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Volume 7
Issue 1
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Non-Coding RNA, Volume 7, Issue 1 (March 2021) – 23 articles

Cover Story (view full-size image): In silico predictions and interactions must be considered pivotal starting points to screen and design novel drugs to counter SARS-CoV-2-induced inflammatory complications. Indeed, we identified selective motifs in the leader sequence of the SARS-CoV-2 genome as promising sites to generate antiviral selective drugs. Notably, major effective mutations currently reported for SARS-CoV-2 variants involve coding regions, whereas reliable mutations in the leader sequence and correlations with the severity of COVID-19 disease are missing. We identified target motifs in the leader sequence suitable for specific bindings with endogenous human miRNAs and lncRNAs that can be therefore considered a conceptual background for the development of RNA-based drugs against COVID-19. View this paper.
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3 pages, 193 KiB  
Editorial
The Non-Coding RNA Journal Club: Highlights on Recent Papers-8
by Sonia Tarallo, Barbara Pardini, Archa H. Fox, Hayley Ingram, Cristian Taccioli, Joseph H. Taube and Sendurai A. Mani
Non-Coding RNA 2021, 7(1), 23; https://doi.org/10.3390/ncrna7010023 - 19 Mar 2021
Cited by 1 | Viewed by 4113
Abstract
We are glad to share with you our eighth Journal Club and to highlight some of the most interesting papers published recently [...] Full article
(This article belongs to the Collection The Non-Coding RNA Journal Club: Highlights on Recent Papers)
22 pages, 1002 KiB  
Review
Non-Syndromic Intellectual Disability and Its Pathways: A Long Noncoding RNA Perspective
by Isabela I. Barros, Vitor Leão, Jessica O. Santis, Reginaldo C. A. Rosa, Danielle B. Brotto, Camila B. Storti, Ádamo D. D. Siena, Greice A. Molfetta and Wilson A. Silva, Jr.
Non-Coding RNA 2021, 7(1), 22; https://doi.org/10.3390/ncrna7010022 - 11 Mar 2021
Cited by 4 | Viewed by 9808
Abstract
Non-syndromic intellectual disability (NS-ID or idiopathic) is a complex neurodevelopmental disorder that represents a global health issue. Although many efforts have been made to characterize it and distinguish it from syndromic intellectual disability (S-ID), the highly heterogeneous aspect of this disorder makes it [...] Read more.
Non-syndromic intellectual disability (NS-ID or idiopathic) is a complex neurodevelopmental disorder that represents a global health issue. Although many efforts have been made to characterize it and distinguish it from syndromic intellectual disability (S-ID), the highly heterogeneous aspect of this disorder makes it difficult to understand its etiology. Long noncoding RNAs (lncRNAs) comprise a large group of transcripts that can act through various mechanisms and be involved in important neurodevelopmental processes. In this sense, comprehending the roles they play in this intricate context is a valuable way of getting new insights about how NS-ID can arise and develop. In this review, we attempt to bring together knowledge available in the literature about lncRNAs involved with molecular and cellular pathways already described in intellectual disability and neural function, to better understand their relevance in NS-ID and the regulatory complexity of this disorder. Full article
(This article belongs to the Special Issue Role of lncRNAs in Brain Development and Disease)
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19 pages, 3048 KiB  
Review
Epigenetic Regulation of Alternative Splicing: How LncRNAs Tailor the Message
by Giuseppina Pisignano and Michael Ladomery
Non-Coding RNA 2021, 7(1), 21; https://doi.org/10.3390/ncrna7010021 - 11 Mar 2021
Cited by 32 | Viewed by 8172
Abstract
Alternative splicing is a highly fine-tuned regulated process and one of the main drivers of proteomic diversity across eukaryotes. The vast majority of human multi-exon genes is alternatively spliced in a cell type- and tissue-specific manner, and defects in alternative splicing can dramatically [...] Read more.
Alternative splicing is a highly fine-tuned regulated process and one of the main drivers of proteomic diversity across eukaryotes. The vast majority of human multi-exon genes is alternatively spliced in a cell type- and tissue-specific manner, and defects in alternative splicing can dramatically alter RNA and protein functions and lead to disease. The eukaryotic genome is also intensively transcribed into long and short non-coding RNAs which account for up to 90% of the entire transcriptome. Over the years, lncRNAs have received considerable attention as important players in the regulation of cellular processes including alternative splicing. In this review, we focus on recent discoveries that show how lncRNAs contribute significantly to the regulation of alternative splicing and explore how they are able to shape the expression of a diverse set of splice isoforms through several mechanisms. With the increasing number of lncRNAs being discovered and characterized, the contribution of lncRNAs to the regulation of alternative splicing is likely to grow significantly. Full article
(This article belongs to the Special Issue Post-transcriptional Regulation through Long Non-coding RNAs (lncRNAs))
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18 pages, 4814 KiB  
Review
LncRNAs in Cardiomyocyte Maturation: New Window for Cardiac Regenerative Medicine
by Maryam Kay and Bahram M. Soltani
Non-Coding RNA 2021, 7(1), 20; https://doi.org/10.3390/ncrna7010020 - 10 Mar 2021
Cited by 6 | Viewed by 4965
Abstract
Cardiomyocyte (CM) maturation, which is characterized by structural, functional, and metabolic specializations, is the last phase of CM development that prepares the cells for efficient and forceful contraction throughout life. Over the past decades, CM maturation has gained increased attention due to the [...] Read more.
Cardiomyocyte (CM) maturation, which is characterized by structural, functional, and metabolic specializations, is the last phase of CM development that prepares the cells for efficient and forceful contraction throughout life. Over the past decades, CM maturation has gained increased attention due to the fact that pluripotent stem cell-derived CMs are structurally, transcriptionally, and functionally immature and embryonic-like, which causes a defect in cell replacement therapy. The current challenge is to discover and understand the molecular mechanisms, which control the CM maturation process. Currently, emerging shreds of evidence emphasize the role of long noncoding RNAs (lncRNAs) in regulating different aspects of CM maturation, including myofibril maturation, electrophysiology, and Ca2+ handling maturation, metabolic maturation and proliferation to hypertrophy transition. Here, we describe the structural and functional characteristics of mature CMs. Furthermore, this review highlights the lncRNAs as crucial regulators of different aspects in CM maturation, which have the potential to be used for mature CM production. With the current advances in oligonucleotide delivery; lncRNAs may serve as putative therapeutic targets to produce highly mature CMs for research and regenerative medicine. Full article
(This article belongs to the Section Long Non-Coding RNA)
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31 pages, 993 KiB  
Review
Approaches to Identify and Characterise the Post-Transcriptional Roles of lncRNAs in Cancer
by Jean-Michel Carter, Daniel Aron Ang, Nicholas Sim, Andrea Budiman and Yinghui Li
Non-Coding RNA 2021, 7(1), 19; https://doi.org/10.3390/ncrna7010019 - 9 Mar 2021
Cited by 7 | Viewed by 5989
Abstract
It is becoming increasingly evident that the non-coding genome and transcriptome exert great influence over their coding counterparts through complex molecular interactions. Among non-coding RNAs (ncRNA), long non-coding RNAs (lncRNAs) in particular present increased potential to participate in dysregulation of post-transcriptional processes through [...] Read more.
It is becoming increasingly evident that the non-coding genome and transcriptome exert great influence over their coding counterparts through complex molecular interactions. Among non-coding RNAs (ncRNA), long non-coding RNAs (lncRNAs) in particular present increased potential to participate in dysregulation of post-transcriptional processes through both RNA and protein interactions. Since such processes can play key roles in contributing to cancer progression, it is desirable to continue expanding the search for lncRNAs impacting cancer through post-transcriptional mechanisms. The sheer diversity of mechanisms requires diverse resources and methods that have been developed and refined over the past decade. We provide an overview of computational resources as well as proven low-to-high throughput techniques to enable identification and characterisation of lncRNAs in their complex interactive contexts. As more cancer research strategies evolve to explore the non-coding genome and transcriptome, we anticipate this will provide a valuable primer and perspective of how these technologies have matured and will continue to evolve to assist researchers in elucidating post-transcriptional roles of lncRNAs in cancer. Full article
(This article belongs to the Special Issue Post-transcriptional Regulation through Long Non-coding RNAs (lncRNAs))
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11 pages, 260 KiB  
Article
miRCOVID-19: Potential Targets of Human miRNAs in SARS-CoV-2 for RNA-Based Drug Discovery
by Tanvir Alam and Leonard Lipovich
Non-Coding RNA 2021, 7(1), 18; https://doi.org/10.3390/ncrna7010018 - 2 Mar 2021
Cited by 37 | Viewed by 5995
Abstract
Sense-antisense interactions of long and short RNAs in human cells are integral to post-transcriptional gene regulation, in particular that of mRNAs by microRNAs. Many viruses, including severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 (the causative agent of coronavirus disease 2019, COVID-19), have RNA [...] Read more.
Sense-antisense interactions of long and short RNAs in human cells are integral to post-transcriptional gene regulation, in particular that of mRNAs by microRNAs. Many viruses, including severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 (the causative agent of coronavirus disease 2019, COVID-19), have RNA genomes, and interactions between host and viral RNAs, while known to be functional in other viral diseases, have not yet been investigated in COVID-19. To remedy this gap in knowledge, we present miRCOVID-19, a computational meta-analysis framework identifying the predicted binding sites of human microRNAs along the SARS-CoV-2 RNA genome. To highlight the potential relevance of SARS-CoV-2-genome-complementary miRNAs to COVID-19 pathogenesis, we assessed their expression in COVID-19-relevant tissues using public transcriptome data. miRCOVID-19 identified 14 high-confidence mature miRNAs that are highly likely to interact with the SARS-CoV-2 genome and are expressed in diverse respiratory epithelial and immune cell types that are relevant to COVID-19 pathogenesis. As a proof of principle, we have shown that human miR-122, a previously known co-factor of another RNA virus, the hepatitis C virus (HCV) whose genome it binds as a prerequisite for pathogenesis, was predicted to also bind the SARS-CoV-2 RNA genome with high affinity, suggesting the perspective of repurposing anti-HCV RNA-based drugs, such as Miravirsen, to treat COVID-19. Our study is the first to identify all high-confidence binding sites of human miRNAs in the SARS-CoV-2 genome using multiple tools. Our work directly facilitates experimental validation of the reported targets, which would accelerate RNA-based drug discovery for COVID-19 and has the potential to provide new avenues for treating symptomatic COVID-19, and block SARS-CoV-2 replication, in humans. Full article
(This article belongs to the Section Small Non-Coding RNA)
25 pages, 2536 KiB  
Review
The Implications of ncRNAs in the Development of Human Diseases
by Elena López-Jiménez and Eduardo Andrés-León
Non-Coding RNA 2021, 7(1), 17; https://doi.org/10.3390/ncrna7010017 - 24 Feb 2021
Cited by 38 | Viewed by 6455
Abstract
The mammalian genome comprehends a small minority of genes that encode for proteins (barely 2% of the total genome in humans) and an immense majority of genes that are transcribed into RNA but not encoded for proteins (ncRNAs). These non-coding genes are intimately [...] Read more.
The mammalian genome comprehends a small minority of genes that encode for proteins (barely 2% of the total genome in humans) and an immense majority of genes that are transcribed into RNA but not encoded for proteins (ncRNAs). These non-coding genes are intimately related to the expression regulation of protein-coding genes. The ncRNAs subtypes differ in their size, so there are long non-coding genes (lncRNAs) and other smaller ones, like microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs). Due to their important role in the maintenance of cellular functioning, any deregulation of the expression profiles of these ncRNAs can dissemble in the development of different types of diseases. Among them, we can highlight some of high incidence in the population, such as cancer, neurodegenerative, or cardiovascular disorders. In addition, thanks to the enormous advances in the field of medical genomics, these same ncRNAs are starting to be used as possible drugs, approved by the FDA, as an effective treatment for diseases. Full article
(This article belongs to the Section Clinical Applications of Non-Coding RNA)
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14 pages, 695 KiB  
Review
The Role of LncRNAs in Translation
by Didem Karakas and Bulent Ozpolat
Non-Coding RNA 2021, 7(1), 16; https://doi.org/10.3390/ncrna7010016 - 20 Feb 2021
Cited by 63 | Viewed by 7068
Abstract
Long non-coding RNAs (lncRNAs), a group of non-protein coding RNAs with lengths of more than 200 nucleotides, exert their effects by binding to DNA, mRNA, microRNA, and proteins and regulate gene expression at the transcriptional, post-transcriptional, translational, and post-translational levels. Depending on cellular [...] Read more.
Long non-coding RNAs (lncRNAs), a group of non-protein coding RNAs with lengths of more than 200 nucleotides, exert their effects by binding to DNA, mRNA, microRNA, and proteins and regulate gene expression at the transcriptional, post-transcriptional, translational, and post-translational levels. Depending on cellular location, lncRNAs are involved in a wide range of cellular functions, including chromatin modification, transcriptional activation, transcriptional interference, scaffolding and regulation of translational machinery. This review highlights recent studies on lncRNAs in the regulation of protein translation by modulating the translational factors (i.e, eIF4E, eIF4G, eIF4A, 4E-BP1, eEF5A) and signaling pathways involved in this process as wells as their potential roles as tumor suppressors or tumor promoters. Full article
(This article belongs to the Special Issue Post-transcriptional Regulation through Long Non-coding RNAs (lncRNAs))
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18 pages, 1104 KiB  
Review
Endogenous Double-Stranded RNA
by Shaymaa Sadeq, Surar Al-Hashimi, Carmen M. Cusack and Andreas Werner
Non-Coding RNA 2021, 7(1), 15; https://doi.org/10.3390/ncrna7010015 - 19 Feb 2021
Cited by 38 | Viewed by 11808
Abstract
The birth of long non-coding RNAs (lncRNAs) is closely associated with the presence and activation of repetitive elements in the genome. The transcription of endogenous retroviruses as well as long and short interspersed elements is not only essential for evolving lncRNAs but is [...] Read more.
The birth of long non-coding RNAs (lncRNAs) is closely associated with the presence and activation of repetitive elements in the genome. The transcription of endogenous retroviruses as well as long and short interspersed elements is not only essential for evolving lncRNAs but is also a significant source of double-stranded RNA (dsRNA). From an lncRNA-centric point of view, the latter is a minor source of bother in the context of the entire cell; however, dsRNA is an essential threat. A viral infection is associated with cytoplasmic dsRNA, and endogenous RNA hybrids only differ from viral dsRNA by the 5′ cap structure. Hence, a multi-layered defense network is in place to protect cells from viral infections but tolerates endogenous dsRNA structures. A first line of defense is established with compartmentalization; whereas endogenous dsRNA is found predominantly confined to the nucleus and the mitochondria, exogenous dsRNA reaches the cytoplasm. Here, various sensor proteins recognize features of dsRNA including the 5′ phosphate group of viral RNAs or hybrids with a particular length but not specific nucleotide sequences. The sensors trigger cellular stress pathways and innate immunity via interferon signaling but also induce apoptosis via caspase activation. Because of its central role in viral recognition and immune activation, dsRNA sensing is implicated in autoimmune diseases and used to treat cancer. Full article
(This article belongs to the Special Issue Post-transcriptional Regulation through Long Non-coding RNAs (lncRNAs))
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16 pages, 3013 KiB  
Article
MicroRNAs and Long Non-Coding RNAs as Potential Candidates to Target Specific Motifs of SARS-CoV-2
by Lucia Natarelli, Luca Parca, Tommaso Mazza, Christian Weber, Fabio Virgili and Deborah Fratantonio
Non-Coding RNA 2021, 7(1), 14; https://doi.org/10.3390/ncrna7010014 - 18 Feb 2021
Cited by 32 | Viewed by 7356
Abstract
The respiratory system is one of the most affected targets of SARS-CoV-2. Various therapies have been utilized to counter viral-induced inflammatory complications, with diverse success rates. Pending the distribution of an effective vaccine to the whole population and the achievement of “herd immunity”, [...] Read more.
The respiratory system is one of the most affected targets of SARS-CoV-2. Various therapies have been utilized to counter viral-induced inflammatory complications, with diverse success rates. Pending the distribution of an effective vaccine to the whole population and the achievement of “herd immunity”, the discovery of novel specific therapies is to be considered a very important objective. Here, we report a computational study demonstrating the existence of target motifs in the SARS-CoV-2 genome suitable for specific binding with endogenous human micro and long non-coding RNAs (miRNAs and lncRNAs, respectively), which can, therefore, be considered a conceptual background for the development of miRNA-based drugs against COVID-19. The SARS-CoV-2 genome contains three motifs in the 5′UTR leader sequence recognized by selective nucleotides within the seed sequence of specific human miRNAs. The seed of 57 microRNAs contained a “GGG” motif that promoted leader sequence-recognition, primarily through offset-6mer sites able to promote microRNAs noncanonical binding to viral RNA. Similarly, lncRNA H19 binds to the 5′UTR of the viral genome and, more specifically, to the transcript of the viral gene Spike, which has a pivotal role in viral infection. Notably, some of the non-coding RNAs identified in our study as candidates for inhibiting SARS-CoV-2 gene expression have already been proposed against diverse viral infections, pulmonary arterial hypertension, and related diseases. Full article
(This article belongs to the Special Issue RNA Therapeutics: From Concepts to Applications)
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18 pages, 1451 KiB  
Review
Non-Coding RNAs in Retinoic Acid as Differentiation and Disease Drivers
by Carlos García-Padilla, Estefanía Lozano-Velasco, Carmen López-Sánchez, Virginio Garcia-Martínez, Amelia Aranega and Diego Franco
Non-Coding RNA 2021, 7(1), 13; https://doi.org/10.3390/ncrna7010013 - 17 Feb 2021
Cited by 4 | Viewed by 4462
Abstract
All-trans retinoic acid (RA) is the most active metabolite of vitamin A. Several studies have described a pivotal role for RA signalling in different biological processes such as cell growth and differentiation, embryonic development and organogenesis. Since RA signalling is highly dose-dependent, a [...] Read more.
All-trans retinoic acid (RA) is the most active metabolite of vitamin A. Several studies have described a pivotal role for RA signalling in different biological processes such as cell growth and differentiation, embryonic development and organogenesis. Since RA signalling is highly dose-dependent, a fine-tuning regulatory mechanism is required. Thus, RA signalling deregulation has a major impact, both in development and disease, related in many cases to oncogenic processes. In this review, we focus on the impact of ncRNA post-transcriptional regulatory mechanisms, especially those of microRNAs and lncRNAs, in RA signalling pathways during differentiation and disease. Full article
(This article belongs to the Special Issue Non-coding RNA: 5th Anniversary)
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17 pages, 1786 KiB  
Review
Plant Long Noncoding RNAs: New Players in the Field of Post-Transcriptional Regulations
by Camille Fonouni-Farde, Federico Ariel and Martin Crespi
Non-Coding RNA 2021, 7(1), 12; https://doi.org/10.3390/ncrna7010012 - 17 Feb 2021
Cited by 24 | Viewed by 6867
Abstract
The first reference to the “C-value paradox” reported an apparent imbalance between organismal genome size and morphological complexity. Since then, next-generation sequencing has revolutionized genomic research and revealed that eukaryotic transcriptomes contain a large fraction of non-protein-coding components. Eukaryotic genomes are pervasively transcribed [...] Read more.
The first reference to the “C-value paradox” reported an apparent imbalance between organismal genome size and morphological complexity. Since then, next-generation sequencing has revolutionized genomic research and revealed that eukaryotic transcriptomes contain a large fraction of non-protein-coding components. Eukaryotic genomes are pervasively transcribed and noncoding regions give rise to a plethora of noncoding RNAs with undeniable biological functions. Among them, long noncoding RNAs (lncRNAs) seem to represent a new layer of gene expression regulation, participating in a wide range of molecular mechanisms at the transcriptional and post-transcriptional levels. In addition to their role in epigenetic regulation, plant lncRNAs have been associated with the degradation of complementary RNAs, the regulation of alternative splicing, protein sub-cellular localization, the promotion of translation and protein post-translational modifications. In this review, we report and integrate numerous and complex mechanisms through which long noncoding transcripts regulate post-transcriptional gene expression in plants. Full article
(This article belongs to the Special Issue Post-transcriptional Regulation through Long Non-coding RNAs (lncRNAs))
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15 pages, 759 KiB  
Review
RNA-Centric Approaches to Profile the RNA–Protein Interaction Landscape on Selected RNAs
by André P. Gerber
Non-Coding RNA 2021, 7(1), 11; https://doi.org/10.3390/ncrna7010011 - 15 Feb 2021
Cited by 16 | Viewed by 7437
Abstract
RNA–protein interactions frame post-transcriptional regulatory networks and modulate transcription and epigenetics. While the technological advances in RNA sequencing have significantly expanded the repertoire of RNAs, recently developed biochemical approaches combined with sensitive mass-spectrometry have revealed hundreds of previously unrecognized and potentially novel RNA-binding [...] Read more.
RNA–protein interactions frame post-transcriptional regulatory networks and modulate transcription and epigenetics. While the technological advances in RNA sequencing have significantly expanded the repertoire of RNAs, recently developed biochemical approaches combined with sensitive mass-spectrometry have revealed hundreds of previously unrecognized and potentially novel RNA-binding proteins. Nevertheless, a major challenge remains to understand how the thousands of RNA molecules and their interacting proteins assemble and control the fate of each individual RNA in a cell. Here, I review recent methodological advances to approach this problem through systematic identification of proteins that interact with particular RNAs in living cells. Thereby, a specific focus is given to in vivo approaches that involve crosslinking of RNA–protein interactions through ultraviolet irradiation or treatment of cells with chemicals, followed by capture of the RNA under study with antisense-oligonucleotides and identification of bound proteins with mass-spectrometry. Several recent studies defining interactomes of long non-coding RNAs, viral RNAs, as well as mRNAs are highlighted, and short reference is given to recent in-cell protein labeling techniques. These recent experimental improvements could open the door for broader applications and to study the remodeling of RNA–protein complexes upon different environmental cues and in disease. Full article
(This article belongs to the Section Computational Biology)
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14 pages, 726 KiB  
Review
Fusion Genes and RNAs in Cancer Development
by Kenzui Taniue and Nobuyoshi Akimitsu
Non-Coding RNA 2021, 7(1), 10; https://doi.org/10.3390/ncrna7010010 - 4 Feb 2021
Cited by 34 | Viewed by 9131
Abstract
Fusion RNAs are a hallmark of some cancers. They result either from chromosomal rearrangements or from splicing mechanisms that are non-chromosomal rearrangements. Chromosomal rearrangements that result in gene fusions are particularly prevalent in sarcomas and hematopoietic malignancies; they are also common in solid [...] Read more.
Fusion RNAs are a hallmark of some cancers. They result either from chromosomal rearrangements or from splicing mechanisms that are non-chromosomal rearrangements. Chromosomal rearrangements that result in gene fusions are particularly prevalent in sarcomas and hematopoietic malignancies; they are also common in solid tumors. The splicing process can also give rise to more complex RNA patterns in cells. Gene fusions frequently affect tyrosine kinases, chromatin regulators, or transcription factors, and can cause constitutive activation, enhancement of downstream signaling, and tumor development, as major drivers of oncogenesis. In addition, some fusion RNAs have been shown to function as noncoding RNAs and to affect cancer progression. Fusion genes and RNAs will therefore become increasingly important as diagnostic and therapeutic targets for cancer development. Here, we discuss the function, biogenesis, detection, clinical relevance, and therapeutic implications of oncogenic fusion genes and RNAs in cancer development. Further understanding the molecular mechanisms that regulate how fusion RNAs form in cancers is critical to the development of therapeutic strategies against tumorigenesis. Full article
(This article belongs to the Special Issue Non-coding RNAs and Cancer Genetics)
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10 pages, 1464 KiB  
Article
miR-24 Targets the Transmembrane Glycoprotein Neuropilin-1 in Human Brain Microvascular Endothelial Cells
by Pasquale Mone, Jessica Gambardella, Xujun Wang, Stanislovas S. Jankauskas, Alessandro Matarese and Gaetano Santulli
Non-Coding RNA 2021, 7(1), 9; https://doi.org/10.3390/ncrna7010009 - 2 Feb 2021
Cited by 47 | Viewed by 6453
Abstract
Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 [...] Read more.
Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). We hypothesized that specific microRNAs can target Neuropilin-1. By combining bioinformatic and functional approaches, we identified miR-24 as a regulator of Neuropilin-1 transcription. Since Neuropilin-1 has been shown to play a key role in the endothelium-mediated regulation of the blood-brain barrier, we validated miR-24 as a functional modulator of Neuropilin-1 in human brain microvascular endothelial cells (hBMECs), which are the most suitable cell line for an in vitro blood–brain barrier model. Full article
(This article belongs to the Special Issue Non-coding RNA: 5th Anniversary)
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9 pages, 501 KiB  
Review
MicroRNAs as Candidate Biomarkers for Alzheimer’s Disease
by Colin Kanach, Jan K. Blusztajn, Andre Fischer and Ivana Delalle
Non-Coding RNA 2021, 7(1), 8; https://doi.org/10.3390/ncrna7010008 - 1 Feb 2021
Cited by 17 | Viewed by 5192
Abstract
The neurological damage of Alzheimer’s disease (AD) is thought to be irreversible upon onset of dementia-like symptoms, as it takes years to decades for occult pathologic changes to become symptomatic. It is thus necessary to identify individuals at risk for the development of [...] Read more.
The neurological damage of Alzheimer’s disease (AD) is thought to be irreversible upon onset of dementia-like symptoms, as it takes years to decades for occult pathologic changes to become symptomatic. It is thus necessary to identify individuals at risk for the development of the disease before symptoms manifest in order to provide early intervention. Surrogate markers are critical for early disease detection, stratification of patients in clinical trials, prediction of disease progression, evaluation of response to treatment, and also insight into pathomechanisms. Here, we review the evidence for a number of microRNAs that may serve as biomarkers with possible mechanistic insights into the AD pathophysiologic processes, years before the clinical manifestation of the disease. Full article
(This article belongs to the Collection Feature Papers in Non-Coding RNA)
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2 pages, 166 KiB  
Editorial
Acknowledgment to Reviewers of Non-Coding RNA in 2020
by Non-Coding RNA Editorial Office
Non-Coding RNA 2021, 7(1), 7; https://doi.org/10.3390/ncrna7010007 - 25 Jan 2021
Viewed by 3357
Abstract
Peer review is the driving force of journal development, and reviewers are gatekeepers who ensure that Non-Coding RNA maintains its standards for the high quality of its published papers [...] Full article
18 pages, 3020 KiB  
Hypothesis
Secondary Structural Model of MALAT1 Becomes Unstructured in Chronic Myeloid Leukemia and Undergoes Structural Rearrangement in Cervical Cancer
by Matthew C. Wang, Phillip J. McCown, Grace E. Schiefelbein and Jessica A. Brown
Non-Coding RNA 2021, 7(1), 6; https://doi.org/10.3390/ncrna7010006 - 13 Jan 2021
Cited by 7 | Viewed by 5035
Abstract
Long noncoding RNAs (lncRNAs) influence cellular function through binding events that often depend on the lncRNA secondary structure. One such lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), is upregulated in many cancer types and has a myriad of protein- and miRNA-binding sites. Recently, [...] Read more.
Long noncoding RNAs (lncRNAs) influence cellular function through binding events that often depend on the lncRNA secondary structure. One such lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), is upregulated in many cancer types and has a myriad of protein- and miRNA-binding sites. Recently, a secondary structural model of MALAT1 in noncancerous cells was proposed to form 194 hairpins and 13 pseudoknots. That study postulated that, in cancer cells, the MALAT1 structure likely varies, thereby influencing cancer progression. This work analyzes how that structural model is expected to change in K562 cells, which originated from a patient with chronic myeloid leukemia (CML), and in HeLa cells, which originated from a patient with cervical cancer. Dimethyl sulfate-sequencing (DMS-Seq) data from K562 cells and psoralen analysis of RNA interactions and structure (PARIS) data from HeLa cells were compared to the working structural model of MALAT1 in noncancerous cells to identify sites that likely undergo structural alterations. MALAT1 in K562 cells is predicted to become more unstructured, with almost 60% of examined hairpins in noncancerous cells losing at least half of their base pairings. Conversely, MALAT1 in HeLa cells is predicted to largely maintain its structure, undergoing 18 novel structural rearrangements. Moreover, 50 validated miRNA-binding sites are affected by putative secondary structural changes in both cancer types, such as miR-217 in K562 cells and miR-20a in HeLa cells. Structural changes unique to K562 cells and HeLa cells provide new mechanistic leads into how the structure of MALAT1 may mediate cancer in a cell-type specific manner. Full article
(This article belongs to the Special Issue Systematic Analysis of lncRNA Structures and Functions)
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11 pages, 1995 KiB  
Article
Evaluation of the Interplay between the ADAR Editome and Immunotherapy in Melanoma
by Marina Tusup, Phil F. Cheng, Ernesto Picardi, Austeja Raziunaite, Reinhard Dummer, Mitchell P. Levesque, Lars E. French, Emmanuella Guenova, Thomas M. Kundig and Steve Pascolo
Non-Coding RNA 2021, 7(1), 5; https://doi.org/10.3390/ncrna7010005 - 12 Jan 2021
Cited by 4 | Viewed by 4638 | Correction
Abstract
Background: RNA editing is a highly conserved posttranscriptional mechanism that contributes to transcriptome diversity. In mammals, it includes nucleobase deaminations that convert cytidine (C) into uridine (U) and adenosine (A) into inosine (I). Evidence from cancer studies indicates that RNA-editing enzymes promote certain [...] Read more.
Background: RNA editing is a highly conserved posttranscriptional mechanism that contributes to transcriptome diversity. In mammals, it includes nucleobase deaminations that convert cytidine (C) into uridine (U) and adenosine (A) into inosine (I). Evidence from cancer studies indicates that RNA-editing enzymes promote certain mechanisms of tumorigenesis. On the other hand, recoding editing in mRNA can generate mutations in proteins that can participate in the Major Histocompatibility Complex (MHC) ligandome and can therefore be recognized by the adaptive immune system. Anti-cancer treatment based on the administration of immune checkpoint inhibitors enhance these natural anti-cancer immune responses. Results: Based on RNA-Seq datasets, we evaluated the editome of melanoma cell lines generated from patients pre- and post-immunotherapy with immune checkpoint inhibitors. Our results reveal a differential editing in Arthrobacter luteus (Alu) sequences between samples pre-therapy and relapses during therapy with immune checkpoint inhibitors. Conclusion: These data pave the way towards the development of new diagnostics and therapies targeted to editing that could help in preventing relapses during immunotherapies. Full article
(This article belongs to the Collection Research on RNA Modification)
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32 pages, 728 KiB  
Review
Exosomes in Immune Regulation
by Heidi Schwarzenbach and Peter B. Gahan
Non-Coding RNA 2021, 7(1), 4; https://doi.org/10.3390/ncrna7010004 - 8 Jan 2021
Cited by 27 | Viewed by 6662
Abstract
Exosomes, small extracellular vesicles mediate intercellular communication by transferring their cargo including DNA, RNA, proteins and lipids from cell to cell. Notably, in the immune system, they have protective functions. However in cancer, exosomes acquire new, immunosuppressive properties that cause the dysregulation of [...] Read more.
Exosomes, small extracellular vesicles mediate intercellular communication by transferring their cargo including DNA, RNA, proteins and lipids from cell to cell. Notably, in the immune system, they have protective functions. However in cancer, exosomes acquire new, immunosuppressive properties that cause the dysregulation of immune cells and immune escape of tumor cells supporting cancer progression and metastasis. Therefore, current investigations focus on the regulation of exosome levels for immunotherapeutic interventions. In this review, we discuss the role of exosomes in immunomodulation of lymphoid and myeloid cells, and their use as immune stimulatory agents to elicit specific cytotoxic responses against the tumor. Full article
(This article belongs to the Collection Feature Papers in Non-Coding RNA)
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13 pages, 683 KiB  
Review
The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization
by Maialen Sebastian-delaCruz, Itziar Gonzalez-Moro, Ane Olazagoitia-Garmendia, Ainara Castellanos-Rubio and Izortze Santin
Non-Coding RNA 2021, 7(1), 3; https://doi.org/10.3390/ncrna7010003 - 5 Jan 2021
Cited by 84 | Viewed by 13338
Abstract
mRNA stability influences gene expression and translation in almost all living organisms, and the levels of mRNA molecules in the cell are determined by a balance between production and decay. Maintaining an accurate balance is crucial for the correct function of a wide [...] Read more.
mRNA stability influences gene expression and translation in almost all living organisms, and the levels of mRNA molecules in the cell are determined by a balance between production and decay. Maintaining an accurate balance is crucial for the correct function of a wide variety of biological processes and to maintain an appropriate cellular homeostasis. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of gene expression through different molecular mechanisms, including mRNA stabilization. In this review we provide an overview on the molecular mechanisms by which lncRNAs modulate mRNA stability and decay. We focus on how lncRNAs interact with RNA binding proteins and microRNAs to avoid mRNA degradation, and also on how lncRNAs modulate epitranscriptomic marks that directly impact on mRNA stability. Full article
(This article belongs to the Special Issue Post-transcriptional Regulation through Long Non-coding RNAs (lncRNAs))
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17 pages, 1460 KiB  
Review
Circular RNAs: Potential Applications as Therapeutic Targets and Biomarkers in Breast Cancer
by Debina Sarkar and Sarah D. Diermeier
Non-Coding RNA 2021, 7(1), 2; https://doi.org/10.3390/ncrna7010002 - 5 Jan 2021
Cited by 18 | Viewed by 6082
Abstract
Circular RNAs (circRNAs) are a class of non-coding RNAs that form a covalently closed loop. A number of functions and mechanisms of action for circRNAs have been reported, including as miRNA sponge, exerting transcriptional and translational regulation, interacting with proteins, and coding for [...] Read more.
Circular RNAs (circRNAs) are a class of non-coding RNAs that form a covalently closed loop. A number of functions and mechanisms of action for circRNAs have been reported, including as miRNA sponge, exerting transcriptional and translational regulation, interacting with proteins, and coding for peptides. CircRNA dysregulation has also been implicated in many cancers, such as breast cancer. Their relatively high stability and presence in bodily fluids makes cancer-associated circRNAs promising candidates as a new biomarker. In this review, we summarize the research undertaken on circRNAs associated with breast cancer, discuss circRNAs as biomarkers, and present circRNA-based therapeutic approaches. Full article
(This article belongs to the Section Clinical Applications of Non-Coding RNA)
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13 pages, 1194 KiB  
Article
Long Non-Coding RNAs in Diffuse Large B-Cell Lymphoma
by Kasper Thystrup Karstensen, Aleks Schein, Andreas Petri, Martin Bøgsted, Karen Dybkær, Shizuka Uchida and Sakari Kauppinen
Non-Coding RNA 2021, 7(1), 1; https://doi.org/10.3390/ncrna7010001 - 28 Dec 2020
Cited by 10 | Viewed by 5047
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Although significant progress has been made in recent years to treat DLBCL patients, 30%–40% of the patients eventually relapse or are refractory to first line treatment, calling for better therapeutic [...] Read more.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Although significant progress has been made in recent years to treat DLBCL patients, 30%–40% of the patients eventually relapse or are refractory to first line treatment, calling for better therapeutic strategies for DLBCL. Long non-coding RNAs (lncRNAs) have emerged as a highly diverse group of non-protein coding transcripts with intriguing molecular functions in human disease, including cancer. Here, we review the current understanding of lncRNAs in the pathogenesis and progression of DLBCL to provide an overview of the field. As the current knowledge of lncRNAs in DLBCL is still in its infancy, we provide molecular signatures of lncRNAs in DLBCL cell lines to assist further lncRNA research in DLBCL. Full article
(This article belongs to the Section Long Non-Coding RNA)
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