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Special Issue "Non-Coding RNAs 2012"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular Biology and Biophysics".

Deadline for manuscript submissions: closed (31 October 2012)

Special Issue Editor

Guest Editor
Prof. Dr. Constantinos Stathopoulos (Website)

Department of Biochemistry, School of Medicine, University of Patras, 1 Asklipiou st., 26504 Patras, Greece
Fax: +30 2610 969167
Interests: tRNA; mRNA; riboswitches; antibiotics; aminoacyl-tRNA synthetases; ribonucleases; translation; ribosome; tRFs

Special Issue Information

Dear Colleagues,

During recent years, a remarkable expansion of the “RNA world” members has been observed with the discovery and characterization of many elusive, so far, RNA molecules of various sizes and regulatory roles, in both eukaryotes and bacteria. In the dawn of this new RNA era, the term “non-coding RNAs” represents not only molecules such as tRNAs, rRNAs and snoRNAs, that cannot be translated into proteins. Instead, it additionally includes a variety of prominent RNA molecules that play distinct and critical roles within the cell. In eukaryotes, these novel members are represented by numerous microRNAs, siRNAs, piRNAs and long non-coding RNAs, that exhibit trans-acting antisense modulating properties. Today, we know that they modulate gene expression by interfering in post-transcriptional level. Moreover, RNA interference-based methodologies have provided the means of studying gene expression at a glance, both in vitro and in vivo, and they have emerged as very delicate and promising therapeutic strategies. In bacteria, the new members are represented by many regulatory RNAs of various sizes, which are also responsible for essential cellular responses. These key elements, can either be embedded in the 5’ end of mRNAs (i.e. riboswitches), they can be small RNAs that act in trans by targeting proteins or RNAs, they can be long antisense RNA modulators (CRISPR RNAs) or they may even have intrinsic activity (like RNase P ribozyme). Whatever their origin, size, structure or specific role, it is more than evident that non-coding RNAs represent a dynamic and expanding family of essential molecules, some of them with deep evolutionary history. Moreover, they are established as valuable novel tools with biotechnological applications or/and targets for combating disease or pathogens. Their discovery and study has great impact not only in the way we approach specific cellular processes today, but also in the way we understand the evolution of life itself.

Prof. Dr. Constantinos Stathopoulos
Guest Editor

Keywords

  • tRNA
  • rRNA
  • snoRNA
  • ribozyme
  • microRNA
  • siRNA
  • piRNA
  • riboswitch
  • sRNA
  • CRISPR RNA

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Published Papers (21 papers)

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Research

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Open AccessArticle Identification and Dynamic Regulation of microRNAs Involved in Salt Stress Responses in Functional Soybean Nodules by High-Throughput Sequencing
Int. J. Mol. Sci. 2013, 14(2), 2717-2738; doi:10.3390/ijms14022717
Received: 10 November 2012 / Revised: 9 January 2013 / Accepted: 15 January 2013 / Published: 28 January 2013
Cited by 15 | PDF Full-text (759 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Both symbiosis between legumes and rhizobia and nitrogen fixation in functional nodules are dramatically affected by salt stress. Better understanding of the molecular mechanisms that regulate the salt tolerance of functional nodules is essential for genetic improvement of nitrogen fixation efficiency. microRNAs [...] Read more.
Both symbiosis between legumes and rhizobia and nitrogen fixation in functional nodules are dramatically affected by salt stress. Better understanding of the molecular mechanisms that regulate the salt tolerance of functional nodules is essential for genetic improvement of nitrogen fixation efficiency. microRNAs (miRNAs) have been implicated in stress responses in many plants and in symbiotic nitrogen fixation (SNF) in soybean. However, the dynamic regulation of miRNAs in functioning nodules during salt stress response remains unknown. We performed deep sequencing of miRNAs to understand the miRNA expression profile in normal or salt stressed-soybean mature nodules. We identified 110 known miRNAs belonging to 61 miRNA families and 128 novel miRNAs belonging to 64 miRNA families. Among them, 104 miRNAs were dramatically differentially expressed (>2-fold or detected only in one library) during salt stress. qRT-PCR analysis of eight miRNAs confirmed that these miRNAs were dynamically regulated in response to salt stress in functional soybean nodules. These data significantly increase the number of miRNAs known to be expressed in soybean nodules, and revealed for the first time a dynamic regulation of miRNAs during salt stress in functional nodules. The findings suggest great potential for miRNAs in functional soybean nodules during salt stress. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessArticle Blood microRNAs in Low or No Risk Ischemic Stroke Patients
Int. J. Mol. Sci. 2013, 14(1), 2072-2084; doi:10.3390/ijms14012072
Received: 6 November 2012 / Revised: 11 December 2012 / Accepted: 17 January 2013 / Published: 22 January 2013
Cited by 14 | PDF Full-text (492 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Ischemic stroke is a multi-factorial disease where some patients present themselves with little or no risk factors. Blood microRNA expression profiles are becoming useful in the diagnosis and prognosis of human diseases. We therefore investigated the blood microRNA profiles in young stroke [...] Read more.
Ischemic stroke is a multi-factorial disease where some patients present themselves with little or no risk factors. Blood microRNA expression profiles are becoming useful in the diagnosis and prognosis of human diseases. We therefore investigated the blood microRNA profiles in young stroke patients who presented with minimal or absence of risk factors for stroke such as type 2 diabetes, dyslipidemia and hypertension. Blood microRNA profiles from these patients varied with stroke subtypes as well as different functional outcomes (based on modified Rankin Score). These microRNAs have been shown to target genes that are involved in stroke pathogenesis. The findings from our study suggest that molecular mechanisms in stroke pathogenesis involving low or no risk ischemic stroke patients could differ substantially from those with pre-existing risk factors. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessArticle Identification of Recurrence Related microRNAs in Hepatocellular Carcinoma after Surgical Resection
Int. J. Mol. Sci. 2013, 14(1), 1105-1118; doi:10.3390/ijms14011105
Received: 31 October 2012 / Revised: 11 December 2012 / Accepted: 24 December 2012 / Published: 8 January 2013
Cited by 11 | PDF Full-text (769 KB) | HTML Full-text | XML Full-text
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers with a high frequency of post-surgical recurrence. It is very critical to diagnose HCC recurrence at an early stage for a better therapeutic treatment. In this study, we examined the microRNA [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers with a high frequency of post-surgical recurrence. It is very critical to diagnose HCC recurrence at an early stage for a better therapeutic treatment. In this study, we examined the microRNA (miRNA) expression profiling in tumor tissues obtained from early and late recurrent HCC patients post-resection, using a microarray assay. A total of 32 miRNAs were identified to be differentially expressed during the progression of recurrence. Among these, 16 miRNAs were upregulated and 16 were downregulated. In addition, this miRNA expression signature was further validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Moreover, functional annotation of predicted target genes of these recurrent HCC-related miRNAs indicates that multiple biological pathways (i.e., focal adhesion pathway, cancer-related pathways and mitogen-activated protein kinase (MAPK) signaling) that are all critical for cancer development and progression, may participate in the recurrence of HCC. Our data suggest potential molecular mechanisms underpinning miRNA-controlled HCC recurrence, and support the notion that miRNA expression signature and miRNA-based therapy can be useful tools for a better diagnosis and treatment stratification of this disease. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Figures

Open AccessArticle Disruption of the Expression of a Non-Coding RNA Significantly Impairs Cellular Differentiation in Toxoplasma gondii
Int. J. Mol. Sci. 2013, 14(1), 611-624; doi:10.3390/ijms14010611
Received: 2 November 2012 / Revised: 14 December 2012 / Accepted: 18 December 2012 / Published: 28 December 2012
Cited by 3 | PDF Full-text (362 KB) | HTML Full-text | XML Full-text
Abstract
The protozoan parasite Toxoplasma gondii is an important human and veterinary pathogen. Asexual replication of T. gondii in humans and intermediate hosts is characterized by two forms: rapidly growing “tachyzoites” and latent “bradyzoite” tissue cysts. Tachyzoites are responsible for acute illness and [...] Read more.
The protozoan parasite Toxoplasma gondii is an important human and veterinary pathogen. Asexual replication of T. gondii in humans and intermediate hosts is characterized by two forms: rapidly growing “tachyzoites” and latent “bradyzoite” tissue cysts. Tachyzoites are responsible for acute illness and congenital neurological birth defects, while the more slowly dividing bradyzoite form can remain latent within the tissues for many years, representing a threat to immunocompromised patients. We have developed a genetic screen to identify regulatory genes that control parasite differentiation and have isolated mutants that fail to convert to bradyzoites. One of these mutants has an insertion disrupting a locus that encodes a developmentally regulated non-coding RNA transcript, named Tg-ncRNA-1. Microarray hybridizations suggest that Tg-ncRNA-1 is involved in the early steps of bradyzoite differentiation. Since Tg-ncRNA-1 does not contain an open reading frame, we used the algorithm Coding Potential Calculator (CPC) that evaluates the protein-coding potential of a transcript, to classify Tg-ncRNA-1. The CPC results strongly indicate that Tg-ncRNA-1 is a non-coding RNA (ncRNA). Interestingly, a previously generated mutant also contains an insertion in Tg-ncRNA-1. We show that both mutants have a decreased ability to form bradyzoites, and complementation of both mutants with wild-type Tg-ncRNA-1 restores the ability of the parasites to differentiate. It has been shown that an important part of bradyzoite differentiation is transcriptionally controlled, but this is the first time that a non-coding RNA is implicated in this process. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessArticle Exploration of the Role of the Non-Coding RNA SbrE in L. monocytogenes Stress Response
Int. J. Mol. Sci. 2013, 14(1), 378-393; doi:10.3390/ijms14010378
Received: 5 November 2012 / Revised: 11 December 2012 / Accepted: 14 December 2012 / Published: 24 December 2012
Cited by 6 | PDF Full-text (268 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
SbrE is a ncRNA in Listeria monocytogenes, reported to be up-regulated by the alternative sigma factor σB. Initial quantitative RT-PCR (qRT-PCR) experiments on parent strains and isogenic ΔsigB strains demonstrated σB-dependent expression of SbrE across the four [...] Read more.
SbrE is a ncRNA in Listeria monocytogenes, reported to be up-regulated by the alternative sigma factor σB. Initial quantitative RT-PCR (qRT-PCR) experiments on parent strains and isogenic ΔsigB strains demonstrated σB-dependent expression of SbrE across the four L. monocytogenes lineages and in L. innocua. Microarray and proteomics (MDLC/MS/MS with iTRAQ labeling) experiments with the L. monocytogenes parent strain and an isogenic ΔsbrE strain identified a single gene (lmo0636) and two proteins (Lmo0637 and Lmo2094) that showed lower expression levels in the ΔsbrE strain. qRT-PCR demonstrated an increase in SbrE transcript levels in stationary phase L. monocytogenes and in bacteria exposed to oxidative stress (mean log2 transcript levels 7.68 ± 0.57 and 1.70 ± 0.71 greater than in mid-log phase cells, respectively). However, no significant differences in growth or survival between the parent strain and ΔsbrE strain were confirmed under a variety of environmental stress conditions tested. Our data suggest that σB-dependent transcription of SbrE represents a conserved mechanism that contributes, across Listeria species, to fine-tuning of gene expression under specific environmental conditions that remain to be defined. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessArticle Expression and Functional Studies on the Noncoding RNA, PRINS
Int. J. Mol. Sci. 2013, 14(1), 205-225; doi:10.3390/ijms14010205
Received: 5 November 2012 / Revised: 30 November 2012 / Accepted: 10 December 2012 / Published: 21 December 2012
Cited by 5 | PDF Full-text (6531 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
PRINS, a noncoding RNA identified earlier by our research group, contributes to psoriasis susceptibility and cellular stress response. We have now studied the cellular and histological distribution of PRINS by using in situ hybridization and demonstrated variable expressions in different human tissues [...] Read more.
PRINS, a noncoding RNA identified earlier by our research group, contributes to psoriasis susceptibility and cellular stress response. We have now studied the cellular and histological distribution of PRINS by using in situ hybridization and demonstrated variable expressions in different human tissues and a consistent staining pattern in epidermal keratinocytes and in vitro cultured keratinocytes. To identify the cellular function(s) of PRINS, we searched for a direct interacting partner(s) of this stress-induced molecule. In HaCaT and NHEK cell lysates, the protein proved to be nucleophosmin (NPM) protein as a potential physical interactor with PRINS. Immunohistochemical experiments revealed an elevated expression of NPM in the dividing cells of the basal layers of psoriatic involved skin samples as compared with healthy and psoriatic uninvolved samples. Others have previously shown that NPM is a ubiquitously expressed nucleolar phosphoprotein which shuttles to the nucleoplasm after UV-B irradiation in fibroblasts and cancer cells. We detected a similar translocation of NPM in UV-B-irradiated cultured keratinocytes. The gene-specific silencing of PRINS resulted in the retention of NPM in the nucleolus of UV-B-irradiated keratinocytes; suggesting that PRINS may play a role in the NPM-mediated cellular stress response in the skin. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessArticle Modelling Translation Initiation under the Influence of sRNA
Int. J. Mol. Sci. 2012, 13(12), 16223-16240; doi:10.3390/ijms131216223
Received: 21 October 2012 / Revised: 21 November 2012 / Accepted: 27 November 2012 / Published: 30 November 2012
Cited by 2 | PDF Full-text (1828 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bacterial small non-coding RNA (sRNA) plays an important role in post-transcriptional gene regulation. Although the number of annotated sRNA is steadily increasing, their functional characterization is still lagging behind. Various computational strategies for finding sRNA–mRNA interactions, and thus putative sRNA targets, were [...] Read more.
Bacterial small non-coding RNA (sRNA) plays an important role in post-transcriptional gene regulation. Although the number of annotated sRNA is steadily increasing, their functional characterization is still lagging behind. Various computational strategies for finding sRNA–mRNA interactions, and thus putative sRNA targets, were developed. Most of them suffer from a high false positive rate. Here, we present a qualitative model to simulate the effect of an sRNA on the translation initiation of a potential target. Information about the ribosome–mRNA interaction, sRNA–mRNA interaction and expression information from deep sequencing experiments is integrated to calculate the change in translation initiation complex formation, as a proxy for translational activity. This model can be used to post-evaluate predicted targets, hence condensing the list of potential targets. We show that our translation initiation model, under the influence of an sRNA, can successfully simulate thirteen out of fifteen tested sRNA–mRNA interactions in a qualitative manner. To show the gain in specificity, we applied our method to a target search for the Escherichia coli sRNA RyhB. Compared with simple target prediction without post-evaluation, we reduce the number of targets to less than one fourth potential targets, considerably reducing the burden of experimental validation. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessCommunication A Tumor Surveillance Model: A Non-Coding RNA Senses Neoplastic Cells and Its Protein Partner Signals Cell Death
Int. J. Mol. Sci. 2012, 13(10), 13134-13139; doi:10.3390/ijms131013134
Received: 31 July 2012 / Revised: 22 September 2012 / Accepted: 26 September 2012 / Published: 12 October 2012
Cited by 4 | PDF Full-text (363 KB) | HTML Full-text | XML Full-text
Abstract
nc886 (= pre-miR-886 or vtRNA2-1) is a non-coding RNA that has been recently identified as a natural repressor for the activity of PKR (Protein Kinase R). The suppression of nc886 activates PKR and thereby provokes a cell death pathway. When combined with [...] Read more.
nc886 (= pre-miR-886 or vtRNA2-1) is a non-coding RNA that has been recently identified as a natural repressor for the activity of PKR (Protein Kinase R). The suppression of nc886 activates PKR and thereby provokes a cell death pathway. When combined with the fact that nc886 is suppressed in a wide range of cancer cells, the nc886-PKR relationship suggests a tumor surveillance model. When neoplastic cells develop and nc886 decreases therein, PKR is released from nc886 and becomes the active phosphorylated form, which initiates an apoptotic cascade to eliminate those cells. The nc886-PKR pathway is distinct from conventional mechanisms, such as the immune surveillance hypothesis or intrinsic mechanisms that check/proofread the genomic integrity, and thus represents a novel example of tumor surveillance. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)

Review

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Open AccessReview MicroRNAs in Human Placental Development and Pregnancy Complications
Int. J. Mol. Sci. 2013, 14(3), 5519-5544; doi:10.3390/ijms14035519
Received: 21 January 2013 / Revised: 26 February 2013 / Accepted: 4 March 2013 / Published: 8 March 2013
Cited by 31 | PDF Full-text (289 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs, which function as critical posttranscriptional regulators of gene expression by promoting mRNA degradation and translational inhibition. Placenta expresses many ubiquitous as well as specific miRNAs. These miRNAs regulate trophoblast cell differentiation, proliferation, apoptosis, invasion/migration, and angiogenesis, [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNAs, which function as critical posttranscriptional regulators of gene expression by promoting mRNA degradation and translational inhibition. Placenta expresses many ubiquitous as well as specific miRNAs. These miRNAs regulate trophoblast cell differentiation, proliferation, apoptosis, invasion/migration, and angiogenesis, suggesting that miRNAs play important roles during placental development. Aberrant miRNAs expression has been linked to pregnancy complications, such as preeclampsia. Recent research of placental miRNAs focuses on identifying placental miRNA species, examining differential expression of miRNAs between placentas from normal and compromised pregnancies, and uncovering the function of miRNAs in the placenta. More studies are required to further understand the functional significance of miRNAs in placental development and to explore the possibility of using miRNAs as biomarkers and therapeutic targets for pregnancy-related disorders. In this paper, we reviewed the current knowledge about the expression and function of miRNAs in placental development, and propose future directions for miRNA studies. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview Small Regulatory RNAs in the Control of Motility and Biofilm Formation in E. coli and Salmonella
Int. J. Mol. Sci. 2013, 14(3), 4560-4579; doi:10.3390/ijms14034560
Received: 18 January 2013 / Revised: 10 February 2013 / Accepted: 16 February 2013 / Published: 26 February 2013
Cited by 42 | PDF Full-text (990 KB) | HTML Full-text | XML Full-text
Abstract
Biofilm formation in Escherichia coli and other enteric bacteria involves the inverse regulation of the synthesis of flagella and biofilm matrix components such as amyloid curli fibres, cellulose, colanic acid and poly-N-acetylglucosamine (PGA). Physiologically, these processes reflect the transition from [...] Read more.
Biofilm formation in Escherichia coli and other enteric bacteria involves the inverse regulation of the synthesis of flagella and biofilm matrix components such as amyloid curli fibres, cellulose, colanic acid and poly-N-acetylglucosamine (PGA). Physiologically, these processes reflect the transition from growth to stationary phase. At the molecular level, they are tightly controlled by various sigma factors competing for RNA polymerase, a series of transcription factors acting in hierarchical regulatory cascades and several nucleotide messengers, including cyclic-di-GMP. In addition, a surprisingly large number of small regulatory RNAs (sRNAs) have been shown to directly or indirectly modulate motility and/or biofilm formation. This review aims at giving an overview of these sRNA regulators and their impact in biofilm formation in E. coli and Salmonella. Special emphasis will be put on sRNAs, that have known targets such as the mRNAs of the flagellar master regulator FlhDC, the stationary phase sigma factor σS (RpoS) and the key biofilm regulator CsgD that have recently been shown to act as major hubs for regulation by multiple sRNAs. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview The Increasing Complexity of the Oncofetal H19 Gene Locus: Functional Dissection and Therapeutic Intervention
Int. J. Mol. Sci. 2013, 14(2), 4298-4316; doi:10.3390/ijms14024298
Received: 3 December 2012 / Revised: 29 January 2013 / Accepted: 6 February 2013 / Published: 21 February 2013
Cited by 23 | PDF Full-text (601 KB) | HTML Full-text | XML Full-text
Abstract
The field of the long non-coding RNA (lncRNA) is advancing rapidly. Currently, it is one of the most popular fields in the biological and medical sciences. It is becoming increasingly obvious that the majority of the human transcriptome has little or no-protein [...] Read more.
The field of the long non-coding RNA (lncRNA) is advancing rapidly. Currently, it is one of the most popular fields in the biological and medical sciences. It is becoming increasingly obvious that the majority of the human transcriptome has little or no-protein coding capacity. Historically, H19 was the first imprinted non-coding RNA (ncRNA) transcript identified, and the H19/IGF2 locus has served as a paradigm for the study of genomic imprinting since its discovery. In recent years, we have extensively investigated the expression of the H19 gene in a number of human cancers and explored the role of H19 RNA in tumor development. Here, we discuss recently published data from our group and others that provide further support for a central role of H19 RNA in the process of tumorigenesis. Furthermore, we focus on major transcriptional modulators of the H19 gene and discuss them in the context of the tumor-promoting activity of the H19 RNA. Based on the pivotal role of the H19 gene in human cancers, we have developed a DNA-based therapeutic approach for the treatment of cancers that have upregulated levels of H19 expression. This approach uses a diphtheria toxin A (DTA) protein expressed under the regulation of the H19 promoter to treat tumors with significant expression of H19 RNA. In this review, we discuss the treatment of four cancer indications in human subjects using this approach, which is currently under development. This represents perhaps one of the very few examples of an existing DNA-based therapy centered on an lncRNA system. Apart from cancer, H19 expression has been reported also in other conditions, syndromes and diseases, where deregulated imprinting at the H19 locus was obvious in some cases and will be summarized below. Moreover, the H19 locus proved to be much more complicated than initially thought. It houses a genomic sequence that can transcribe, yielding various transcriptional outputs, both in sense and antisense directions. The major transcriptional outputs of the H19 locus are presented here. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview Modulation of Cancer Traits by Tumor Suppressor microRNAs
Int. J. Mol. Sci. 2013, 14(1), 1822-1842; doi:10.3390/ijms14011822
Received: 20 November 2012 / Revised: 28 December 2012 / Accepted: 10 January 2013 / Published: 16 January 2013
Cited by 11 | PDF Full-text (687 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs) are potent post-transcriptional regulators of gene expression. In mammalian cells, miRNAs typically suppress mRNA stability and/or translation through partial complementarity with target mRNAs. Each miRNA can regulate a wide range of mRNAs, and a single mRNA can be regulated by [...] Read more.
MicroRNAs (miRNAs) are potent post-transcriptional regulators of gene expression. In mammalian cells, miRNAs typically suppress mRNA stability and/or translation through partial complementarity with target mRNAs. Each miRNA can regulate a wide range of mRNAs, and a single mRNA can be regulated by multiple miRNAs. Through these complex regulatory interactions, miRNAs participate in many cellular processes, including carcinogenesis. By altering gene expression patterns, cancer cells can develop specific phenotypes that allow them to proliferate, survive, secure oxygen and nutrients, evade immune recognition, invade other tissues and metastasize. At the same time, cancer cells acquire miRNA signature patterns distinct from those of normal cells; the differentially expressed miRNAs contribute to enabling the cancer traits. Over the past decade, several miRNAs have been identified, which functioned as oncogenic miRNAs (oncomiRs) or tumor-suppressive miRNAs (TS-miRNAs). In this review, we focus specifically on TS-miRNAs and their effects on well-established cancer traits. We also discuss the rising interest in TS-miRNAs in cancer therapy. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview Role of RNA Interference (RNAi) in the Moss Physcomitrella patens
Int. J. Mol. Sci. 2013, 14(1), 1516-1540; doi:10.3390/ijms14011516
Received: 21 November 2012 / Revised: 9 December 2012 / Accepted: 10 December 2012 / Published: 14 January 2013
Cited by 7 | PDF Full-text (956 KB) | HTML Full-text | XML Full-text
Abstract
RNA interference (RNAi) is a mechanism that regulates genes by either transcriptional (TGS) or posttranscriptional gene silencing (PTGS), required for genome maintenance and proper development of an organism. Small non-coding RNAs are the key players in RNAi and have been intensively studied [...] Read more.
RNA interference (RNAi) is a mechanism that regulates genes by either transcriptional (TGS) or posttranscriptional gene silencing (PTGS), required for genome maintenance and proper development of an organism. Small non-coding RNAs are the key players in RNAi and have been intensively studied in eukaryotes. In plants, several classes of small RNAs with specific sizes and dedicated functions have evolved. The major classes of small RNAs include microRNAs (miRNAs) and small interfering RNAs (siRNAs), which differ in their biogenesis. miRNAs are synthesized from a short hairpin structure while siRNAs are derived from long double-stranded RNAs (dsRNA). Both miRNA and siRNAs control the expression of cognate target RNAs by binding to reverse complementary sequences mediating cleavage or translational inhibition of the target RNA. They also act on the DNA and cause epigenetic changes such as DNA methylation and histone modifications. In the last years, the analysis of plant RNAi pathways was extended to the bryophyte Physcomitrella patens, a non-flowering, non-vascular ancient land plant that diverged from the lineage of seed plants approximately 450 million years ago. Based on a number of characteristic features and its phylogenetic key position in land plant evolution P. patens emerged as a plant model species to address basic as well as applied topics in plant biology. Here we summarize the current knowledge on the role of RNAi in P. patens that shows functional overlap with RNAi pathways from seed plants, and also unique features specific to this species. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview RUNX1: A MicroRNA Hub in Normal and Malignant Hematopoiesis
Int. J. Mol. Sci. 2013, 14(1), 1566-1588; doi:10.3390/ijms14011566
Received: 12 December 2012 / Revised: 31 December 2012 / Accepted: 4 January 2013 / Published: 14 January 2013
Cited by 13 | PDF Full-text (550 KB) | HTML Full-text | XML Full-text
Abstract
Hematopoietic development is orchestrated by gene regulatory networks that progressively induce lineage-specific transcriptional programs. To guarantee the appropriate level of complexity, flexibility, and robustness, these networks rely on transcriptional and post-transcriptional circuits involving both transcription factors (TFs) and microRNAs (miRNAs). The focus [...] Read more.
Hematopoietic development is orchestrated by gene regulatory networks that progressively induce lineage-specific transcriptional programs. To guarantee the appropriate level of complexity, flexibility, and robustness, these networks rely on transcriptional and post-transcriptional circuits involving both transcription factors (TFs) and microRNAs (miRNAs). The focus of this review is on RUNX1 (AML1), a master hematopoietic transcription factor which is at the center of miRNA circuits necessary for both embryonic and post-natal hematopoiesis. Interference with components of these circuits can perturb RUNX1-controlled coding and non-coding transcriptional programs in leukemia. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview Recent Insights and Novel Bioinformatics Tools to Understand the Role of MicroRNAs Binding to 5' Untranslated Region
Int. J. Mol. Sci. 2013, 14(1), 480-495; doi:10.3390/ijms14010480
Received: 12 November 2012 / Revised: 6 December 2012 / Accepted: 6 December 2012 / Published: 27 December 2012
Cited by 22 | PDF Full-text (363 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through the binding of the 3' untranslated region (3'UTR) of specific mRNAs. MiRNAs are post-transcriptional regulators and determine the repression of translation processes or the degradation of mRNA targets. Recently, another kind [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through the binding of the 3' untranslated region (3'UTR) of specific mRNAs. MiRNAs are post-transcriptional regulators and determine the repression of translation processes or the degradation of mRNA targets. Recently, another kind of miRNA-mediated regulation of translation (repression or activation) involving the binding of miRNA to the 5'UTR of target gene has been reported. The possible interactions and the mechanism of action have been reported in many works that we reviewed here. Moreover, we discussed also the available bioinformatics tools for predicting the miRNA binding sites in the 5'UTR and public databases collecting this information. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview Long Non-Coding RNAs and p53 Regulation
Int. J. Mol. Sci. 2012, 13(12), 16708-16717; doi:10.3390/ijms131216708
Received: 5 November 2012 / Revised: 3 December 2012 / Accepted: 3 December 2012 / Published: 6 December 2012
Cited by 9 | PDF Full-text (299 KB) | HTML Full-text | XML Full-text
Abstract
The advent of novel and high-throughput sequencing (next generation) technologies allowed for the sequencing of the genome at an unprecedented depth. The majority of transcribed RNAs have been classified as non-coding RNAs. Among them, long non-coding RNAs (lncRNAs) are emerging as important [...] Read more.
The advent of novel and high-throughput sequencing (next generation) technologies allowed for the sequencing of the genome at an unprecedented depth. The majority of transcribed RNAs have been classified as non-coding RNAs. Among them, long non-coding RNAs (lncRNAs) are emerging as important regulators in many biological processes. Here, we discuss the role of those lncRNAs which are under the control of p53 or that are able to regulate its activity, due to the central role of p53 pathway in many conditions. We also briefly discussed the emerging need of having novel strategies and computational tools to completely unravel the multifaceted roles of lncRNAs and to pave the way to the development of novel diagnostic and therapeutic applications based on these peculiar molecules. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview Epigenetic Deregulation of MicroRNAs in Rhabdomyosarcoma and Neuroblastoma and Translational Perspectives
Int. J. Mol. Sci. 2012, 13(12), 16554-16579; doi:10.3390/ijms131216554
Received: 29 October 2012 / Revised: 21 November 2012 / Accepted: 21 November 2012 / Published: 5 December 2012
Cited by 2 | PDF Full-text (564 KB) | HTML Full-text | XML Full-text
Abstract
Gene expression control mediated by microRNAs and epigenetic remodeling of chromatin are interconnected processes often involved in feedback regulatory loops, which strictly guide proper tissue differentiation during embryonal development. Altered expression of microRNAs is one of the mechanisms leading to pathologic conditions, [...] Read more.
Gene expression control mediated by microRNAs and epigenetic remodeling of chromatin are interconnected processes often involved in feedback regulatory loops, which strictly guide proper tissue differentiation during embryonal development. Altered expression of microRNAs is one of the mechanisms leading to pathologic conditions, such as cancer. Several lines of evidence pointed to epigenetic alterations as responsible for aberrant microRNA expression in human cancers. Rhabdomyosarcoma and neuroblastoma are pediatric cancers derived from cells presenting features of skeletal muscle and neuronal precursors, respectively, blocked at different stages of differentiation. Consistently, tumor cells express tissue markers of origin but are unable to terminally differentiate. Several microRNAs playing a key role during tissue differentiation are often epigenetically downregulated in rhabdomyosarcoma and neuroblastoma and behave as tumor suppressors when re-expressed. Recently, inhibition of epigenetic modulators in adult tumors has provided encouraging results causing re-expression of anti-tumor master gene pathways. Thus, a similar approach could be used to correct the aberrant epigenetic regulation of microRNAs in rhabdomyosarcoma and neuroblastoma. The present review highlights the current insights on epigenetically deregulated microRNAs in rhabdomyosarcoma and neuroblastoma and their role in tumorigenesis and developmental pathways. The translational clinical implications and challenges regarding modulation of epigenetic chromatin remodeling/microRNAs interconnections are also discussed. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview MicroRNAs in Metal Stress: Specific Roles or Secondary Responses?
Int. J. Mol. Sci. 2012, 13(12), 15826-15847; doi:10.3390/ijms131215826
Received: 1 November 2012 / Revised: 20 November 2012 / Accepted: 21 November 2012 / Published: 27 November 2012
Cited by 29 | PDF Full-text (358 KB) | HTML Full-text | XML Full-text
Abstract
In plants, microRNAs (miRNAs) control various biological processes by negatively regulating the expression of complementary target genes, either (1) post-transcriptionally by cleavage or translational inhibition of target mRNA, or (2) transcriptionally by methylation of target DNA. Besides their role in developmental processes, [...] Read more.
In plants, microRNAs (miRNAs) control various biological processes by negatively regulating the expression of complementary target genes, either (1) post-transcriptionally by cleavage or translational inhibition of target mRNA, or (2) transcriptionally by methylation of target DNA. Besides their role in developmental processes, miRNAs are main players in stress responses, including metal stress responses. Exposure of plants to excess metal concentrations disturbs the cellular redox balance and enhances ROS accumulation, eventually leading to oxidative damage or signaling. Plants modify their gene expression by the activity of miRNAs in response to metal toxicity to regulate (1) complexation of excess metals, (2) defense against oxidative stress and (3) signal transduction for controlling various biological responses. This review focuses on the biogenesis, working mechanisms and functioning of miRNAs in plants. In a final part, our current knowledge on the regulatory roles of miRNAs in plant metal stress responses is highlighted, and whether stress-regulated miRNAs have specific roles or are secondary consequences is discussed. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview Identification of kakusei, a Nuclear Non-Coding RNA, as an Immediate Early Gene from the Honeybee, and Its Application for Neuroethological Study
Int. J. Mol. Sci. 2012, 13(12), 15496-15509; doi:10.3390/ijms131215496
Received: 29 October 2012 / Revised: 16 November 2012 / Accepted: 19 November 2012 / Published: 22 November 2012
Cited by 6 | PDF Full-text (4197 KB) | HTML Full-text | XML Full-text
Abstract
The honeybee is a social insect that exhibits various social behaviors. To elucidate the neural basis of honeybee behavior, we detected neural activity in freely-moving honeybee workers using an immediate early gene (IEG) that is expressed in a neural activity-dependent manner. In [...] Read more.
The honeybee is a social insect that exhibits various social behaviors. To elucidate the neural basis of honeybee behavior, we detected neural activity in freely-moving honeybee workers using an immediate early gene (IEG) that is expressed in a neural activity-dependent manner. In European honeybees (Apis mellifera), we identified a novel nuclear non-coding RNA, termed kakusei, as the first insect IEG, and revealed the neural activity pattern in foragers. In addition, we isolated a homologue of kakusei, termed Acks, from the Japanese honeybee (Apis cerana), and detected active neurons in workers fighting with the giant hornet. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)
Open AccessReview Flexible and Versatile as a Chameleon—Sophisticated Functions of microRNA-199a
Int. J. Mol. Sci. 2012, 13(7), 8449-8466; doi:10.3390/ijms13078449
Received: 8 June 2012 / Revised: 29 June 2012 / Accepted: 2 July 2012 / Published: 9 July 2012
Cited by 17 | PDF Full-text (427 KB) | HTML Full-text | XML Full-text
Abstract
Although widely studied in the past decade, our knowledge of the functional role of microRNAs (miRNAs) remains limited. Among the many miRNAs identified in humans, we focus on miR-199a due to its varied and important functions in diverse models and systems. Its [...] Read more.
Although widely studied in the past decade, our knowledge of the functional role of microRNAs (miRNAs) remains limited. Among the many miRNAs identified in humans, we focus on miR-199a due to its varied and important functions in diverse models and systems. Its expression is finely regulated by promoter methylation and direct binding of transcription factors such as TWIST1. During tumorigenesis, depending on the nature of the cancer, miR-199a, especially its -3p mature form, may act as either a potential tumor suppressor or an oncogene. Its 5p mature form has been shown to protect cardiomyocytes from hypoxic damage via its action on HIF1α. It also has a functional role in stem cell differentiation, embryo development, hepatitis, liver fibrosis, etc. Though it has varied biological activities, its regulation has not been reviewed. The varied and protean functions of miR-199a suggest that efforts to generalize the action of a miRNA are problematic. This review provides a comprehensive survey of the literature on miR-199a as an example of the complexity of miRNA biology and suggests future directions for miRNA research. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)

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Open AccessLetter CentroidAlign-Web: A Fast and Accurate Multiple Aligner for Long Non-Coding RNAs
Int. J. Mol. Sci. 2013, 14(3), 6144-6156; doi:10.3390/ijms14036144
Received: 20 November 2012 / Revised: 28 January 2013 / Accepted: 28 February 2013 / Published: 18 March 2013
Cited by 3 | PDF Full-text (639 KB) | HTML Full-text | XML Full-text
Abstract
Due to the recent discovery of non-coding RNAs (ncRNAs), multiple sequence alignment (MSA) of those long RNA sequences is becoming increasingly important for classifying and determining the functional motifs in RNAs. However, not only primary (nucleotide) sequences, but also secondary structures of [...] Read more.
Due to the recent discovery of non-coding RNAs (ncRNAs), multiple sequence alignment (MSA) of those long RNA sequences is becoming increasingly important for classifying and determining the functional motifs in RNAs. However, not only primary (nucleotide) sequences, but also secondary structures of ncRNAs are closely related to their function and are conserved evolutionarily. Hence, information about secondary structures should be considered in the sequence alignment of ncRNAs. Yet, in general, a huge computational time is required in order to compute MSAs, taking secondary structure information into account. In this paper, we describe a fast and accurate web server, called CentroidAlign-Web, which can handle long RNA sequences. The web server also appropriately incorporates information about known secondary structures into MSAs. Computational experiments indicate that our web server is fast and accurate enough to handle long RNA sequences. CentroidAlign-Web is freely available from http://centroidalign.ncrna.org/. Full article
(This article belongs to the Special Issue Non-Coding RNAs 2012)

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