistrati, Alexandru Ionut Gilea, Camilla Ceccatelli Berti, Enrico Baruffini and Cristina Dallabona
Int. J. Mol. Sci. 2023, 24(3), 2178; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032178 - 22 Jan 2023
Cited by 3 | Viewed by 1450
Abstract
In eukaryotes, mitochondrial RNAs (mt-tRNAs and mt-rRNAs) are subject to specific nucleotide modifications, which are critical for distinct functions linked to the synthesis of mitochondrial proteins encoded by mitochondrial genes, and thus for oxidative phosphorylation. In recent years, mutations in genes encoding for [...] Read more.
In eukaryotes, mitochondrial RNAs (mt-tRNAs and mt-rRNAs) are subject to specific nucleotide modifications, which are critical for distinct functions linked to the synthesis of mitochondrial proteins encoded by mitochondrial genes, and thus for oxidative phosphorylation. In recent years, mutations in genes encoding for mt-RNAs modifying enzymes have been identified as being causative of primary mitochondrial diseases, which have been called modopathies. These latter pathologies can be caused by mutations in genes involved in the modification either of tRNAs or of rRNAs, resulting in the absence of/decrease in a specific nucleotide modification and thus on the impairment of the efficiency or the accuracy of the mitochondrial protein synthesis. Most of these mutations are sporadic or private, thus it is fundamental that their pathogenicity is confirmed through the use of a model system. This review will focus on the activity of genes that, when mutated, are associated with modopathies, on the molecular mechanisms through which the enzymes introduce the nucleotide modifications, on the pathological phenotypes associated with mutations in these genes and on the contribution of the yeast Saccharomyces cerevisiae to confirming the pathogenicity of novel mutations and, in some cases, for defining the molecular defects. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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12 pages, 468 KiB  
Review
Are We Studying Non-Coding RNAs Correctly? Lessons from nc886
by Yong Sun Lee
Int. J. Mol. Sci. 2022, 23(8), 4251; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084251 - 12 Apr 2022
Cited by 10 | Viewed by 1734
Abstract
Non-coding RNAs (ncRNAs), such as microRNAs or long ncRNAs, have brought about a new paradigm in the regulation of gene expression. Sequencing technologies have detected transcripts with tremendous sensitivity and throughput and revealed that the majority of them lack protein-coding potential. Myriad articles [...] Read more.
Non-coding RNAs (ncRNAs), such as microRNAs or long ncRNAs, have brought about a new paradigm in the regulation of gene expression. Sequencing technologies have detected transcripts with tremendous sensitivity and throughput and revealed that the majority of them lack protein-coding potential. Myriad articles have investigated numerous ncRNAs and many of them claim that ncRNAs play gene-regulatory roles. However, it is questionable whether all these articles draw conclusions through cautious gain- and loss-of function experiments whose design was reasonably based on an ncRNA’s correct identity and features. In this review, these issues are discussed with a regulatory ncRNA, nc886, as an example case to represent cautions and guidelines when studying ncRNAs. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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17 pages, 862 KiB  
Review
The Role of MicroRNAs in Proteostasis Decline and Protein Aggregation during Brain and Skeletal Muscle Aging
by Stephany Francisco, Vera Martinho, Margarida Ferreira, Andreia Reis, Gabriela Moura, Ana Raquel Soares and Manuel A. S. Santos
Int. J. Mol. Sci. 2022, 23(6), 3232; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063232 - 17 Mar 2022
Cited by 8 | Viewed by 2371
Abstract
Aging can be defined as the progressive deterioration of cellular, tissue, and organismal function over time. Alterations in protein homeostasis, also known as proteostasis, are a hallmark of aging that lead to proteome imbalances and protein aggregation, phenomena that also occur in age-related [...] Read more.
Aging can be defined as the progressive deterioration of cellular, tissue, and organismal function over time. Alterations in protein homeostasis, also known as proteostasis, are a hallmark of aging that lead to proteome imbalances and protein aggregation, phenomena that also occur in age-related diseases. Among the various proteostasis regulators, microRNAs (miRNAs) have been reported to play important roles in the post-transcriptional control of genes involved in maintaining proteostasis during the lifespan in several organismal tissues. In this review, we consolidate recently published reports that demonstrate how miRNAs regulate fundamental proteostasis-related processes relevant to tissue aging, with emphasis on the two most studied tissues, brain tissue and skeletal muscle. We also explore an emerging perspective on the role of miRNA regulatory networks in age-related protein aggregation, a known hallmark of aging and age-related diseases, to elucidate potential miRNA candidates for anti-aging diagnostic and therapeutic targets. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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16 pages, 1024 KiB  
Review
Vitamin D May Protect against Breast Cancer through the Regulation of Long Noncoding RNAs by VDR Signaling
by Janusz Blasiak, Jan Chojnacki, Elzbieta Pawlowska, Aleksandra Jablkowska and Cezary Chojnacki
Int. J. Mol. Sci. 2022, 23(6), 3189; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063189 - 16 Mar 2022
Cited by 8 | Viewed by 3482
Abstract
Dietary vitamin D3 has attracted wide interest as a natural compound for breast cancer prevention and therapy, supported by in vitro and animal studies. The exact mechanism of such action of vitamin D3 is unknown and may include several independent or partly dependent [...] Read more.
Dietary vitamin D3 has attracted wide interest as a natural compound for breast cancer prevention and therapy, supported by in vitro and animal studies. The exact mechanism of such action of vitamin D3 is unknown and may include several independent or partly dependent pathways. The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D, calcitriol), binds to the vitamin D receptor (VDR) and induces its translocation to the nucleus, where it transactivates a myriad of genes. Vitamin D3 is involved in the maintenance of a normal epigenetic profile whose disturbance may contribute to breast cancer. In general, the protective effect of vitamin D3 against breast cancer is underlined by inhibition of proliferation and migration, stimulation of differentiation and apoptosis, and inhibition of epithelial/mesenchymal transition in breast cells. Vitamin D3 may also inhibit the transformation of normal mammary progenitors into breast cancer stem cells that initiate and sustain the growth of breast tumors. As long noncoding RNAs (lncRNAs) play an important role in breast cancer pathogenesis, and the specific mechanisms underlying this role are poorly understood, we provided several arguments that vitamin D3/VDR may induce protective effects in breast cancer through modulation of lncRNAs that are important for breast cancer pathogenesis. The main lncRNAs candidates to mediate the protective effect of vitamin D3 in breast cancer are lncBCAS1-4_1, AFAP1 antisense RNA 1 (AFAP1-AS1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), long intergenic non-protein-coding RNA 511 (LINC00511), LINC00346, small nucleolar RNA host gene 6 (SNHG6), and SNHG16, but there is a rationale to explore several other lncRNAs. Full article
(This article belongs to the Special Issue RNA Regulatory Networks 2.0)
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31 pages, 8825 KiB  
Review
A Census and Categorization Method of Epitranscriptomic Marks
by Julia Mathlin, Loredana Le Pera and Teresa Colombo
Int. J. Mol. Sci. 2020, 21(13), 4684; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134684 - 30 Jun 2020
Cited by 25 | Viewed by 4307
Abstract
In the past few years, thorough investigation of chemical modifications operated in the cells on ribonucleic acid (RNA) molecules is gaining momentum. This new field of research has been dubbed “epitranscriptomics”, in analogy to best-known epigenomics, to stress the potential of ensembles of [...] Read more.
In the past few years, thorough investigation of chemical modifications operated in the cells on ribonucleic acid (RNA) molecules is gaining momentum. This new field of research has been dubbed “epitranscriptomics”, in analogy to best-known epigenomics, to stress the potential of ensembles of RNA modifications to constitute a post-transcriptional regulatory layer of gene expression orchestrated by writer, reader, and eraser RNA-binding proteins (RBPs). In fact, epitranscriptomics aims at identifying and characterizing all functionally relevant changes involving both non-substitutional chemical modifications and editing events made to the transcriptome. Indeed, several types of RNA modifications that impact gene expression have been reported so far in different species of cellular RNAs, including ribosomal RNAs, transfer RNAs, small nuclear RNAs, messenger RNAs, and long non-coding RNAs. Supporting functional relevance of this largely unknown regulatory mechanism, several human diseases have been associated directly to RNA modifications or to RBPs that may play as effectors of epitranscriptomic marks. However, an exhaustive epitranscriptome’s characterization, aimed to systematically classify all RNA modifications and clarify rules, actors, and outcomes of this promising regulatory code, is currently not available, mainly hampered by lack of suitable detecting technologies. This is an unfortunate limitation that, thanks to an unprecedented pace of technological advancements especially in the sequencing technology field, is likely to be overcome soon. Here, we review the current knowledge on epitranscriptomic marks and propose a categorization method based on the reference ribonucleotide and its rounds of modifications (“stages”) until reaching the given modified form. We believe that this classification scheme can be useful to coherently organize the expanding number of discovered RNA modifications. Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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24 pages, 1736 KiB  
Review
The Sophisticated Transcriptional Response Governed by Transposable Elements in Human Health and Disease
by Federica Marasca, Erica Gasparotto, Benedetto Polimeni, Rebecca Vadalà, Valeria Ranzani and Beatrice Bodega
Int. J. Mol. Sci. 2020, 21(9), 3201; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093201 - 30 Apr 2020
Cited by 6 | Viewed by 5044
Abstract
Transposable elements (TEs), which cover ~45% of the human genome, although firstly considered as “selfish” DNA, are nowadays recognized as driving forces in eukaryotic genome evolution. This capability resides in generating a plethora of sophisticated RNA regulatory networks that influence the cell type [...] Read more.
Transposable elements (TEs), which cover ~45% of the human genome, although firstly considered as “selfish” DNA, are nowadays recognized as driving forces in eukaryotic genome evolution. This capability resides in generating a plethora of sophisticated RNA regulatory networks that influence the cell type specific transcriptome in health and disease. Indeed, TEs are transcribed and their RNAs mediate multi-layered transcriptional regulatory functions in cellular identity establishment, but also in the regulation of cellular plasticity and adaptability to environmental cues, as occurs in the immune response. Moreover, TEs transcriptional deregulation also evolved to promote pathogenesis, as in autoimmune and inflammatory diseases and cancers. Importantly, many of these findings have been achieved through the employment of Next Generation Sequencing (NGS) technologies and bioinformatic tools that are in continuous improvement to overcome the limitations of analyzing TEs sequences. However, they are highly homologous, and their annotation is still ambiguous. Here, we will review some of the most recent findings, questions and improvements to study at high resolution this intriguing portion of the human genome in health and diseases, opening the scenario to novel therapeutic opportunities. Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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22 pages, 2174 KiB  
Review
Interspecies Communication in Holobionts by Non-Coding RNA Exchange
by Ana Lúcia Leitão, Marina C. Costa, André F. Gabriel and Francisco J. Enguita
Int. J. Mol. Sci. 2020, 21(7), 2333; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072333 - 27 Mar 2020
Cited by 20 | Viewed by 4587
Abstract
Complex organisms are associations of different cells that coexist and collaborate creating a living consortium, the holobiont. The relationships between the holobiont members are essential for proper homeostasis of the organisms, and they are founded on the establishment of complex inter-connections between all [...] Read more.
Complex organisms are associations of different cells that coexist and collaborate creating a living consortium, the holobiont. The relationships between the holobiont members are essential for proper homeostasis of the organisms, and they are founded on the establishment of complex inter-connections between all the cells. Non-coding RNAs are regulatory molecules that can also act as communication signals between cells, being involved in either homeostasis or dysbiosis of the holobionts. Eukaryotic and prokaryotic cells can transmit signals via non-coding RNAs while using specific extracellular conveyors that travel to the target cell and can be translated into a regulatory response by dedicated molecular machinery. Within holobionts, non-coding RNA regulatory signaling is involved in symbiotic and pathogenic relationships among the cells. This review analyzes current knowledge regarding the role of non-coding RNAs in cell-to-cell communication, with a special focus on the signaling between cells in multi-organism consortia. Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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14 pages, 520 KiB  
Review
Mutual Regulation of RNA Silencing and the IFN Response as an Antiviral Defense System in Mammalian Cells
by Tomoko Takahashi and Kumiko Ui-Tei
Int. J. Mol. Sci. 2020, 21(4), 1348; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041348 - 17 Feb 2020
Cited by 12 | Viewed by 8984
Abstract
RNA silencing is a posttranscriptional gene silencing mechanism directed by endogenous small non-coding RNAs called microRNAs (miRNAs). By contrast, the type-I interferon (IFN) response is an innate immune response induced by exogenous RNAs, such as viral RNAs. Endogenous and exogenous RNAs have typical [...] Read more.
RNA silencing is a posttranscriptional gene silencing mechanism directed by endogenous small non-coding RNAs called microRNAs (miRNAs). By contrast, the type-I interferon (IFN) response is an innate immune response induced by exogenous RNAs, such as viral RNAs. Endogenous and exogenous RNAs have typical structural features and are recognized accurately by specific RNA-binding proteins in each pathway. In mammalian cells, both RNA silencing and the IFN response are induced by double-stranded RNAs (dsRNAs) in the cytoplasm, but have long been considered two independent pathways. However, recent reports have shed light on crosstalk between the two pathways, which are mutually regulated by protein–protein interactions triggered by viral infection. This review provides brief overviews of RNA silencing and the IFN response and an outline of the molecular mechanism of their crosstalk and its biological implications. Crosstalk between RNA silencing and the IFN response may reveal a novel antiviral defense system that is regulated by miRNAs in mammalian cells. Full article
(This article belongs to the Special Issue RNA Regulatory Networks)
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