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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 (31 August 2020) | Viewed by 47539

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Special Issue Editors

Dr. Francisco J. Enguita

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Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-004 Lisboa, Portugal
Interests: non-coding RNAs; cardiovascular diseases; infectious diseases; cell-to-cell communication; circulating RNAs; biomarkers
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Prof. Dr. John Mattick

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Guest Editor

Green Templeton College, University of Oxford, Oxford, UK
Interests: non-coding RNA biology; RNA structure-function relationships; development; epigenetic regulation; neurological diseases; cardiovascular diseases; cancer; infectious diseases; cell organization; cell-to-cell communication; circulating RNAs; biomarkers
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 non-coding 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, and that may be perturbed in cancer and neurological disorders, among others. Moreover, the expansion of the complement of ncRNAs in the 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-centred regulatory networks in the context of development, brain function, cell physiology, and human disease. We will also collect papers from The 3rd International Symposium on Frontiers in Molecular Science—RNA Regulatory Networks (ISFMS 2019), organized by Universidade de Lisboa, which will be held in Lisbon (Portugal) from 26–28th June 2019. This meeting will analyze the centrality of RNA regulation in biological processes and human disease, and will constitute an excellent opportunity for the interchange of ideas and the presentation of new scientific developments in the field. It will consider the many dimensions of RNA regulation in development and disease, RNA structure-function relationships, the mechanisms by which plasticity is introduced, and the role of RNA in transgenerational communication.

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

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Keywords

RNA-based regulation
non-coding 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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RNA Regulatory Networks 2.0 in International Journal of Molecular Sciences (21 articles)

Published Papers (9 papers)

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Research

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20 pages, 3352 KiB

Open AccessArticle

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://doi.org/10.3390/ijms21165605 - 5 Aug 2020

Cited by 7 | Viewed by 3580

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. 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

Open AccessArticle

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://doi.org/10.3390/ijms21041234 - 12 Feb 2020

Cited by 3 | Viewed by 3657

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 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

Open AccessArticle

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://doi.org/10.3390/ijms21030767 - 24 Jan 2020

Cited by 31 | Viewed by 5182

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 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

Open AccessArticle

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://doi.org/10.3390/ijms20122923 - 14 Jun 2019

Cited by 38 | Viewed by 4154

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 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

Open AccessArticle

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://doi.org/10.3390/ijms20030643 - 2 Feb 2019

Cited by 9 | Viewed by 4293

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 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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31 pages, 8825 KiB

Open AccessReview

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://doi.org/10.3390/ijms21134684 - 30 Jun 2020

Cited by 27 | Viewed by 5029

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 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

Open AccessReview

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://doi.org/10.3390/ijms21093201 - 30 Apr 2020

Cited by 8 | Viewed by 5748

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 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

Open AccessReview

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://doi.org/10.3390/ijms21072333 - 27 Mar 2020

Cited by 23 | Viewed by 5219

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 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

Open AccessReview

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://doi.org/10.3390/ijms21041348 - 17 Feb 2020

Cited by 14 | Viewed by 9730

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 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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