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RNA Regulatory Networks at the Crossroad of Human Diseases

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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 (28 February 2021) | Viewed by 36670

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Prof. Nicoletta Potenza

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Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania “L. Vanvitelli”, Via Vivaldi, 43-81100 Caserta, Italy
Interests: microRNAs; lncRNA; non-coding RNA; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Exploration of the transcriptome space has turned the spotlight on the dark side of the RNA planet, non-coding RNAs (ncRNAs), previously overlooked by conventional protein-coding studies. It has become increasingly clear that ncRNAs constitute the largest class of RNA transcripts, resulting from pervasive transcription of the genome, of which only 1–2% code for proteins. ncRNAs comprise different RNA species, which can be broadly categorized into short ncRNAs, including microRNAs (miRNA), and long ncRNAs (lncRNAs), such as lincRNA, antisense RNAs, pseudogenes and circular RNAs. We are now in an exciting era, which is unveiling the previously unappreciated regulatory power of all these RNA species and their functional interactions. Various studies have demonstrated that ncRNAs engage in competitive regulatory interactions, known as competing endogenous RNA (ceRNA) networks, ceRNET, whereby miRNAs and lncRNAs modulate each other, since miRNAs can regulate the expression of lncRNAs, which in turn regulate miRNAs by competing with the binding to mRNA targets. In this scenario, coding transcripts themselves could have a regulatory power beyond their coding potential, when they compete for binding to shared miRNAs.

Untangling such RNA-based networks is now outlining their relevant role in a wide range of biological pathways; the unbalancing of any network component can act as a driving force for human diseases, as demonstrated for various cancer types. ceRNET research is still in its infancy, but could fulfill the promise to gain a deeper insight into molecular mechanisms underlying human diseases, and probably of the identification of new biomarkers and therapeutic targets.

This special issue welcomes original research manuscripts, unraveling novel RNA regulatory networks and their impact on human diseases, possible rules for ncRNA structure-function relationships, or reporting innovative methodological approaches, including new bioinformatics tools; critical review manuscripts with a perspective vision setting the stage for future research are also especially welcome.

Note: Welcome to publish your research in our new special issue "RNA Regulatory Networks at the Crossroad of Human 2.0" (Deadline: 28 February 2022.)

Prof. Nicoletta Potenza
Guest Editor

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Keywords

Non-coding RNA
microRNA
piRNA
lncRNA
circRNA
disease pathogenesis
developmental defects
cancer

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Published Papers (10 papers)

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Research

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19 pages, 4810 KiB

Open AccessArticle

Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease

by Carolina Kymie Vasques Nonaka, Gabriela Louise Sampaio, Luciana de Aragão França, Bruno Raphael Cavalcante, Katia Nunes Silva, Ricardo Khouri, Felipe Guimarães Torres, Cassio Santana Meira, Emanuelle de Souza Santos, Carolina Thé Macedo, Bruno Diaz Paredes, Vinicius Pinto Costa Rocha, Silvia Regina Rogatto, Ricardo Ribeiro dos Santos, Bruno Solano de Freitas Souza and Milena Botelho Pereira Soares

Int. J. Mol. Sci. 2021, 22(7), 3307; https://doi.org/10.3390/ijms22073307 - 24 Mar 2021

Cited by 29 | Viewed by 3242

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), remains a serious public health problem for which there is no effective treatment in the chronic stage. Intense cardiac fibrosis and inflammation are hallmarks of chronic Chagas disease cardiomyopathy (CCC). Previously, we identified upregulation of circulating and cardiac miR-21, a pro-fibrotic microRNA (miRNA), in subjects with CCC. Here, we explored the potential role of miR-21 as a therapeutic target in a model of chronic Chagas disease. PCR array-based 88 microRNA screening was performed in heart samples obtained from C57Bl/6 mice chronically infected with T. cruzi and serum samples collected from CCC patients. MiR-21 was found upregulated in both human and mouse samples, which was corroborated by an in silico analysis of miRNA-mRNA target prediction. In vitro miR-21 functional assays (gain-and loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and collagen expression upon transforming growth factor beta 1 (TGFβ1) and T. cruzi stimulation, while miR-21 blockage reduced collagen expression. Finally, treatment of T. cruzi-infected mice with locked nucleic acid (LNA)-anti-miR-21 inhibitor promoted a significant reduction in cardiac fibrosis. Our data suggest that miR-21 is a mediator involved in the pathogenesis of cardiac fibrosis and indicates the pharmacological silencing of miR-21 as a potential therapeutic approach for CCC. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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15 pages, 21419 KiB

Open AccessArticle

An Analysis of Differentially Expressed Coding and Long Non-Coding RNAs in Multiple Models of Skeletal Muscle Atrophy

by Keisuke Hitachi, Masashi Nakatani, Yuri Kiyofuji, Hidehito Inagaki, Hiroki Kurahashi and Kunihiro Tsuchida

Int. J. Mol. Sci. 2021, 22(5), 2558; https://doi.org/10.3390/ijms22052558 - 4 Mar 2021

Cited by 8 | Viewed by 3305

Abstract

The loss of skeletal muscle mass (muscle atrophy or wasting) caused by aging, diseases, and injury decreases quality of life, survival rates, and healthy life expectancy in humans. Although long non-coding RNAs (lncRNAs) have been implicated in skeletal muscle formation and differentiation, their precise roles in muscle atrophy remain unclear. In this study, we used RNA-sequencing (RNA-Seq) to examine changes in the expression of lncRNAs in four muscle atrophy conditions (denervation, casting, fasting, and cancer cachexia) in mice. We successfully identified 33 annotated lncRNAs and 18 novel lncRNAs with common expression changes in all four muscle atrophy conditions. Furthermore, an analysis of lncRNA–mRNA correlations revealed that several lncRNAs affected small molecule biosynthetic processes during muscle atrophy. These results provide novel insights into the lncRNA-mediated regulatory mechanism underlying muscle atrophy and may be useful for the identification of promising therapeutic targets. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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9 pages, 1535 KiB

Open AccessArticle

An Exon-Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing-Defective spf/ash Mouse Model of Ornithine Transcarbamylase Deficiency

by Dario Balestra, Mattia Ferrarese, Silvia Lombardi, Nicole Ziliotto, Alessio Branchini, Naomi Petersen, Piter Bosma, Mirko Pinotti and Stan F. J. van de Graaf

Int. J. Mol. Sci. 2020, 21(22), 8735; https://doi.org/10.3390/ijms21228735 - 19 Nov 2020

Cited by 6 | Viewed by 2963

Abstract

OTC splicing mutations are generally associated with the severest and early disease onset of ornithine transcarbamylase deficiency (OTCD), the most common urea cycle disorder. Noticeably, splicing defects can be rescued by spliceosomal U1snRNA variants, which showed their efficacy in cellular and animal models. Here, we challenged an U1snRNA variant in the OTCD mouse model (spf/ash) carrying the mutation c.386G > A (p.R129H), also reported in OTCD patients. It is known that the R129H change does not impair protein function but affects pre-mRNA splicing since it is located within the 5′ splice site. Through in vitro studies, we identified an Exon Specific U1snRNA (ExSpeU1^O3) that targets an intronic region downstream of the defective exon 4 and rescues exon inclusion. The adeno-associated virus (AAV8)-mediated delivery of the ExSpeU1^O3 to mouse hepatocytes, although in the presence of a modest transduction efficiency, led to increased levels of correct OTC transcripts (from 6.1 ± 1.4% to 17.2 ± 4.5%, p = 0.0033). Consistently, this resulted in increased liver expression of OTC protein, as demonstrated by Western blotting (~3 fold increase) and immunostaining. Altogether data provide the early proof-of-principle of the efficacy of ExSpeU1 in the spf/ash mouse model and encourage further studies to assess the potential of RNA therapeutics for OTCD caused by aberrant splicing. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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23 pages, 24608 KiB

Open AccessArticle

Spliceosome-Associated microRNAs Signify Breast Cancer Cells and Portray Potential Novel Nuclear Targets

by Shelly Mahlab-Aviv, Keren Zohar, Yael Cohen, Ayelet R. Peretz, Tsiona Eliyahu, Michal Linial and Ruth Sperling

Int. J. Mol. Sci. 2020, 21(21), 8132; https://doi.org/10.3390/ijms21218132 - 30 Oct 2020

Cited by 13 | Viewed by 3096

Abstract

MicroRNAs (miRNAs) act as negative regulators of gene expression in the cytoplasm. Previous studies have identified the presence of miRNAs in the nucleus. Here we study human breast cancer-derived cell-lines (MCF-7 and MDA-MB-231) and a non-tumorigenic cell-line (MCF-10A) and compare their miRNA sequences at the spliceosome fraction (SF). We report that the levels of miRNAs found in the spliceosome, their identity, and pre-miRNA segmental composition are cell-line specific. One such miRNA is miR-7704 whose genomic position overlaps HAGLR, a cancer-related lncRNA. We detected an inverse expression of miR-7704 and HAGLR in the tested cell lines. Specifically, inhibition of miR-7704 caused an increase in HAGLR expression. Furthermore, elevated levels of miR-7704 slightly altered the cell-cycle in MDA-MB-231. Altogether, we show that SF-miR-7704 acts as a tumor-suppressor gene with HAGLR being its nuclear target. The relative levels of miRNAs found in the spliceosome fractions (e.g., miR-100, miR-30a, and let-7 family) in non-tumorigenic relative to cancer-derived cell-lines was monitored. We found that the expression trend of the abundant miRNAs in SF was different from that reported in the literature and from the observation of large cohorts of breast cancer patients, suggesting that many SF-miRNAs act on targets that are different from the cytoplasmic ones. Altogether, we report on the potential of SF-miRNAs as an unexplored route for cancerous cell state. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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10 pages, 1083 KiB

Open AccessArticle

Circulating MiRNA-195-5p and -451a in Diabetic Patients with Transient and Acute Ischemic Stroke in the Emergency Department

by Mauro Giordano, Maria Consiglia Trotta, Tiziana Ciarambino, Michele D’Amico, Marilena Galdiero, Federico Schettini, Diego Paternosto, Marta Salzillo, Roberto Alfano, Vincenzo Andreone, Lorenzo Salvatore Malatino, Gianni Biolo, Giuseppe Paolisso and Luigi Elio Adinolfi

Int. J. Mol. Sci. 2020, 21(20), 7615; https://doi.org/10.3390/ijms21207615 - 15 Oct 2020

Cited by 26 | Viewed by 2590

Abstract

(1) Background: Circulating micro-RNAs (miRNAs) modulate the expression of molecules in diabetes. We evaluated the expression of serum miRNA-195-5p and -451a in diabetic patients with ischemic stroke and correlated them with two markers of brain tissue integrity. (2) Methods: Seventy-eight subjects with acute ischemic stroke (AIS) or transient ischemic attack (TIA) (40 with diabetes) were enrolled. Serum miRNA levels, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGF-A) were assessed at admission and 24 and 72 h after a post-ischemic stroke, and were compared to 20 controls. (3) Results: Both circulating miRNAs were two-fold up-regulated in diabetic AIS and TIA patients compared to non-diabetics. Their levels progressively decreased at 24 and 72 h in both AIS and TIA patients. Interestingly, in the non-diabetic TIA group, both circulating miRNAs, although higher than the controls, tended to achieve a complete decay after 72 h. Furthermore, miRNA-195-5p and miRNA-451a levels inversely correlated with both BDNF and VEGF-A serum levels. (4) Conclusions: These data show a different profile of both micro-RNAs in diabetic versus non-diabetic patients after acute ischemic stroke, suggesting their pivotal role in cerebrovascular ischemic attack. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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13 pages, 976 KiB

Open AccessCommunication

A Novel ceRNA Regulatory Network Involving the Long Non-Coding Antisense RNA SPACA6P-AS, miR-125a and its mRNA Targets in Hepatocarcinoma Cells

by Armando Di Palo, Chiara Siniscalchi, Nicola Mosca, Aniello Russo and Nicoletta Potenza

Int. J. Mol. Sci. 2020, 21(14), 5068; https://doi.org/10.3390/ijms21145068 - 17 Jul 2020

Cited by 22 | Viewed by 2429

Abstract

MicroRNAs (miRNA), and more recently long non-coding RNAs (lncRNA), are emerging as a driving force for hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death. In this work, we investigated a possible RNA regulatory network involving two oncosuppressive miRNAs, miR-125a and let-7e, and a long non-coding antisense RNA, SPACA6P-AS (SP-AS), all transcribed from the same locus, with SP-AS in the opposite direction and thus carrying complementary sequences to the miRNAs. In vitro experiments validated the binding of the miRNAs to SP-AS. Then, the boosting of either the miRNAs or SP-AS levels demonstrated their reciprocal inhibition. In addition, overexpression of SP-AS resulted in a reduced silencing activity of miR-125a and let-7e toward their key oncogenic targets, i.e., Lin28b, MMP11, SIRT7, Zbtb7a, Cyclin D1, CDC25B, HMGA2, that resulted significantly upregulated. Finally, the analysis of 374 HCC samples in comparison to 50 normal liver tissues showed an upregulation of SP-AS and a reverse expression of miR-125a, not observed for let-7e; consistently, miR-125a oncogenic targets were upregulated. Overall, the data depict a novel competing endogenous RNA (ceRNA) network, ceRNET, whereby miR-125a can regulate the expression of SP-AS, which in turn regulates the miRNA by competing with the binding to the mRNA targets. We speculate that the unbalancing of any network component may contribute to hepatocarcinogenesis. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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Review

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19 pages, 1449 KiB

Open AccessReview

Decoding the Roles of Long Noncoding RNAs in Hepatocellular Carcinoma

by Lok-Sze Wong and Chun-Ming Wong

Int. J. Mol. Sci. 2021, 22(6), 3137; https://doi.org/10.3390/ijms22063137 - 19 Mar 2021

Cited by 21 | Viewed by 3799

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. HCC is associated with several etiological factors, including HBV/HCV infections, cirrhosis, and fatty liver diseases. However, the molecular mechanism underlying HCC development remains largely elusive. The advent of high-throughput sequencing has unveiled an unprecedented discovery of a plethora of long noncoding RNAs (lncRNAs). Despite the lack of coding capacity, lncRNAs have key roles in gene regulation through interacting with various biomolecules. It is increasingly evident that the dysregulation of lncRNAs is inextricably linked to HCC cancer phenotypes, suggesting that lncRNAs are potential prognostic markers and therapeutic targets. In light of the emerging research in the study of the regulatory roles of lncRNAs in HCC, we discuss the association of lncRNAs with HCC. We link the biological processes influenced by lncRNAs to cancer hallmarks in HCC and describe the associated functional mechanisms. This review sheds light on future research directions, including the potential therapeutic applications of lncRNAs. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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13 pages, 735 KiB

Open AccessReview

The Roles of MicroRNAs in Male Infertility

by Madalina Gabriela Barbu, Dana Claudia Thompson, Nicolae Suciu, Silviu Cristian Voinea, Dragos Cretoiu and Dragos Valentin Predescu

Int. J. Mol. Sci. 2021, 22(6), 2910; https://doi.org/10.3390/ijms22062910 - 13 Mar 2021

Cited by 36 | Viewed by 5026

Abstract

MicroRNAs applications were vastly studied throughout the years, spanning from potential cancer biomarkers to targeted therapies for various diseases. Out of these utilizations, this paper focuses on their role in male infertility. Approximately 10–15% of worldwide couples are affected by infertility. Out of these, 50% are due to male determinants. The majority of cases still have an undetermined cause. Previous studies have found that the aberrant expression of microRNAs could be linked to certain reproductive dysfunctions in males. Further on, this study looked into the most recent literature published on this subject in order to assess the connection between the up-/down-regulation of various microRNAs and the roles they play in male infertility. MicroRNAs were found to be abundant and stable in the seminal liquid, which led to a facile identification using regular RNA detection methods. It was observed that the concentration of microRNAs in semen was modified in the case of patients suffering from asthenozoospermia and azoospermia. Moreover, idiopathic male infertility was associated with a single nucleotide polymorphism of the microRNA binding site. Future studies should focus their attention on discovering future treatments against male infertility targeting specific microRNAs and also on developing new and improved contraceptive methods. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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16 pages, 716 KiB

Open AccessReview

The Roles of Host 5-Methylcytosine RNA Methyltransferases during Viral Infections

by Maciej Wnuk, Piotr Slipek, Mateusz Dziedzic and Anna Lewinska

Int. J. Mol. Sci. 2020, 21(21), 8176; https://doi.org/10.3390/ijms21218176 - 31 Oct 2020

Cited by 27 | Viewed by 5103

Abstract

Eukaryotic 5-methylcytosine RNA methyltransferases catalyze the transfer of a methyl group to the fifth carbon of a cytosine base in RNA sequences to produce 5-methylcytosine (m⁵C). m⁵C RNA methyltransferases play a crucial role in the maintenance of functionality and stability of RNA. Viruses have developed a number of strategies to suppress host innate immunity and ensure efficient transcription and translation for the replication of new virions. One such viral strategy is to use host m⁵C RNA methyltransferases to modify viral RNA and thus to affect antiviral host responses. Here, we summarize the latest findings concerning the roles of m⁵C RNA methyltransferases, namely, NOL1/NOP2/SUN domain (NSUN) proteins and DNA methyltransferase 2/tRNA methyltransferase 1 (DNMT2/TRDMT1) during viral infections. Moreover, the use of m⁵C RNA methyltransferase inhibitors as an antiviral therapy is discussed. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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23 pages, 572 KiB

Open AccessReview

Small RNAs, Big Diseases

by Iwona Rzeszutek and Aditi Singh

Int. J. Mol. Sci. 2020, 21(16), 5699; https://doi.org/10.3390/ijms21165699 - 9 Aug 2020

Cited by 8 | Viewed by 3958

Abstract

The past two decades have seen extensive research done to pinpoint the role of microRNAs (miRNAs) that have led to discovering thousands of miRNAs in humans. It is not, therefore, surprising to see many of them implicated in a number of common as well as rare human diseases. In this review article, we summarize the progress in our understanding of miRNA-related research in conjunction with different types of cancers and neurodegenerative diseases, as well as their potential in generating more reliable diagnostic and therapeutic approaches. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases)

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