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Special Issue "Non-Coding RNA Biogenesis and Function"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 31 January 2020.

Special Issue Editor

Dr. Mariangela Morlando
E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, Via del Giochetto, 06123 Perugia, Italy
Interests: molecular biology; regulation of gene expression; noncoding RNA biogenesis and function

Special Issue Information

Dear Colleagues,

In the last few decades, we have witnessed an extraordinary progress in the knowledge of how the noncoding part of the eukaryotic genome determines the organism’s complexity. In particular, higher eukaryote genomes produce different classes of regulatory noncoding RNAs (ncRNA), with examples including short RNA molecules of 22–35 nucleotides (nts), such as microRNAs and PIWI-interacting RNAs (piRNAs), as well as transcripts such as the long noncoding RNAs (lncRNAs), which are generally referred to as noncoding molecules longer than 200 nts, and the newly emerging class of circular RNAs (circRNAs). All these ncRNAs hold important regulatory roles in a wide range of biological processes, operating at any step throughout the genetic expression process from transcription to RNA maturation and translation. However, the regulatory functions of many ncRNAs are not yet known, and this provides a rich environment for the development of new bioinformatics tools and experimental approaches for functional studies.

More importantly, deregulation of ncRNAs has been associated with a variety of different diseases, and emerging studies suggest that they represent a new potential class of diagnostic and prognostic biomarkers.

The present Special Issue is aimed at collecting latest advances and outstanding researches investigating biogenesis and function of different classes of ncRNAs and their possible involvement in disease pathogenesis. Original research and review manuscripts are welcome.

Dr. Mariangela Morlando
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

  • Long noncoding RNAs (lncRNAs)
  • MicroRNAs
  • PIWI-interacting RNAs (piRNAs)
  • Circular RNAs (circRNAs)
  • RNA maturation and translation
  • Deregulation of ncRNAs
  • Disease pathogenesis
  • Biological processes
  • Non-coding RNA biogenesis

Published Papers (10 papers)

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Research

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Open AccessArticle
Secondary Structural Model of Human MALAT1 Reveals Multiple Structure–Function Relationships
Int. J. Mol. Sci. 2019, 20(22), 5610; https://doi.org/10.3390/ijms20225610 - 09 Nov 2019
Abstract
Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an abundant nuclear-localized long noncoding RNA (lncRNA) that has significant roles in cancer. While the interacting partners and evolutionary sequence conservation of MALAT1 have been examined, much of the structure of MALAT1 is unknown. Here, [...] Read more.
Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an abundant nuclear-localized long noncoding RNA (lncRNA) that has significant roles in cancer. While the interacting partners and evolutionary sequence conservation of MALAT1 have been examined, much of the structure of MALAT1 is unknown. Here, we propose a hypothetical secondary structural model for 8425 nucleotides of human MALAT1 using three experimental datasets that probed RNA structures in vitro and in various human cell lines. Our model indicates that approximately half of human MALAT1 is structured, forming 194 helices, 13 pseudoknots, five structured tetraloops, nine structured internal loops, and 13 intramolecular long-range interactions that give rise to several multiway junctions. Evolutionary conservation and covariation analyses support 153 of 194 helices in 51 mammalian MALAT1 homologs and 42 of 194 helices in 53 vertebrate MALAT1 homologs, thereby identifying an evolutionarily conserved core that likely has important functional roles in mammals and vertebrates. Data mining revealed that RNA modifications, somatic cancer-associated mutations, and single-nucleotide polymorphisms may induce structural rearrangements that sequester or expose binding sites for several cancer-associated microRNAs. Our findings reveal new mechanistic leads into the roles of MALAT1 by identifying several intriguing structure–function relationships in which the dynamic structure of MALAT1 underlies its biological functions. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Open AccessArticle
Transcriptome Analysis Implicates Involvement of Long Noncoding RNAs in Cytoplasmic Male Sterility and Fertility Restoration in Cotton
Int. J. Mol. Sci. 2019, 20(22), 5530; https://doi.org/10.3390/ijms20225530 - 06 Nov 2019
Abstract
The cytoplasmic male sterility (CMS)/restorer-of-fertility system is an important tool to exploit heterosis during commercially hybrid seed production. The importance of long noncoding RNAs (lncRNAs) in plant development is recognized, but few analyses of lncRNAs during anther development of three-line hybrid cotton (CMS-D2 [...] Read more.
The cytoplasmic male sterility (CMS)/restorer-of-fertility system is an important tool to exploit heterosis during commercially hybrid seed production. The importance of long noncoding RNAs (lncRNAs) in plant development is recognized, but few analyses of lncRNAs during anther development of three-line hybrid cotton (CMS-D2 line A, maintainer line B, restorer-of-fertility line R) have been reported. Here, we performed transcriptome sequencing during anther development in three-line hybrid cotton. A total of 80,695 lncRNAs were identified, in which 43,347 and 44,739 lncRNAs were differentially expressed in A–B and A–R comparisons, respectively. These lncRNAs represent functional candidates involved in CMS and fertility restoration. GO analysis indicated that cellular hormone metabolic processes and oxidation–reduction reaction processes might be involved in CMS, and cellular component morphogenesis and small molecular biosynthetic processes might participate in fertility restoration. Additionally, 63 lncRNAs were identified as putative precursors of 35 miRNAs, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed a similar expression pattern to RNA-seq data. Furthermore, construction of lncRNA regulatory networks indicated that several miRNA–lncRNA–mRNA networks might be involved in CMS and fertility restoration. Our findings provide systematic identification of lncRNAs during anther development and lays a solid foundation for the regulatory mechanisms and utilization in hybrid cotton breeding. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Open AccessArticle
Long Non-Coding RNA GAS5 and Intestinal MMP2 and MMP9 Expression: A Translational Study in Pediatric Patients with IBD
Int. J. Mol. Sci. 2019, 20(21), 5280; https://doi.org/10.3390/ijms20215280 - 24 Oct 2019
Abstract
Background: The long non-coding RNA (lncRNA) growth arrest–specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role [...] Read more.
Background: The long non-coding RNA (lncRNA) growth arrest–specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. Methods: In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. Results: Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. Conclusion: These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Open AccessArticle
Functional Prediction of Candidate MicroRNAs for CRC Management Using in Silico Approach
Int. J. Mol. Sci. 2019, 20(20), 5190; https://doi.org/10.3390/ijms20205190 - 19 Oct 2019
Abstract
Approximately 30–50% of malignant growths can be prevented by avoiding risk factors and implementing evidence-based strategies. Colorectal cancer (CRC) accounted for the second most common cancer and the third most common cause of cancer death worldwide. This cancer subtype can be reduced by [...] Read more.
Approximately 30–50% of malignant growths can be prevented by avoiding risk factors and implementing evidence-based strategies. Colorectal cancer (CRC) accounted for the second most common cancer and the third most common cause of cancer death worldwide. This cancer subtype can be reduced by early detection and patients’ management. In this study, the functional roles of the identified microRNAs were determined using an in silico pipeline. Five microRNAs identified using an in silico approach alongside their seven target genes from our previous study were used as datasets in this study. Furthermore, the secondary structure and the thermodynamic energies of the microRNAs were revealed by Mfold algorithm. The triplex binding ability of the oligonucleotide with the target promoters were analyzed by Trident. Finally, evolutionary stage-specific somatic events and co-expression analysis of the target genes in CRC were analyzed by SEECancer and GeneMANIA plugin in Cytoscape. Four of the five microRNAs have the potential to form more than one secondary structure. The ranges of the observed/expected ratio of CpG dinucleotides of these genes range from 0.60 to 1.22. Three of the candidate microRNA were capable of forming multiple triplexes along with three of the target mRNAs. Four of the total targets were involved in either early or metastatic stage-specific events while three other genes were either a product of antecedent or subsequent events of the four genes implicated in CRC. The secondary structure of the candidate microRNAs can be used to explain the different degrees of genetic regulation in CRC due to their conformational role to modulate target interaction. Furthermore, due to the regulation of important genes in the CRC pathway and the enrichment of the microRNA with triplex binding sites, they may be a useful diagnostic biomarker for the disease subtype. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Open AccessArticle
MicroRNA Biogenesis Pathway Genes Are Deregulated in Colorectal Cancer
Int. J. Mol. Sci. 2019, 20(18), 4460; https://doi.org/10.3390/ijms20184460 - 10 Sep 2019
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Each step of their production and maturation has to be strictly regulated, as any disruption of control mechanisms may lead to cancer. Thus, we have measured the expression of 19 genes involved [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Each step of their production and maturation has to be strictly regulated, as any disruption of control mechanisms may lead to cancer. Thus, we have measured the expression of 19 genes involved in miRNAs biogenesis pathway in tumor tissues of 239 colorectal cancer (CRC) patients, 17 CRC patients with liver metastases and 239 adjacent tissues using real-time PCR. Subsequently, the expression of analyzed genes was correlated with the clinical-pathological features as well as with the survival of patients. In total, significant over-expression of all analyzed genes was observed in tumor tissues as well as in liver metastases except for LIN28A/B. Furthermore, it was shown that the deregulated levels of some of the analyzed genes significantly correlate with tumor stage, grade, location, size and lymph node positivity. Finally, high levels of DROSHA and TARBP2 were associated with shorter disease-free survival, while the over-expression of XPO5, TNRC6A and DDX17 was detected in tissues of patients with shorter overall survival and poor prognosis. Our data indicate that changed levels of miRNA biogenesis genes may contribute to origin as well as progression of CRC; thus, these molecules could serve as potential therapeutic targets. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Open AccessArticle
Analysis of the Association Between MicroRNA Biogenesis Gene Polymorphisms and Venous Thromboembolism in Koreans
Int. J. Mol. Sci. 2019, 20(15), 3771; https://doi.org/10.3390/ijms20153771 - 01 Aug 2019
Abstract
Venous thromboembolism (VTE) involves the formation of a blood clot, typically in the deep veins of the leg or arm (deep vein thrombosis), which then travels via the circulatory system and ultimately lodges in the lungs, resulting in pulmonary embolism. A number of [...] Read more.
Venous thromboembolism (VTE) involves the formation of a blood clot, typically in the deep veins of the leg or arm (deep vein thrombosis), which then travels via the circulatory system and ultimately lodges in the lungs, resulting in pulmonary embolism. A number of microRNAs (miRNAs) are well-known regulators of thrombosis and thrombolysis, and mutations in miRNA biogenesis genes, such as DICER1, DROSHA have been implicated in miRNA synthesis and function. We investigated the genetic association between polymorphisms in four miRNA biogenesis genes, DICER1 rs3742330A > G, DROSHA rs10719T > C, RAN rs14035C > T and XPO5 rs11077A > C, and VTE in 503 Koreans: 300 controls and 203 patients. Genotyping was assessed with polymerase chain reaction-restriction fragment length polymorphism assays. We detected associations between polymorphisms in RAN and XPO5 and VTE prevalence (RAN rs14035CC + CT versus TT: p = 0.018; XPO5 rs11077AA + AC versus CC: p < 0.001). Analysis of allele combinations of all four polymorphisms (DICER1, DROSHA, RAN, XPO5) revealed that A-T-T-A was associated with decreased VTE prevalence (p = 0.0002), and A-T-C-C was associated with increased VTE prevalence (p = 0.027). Moreover, in subjects with provoked VTE, the DROSHA rs10719T > C, polymorphism was associated with increased disease prevalence (TT versus TC + CC: p < 0.039). Our study demonstrates that RAN and XPO5 polymorphisms are associated with risk for VTE in Korean subjects. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)

Review

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Open AccessReview
Exploring the Regulatory Role of Circular RNAs in Neurodegenerative Disorders
Int. J. Mol. Sci. 2019, 20(21), 5477; https://doi.org/10.3390/ijms20215477 - 04 Nov 2019
Abstract
Circular RNAs (circRNAs) are a distinctive class of regulatory non-coding RNAs characterised by the presence of covalently closed ends. They are evolutionary conserved molecules, and although detected in different tissues, circRNAs resulted specifically enriched in the nervous system. Recent studies have shown that [...] Read more.
Circular RNAs (circRNAs) are a distinctive class of regulatory non-coding RNAs characterised by the presence of covalently closed ends. They are evolutionary conserved molecules, and although detected in different tissues, circRNAs resulted specifically enriched in the nervous system. Recent studies have shown that circRNAs are dynamically modulated during neuronal development and aging, that circRNAs are enriched at synaptic levels and resulted modulated after synaptic plasticity induction. This has suggested that circRNAs might play an important role in neuronal specification and activity. Despite the exact function of circRNAs is still poorly understood, emerging evidence indicates that circRNAs have important regulatory functions that might extensively contribute to the dynamic modulation of gene expression that supports neuronal pathways. More interestingly, deregulation of circRNAs expression has been linked with various pathological conditions. In this review, we describe current advances in the field of circRNA biogenesis and function in the nervous system both in physiological and in pathological conditions, and we specifically lay out their association with neurodegenerative diseases. Furthermore, we discuss the opportunity to exploit circRNAs for innovative therapeutic approaches and, due to their high stability, to use circRNAs as suitable biomarkers for diagnosis and disease progression. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Open AccessReview
Long Non-Coding RNAs and Related Molecular Pathways in the Pathogenesis of Epilepsy
Int. J. Mol. Sci. 2019, 20(19), 4898; https://doi.org/10.3390/ijms20194898 - 02 Oct 2019
Abstract
Epilepsy represents one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS). Recurrent seizures are the cardinal clinical manifestation. Although it has been reported that the underlying pathological processes include inflammation, changes in synaptic strength, [...] Read more.
Epilepsy represents one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS). Recurrent seizures are the cardinal clinical manifestation. Although it has been reported that the underlying pathological processes include inflammation, changes in synaptic strength, apoptosis, and ion channels dysfunction, currently the pathogenesis of epilepsy is not yet completely understood. Long non-coding RNAs (lncRNAs), a class of long transcripts without protein-coding capacity, have emerged as regulatory molecules that are involved in a wide variety of biological processes. A growing number of studies reported that lncRNAs participate in the regulation of pathological processes of epilepsy and they are dysregulated during epileptogenesis. Moreover, an aberrant expression of lncRNAs linked to epilepsy has been observed both in patients and in animal models. In this review, we summarize latest advances concerning the mechanisms of action and the involvement of the most dysregulated lncRNAs in epilepsy. However, the functional roles of lncRNAs in the disease pathogenesis are still to be explored and we are only at the beginning. Additional studies are needed for the complete understanding of the underlying mechanisms and they would result in the use of lncRNAs as diagnostic biomarkers and novel therapeutic targets. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Open AccessReview
Human Circulating miRNAs Real-time qRT-PCR-based Analysis: An Overview of Endogenous Reference Genes Used for Data Normalization
Int. J. Mol. Sci. 2019, 20(18), 4353; https://doi.org/10.3390/ijms20184353 - 05 Sep 2019
Abstract
miRNAs are small non-coding RNAs of about 18–25 nucleotides that negatively regulate gene expression at the post-transcriptional level. It was reported that a deregulation of their expression patterns correlates to the onset and progression of various diseases. Recently, these molecules have been identified [...] Read more.
miRNAs are small non-coding RNAs of about 18–25 nucleotides that negatively regulate gene expression at the post-transcriptional level. It was reported that a deregulation of their expression patterns correlates to the onset and progression of various diseases. Recently, these molecules have been identified in a great plethora of biological fluids, and have also been proposed as potential diagnostic and prognostic biomarkers. Actually, real time quantitative polymerase chain reaction is the most widely used approach for circulating miRNAs (c-miRNAs) expression profiling. Nevertheless, the debate on the choice of the most suitable endogenous reference genes for c-miRNAs expression levels normalization is still open. In this regard, numerous research groups are focusing their efforts upon identifying specific, highly stable, endogenous c-mRNAs. The aim of this review is to provide an overview on the reference genes currently used in the study of various pathologies, offering to researchers the opportunity to select the appropriate molecules for c-miRNA levels normalization, when their choosing is based upon literature data. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Open AccessReview
Circular RNAs: Biogenesis, Mechanism, and Function in Human Cancers
Int. J. Mol. Sci. 2019, 20(16), 3926; https://doi.org/10.3390/ijms20163926 - 13 Aug 2019
Abstract
CircRNAs are a class of noncoding RNA species with a circular configuration that is formed by either typical spliceosome-mediated or lariat-type splicing. The expression of circRNAs is usually abnormal in many cancers. Several circRNAs have been demonstrated to play important roles in carcinogenesis. [...] Read more.
CircRNAs are a class of noncoding RNA species with a circular configuration that is formed by either typical spliceosome-mediated or lariat-type splicing. The expression of circRNAs is usually abnormal in many cancers. Several circRNAs have been demonstrated to play important roles in carcinogenesis. In this review, we will first provide an introduction of circRNAs biogenesis, especially the regulation of circRNA by RNA-binding proteins, then we will focus on the recent findings of circRNA molecular mechanisms and functions in cancer development. Finally, some open questions are also discussed. Full article
(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Circular RNA in myeloid malignancies: emerging roles and unanswered questions

Eileen Wedge1, Lasse Sommer Kristiansen2 and Kirsten Grønbæk1

  1. Department of Hematology, Rigshospitalet, Copenhagen
  2. Aarhus University

AbstractThe myeloid malignancies include a spectrum of disease from clonal cytopenia of undetermined significance to myelodysplastic syndrome and acute myeloid leukemia, as well as myeloproliferative neoplasms. They represent an ongoing challenge in both biological understanding and clinical treatment, due to high levels of phenotypic and genotypic heterogeneity at both population and intratumoral levels and complex interactions with the bone marrow microenvironment. Mutations in spliceosome components and epigenetic regulators are abundant in CCUS and MDS, and roles have been identified for other types of non-coding RNA in these diseases. Circular RNAs are stable molecules produced by 3’ to 5’ backsplicing, related to complementary flanking sequences or intron skipping events. Numerous circRNA functions have been discovered in recent years, including microRNA sponging and roles in immune signaling pathways. Distinct circRNA expression profiles have been described for the different cell types of normal human hematopoiesis, and several studies have identified circRNAs associated with phenotypes, treatment response or prognosis in AML. This review discusses existing evidence for the significance of circular RNA in myeloid malignancies, as well as exploring promising directions for future investigation.  

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