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Special Issue "Regulation by non-coding RNAs 2013"

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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 (15 October 2013)

Special Issue Editors

Guest Editor
Prof. Dr. Nicholas Delihas

Department of Molecular Genetics and Microbiology, School of Medicine, 158 Life Sciences Building, Stony Brook University, Stony Brook, NY 11794, USA
Website | E-Mail
Fax: +1 631 632 9797
Interests: regulation of gene expression by small RNAs; add- analysis of functions of non-coding genomic regions of human chromosomes; repetitive sequences in human chromosome 22
Co-Guest Editor
Prof. Dr. Constantinos Stathopoulos

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

Special Issue Information

Dear Colleagues,

Regulatory non-protein-coding RNA genes and their transcripts were first found and characterized in bacteria but encompass all biological kingdoms. The complexity of non-coding RNAs (ncRNAs) in terms of number and types increases with degree of biological development, whereby humans and other primates appear to have the largest number. Many regulatory ncRNAs base-pair to a target RNA or DNA and inhibit target function. Bacterial ncRNA genes largely respond to environmental stress conditions and help protect the organism from adverse conditions. The prokaryotic RNAs are for the most part small (<200 bp) and are commonly referred to as small regulatory RNAs (sRNAs). Eukaryotic RNAs consist of small <200 nt RNAs and large >200 nt (termed lncRNAs). The eukaryotic small RNAs include miRNAs, siRNAs, and piRNAs. miRNAs inhibit mRNA functions and may also be associated with cancer. lncRNAs functions are multifaceted and include epigenetic regulation and animal development. The bacterial and archeal immune system CRISPR, and the eukaryotic piwi-interacting RNAs (piRNA) immune system that inhibits mobile elements in germ line cells both function by via RNA transcript/ target DNA heteroduplex base-pairing are a specific class of RNAs that protect cells from invading transposons/and or viruses. siRNAs function in plant and invertebrate immune systems and protect against viral infections. Additionally, small RNA fragments derived from snoRNAs and tRNAs as well as18 nt RNAs (tiRNAs) derived from eukaryotic transcription start sites may play a role in regulation. Exciting new findings with non-protein coding sequences of the human genome show that a major portion of the genome is transcribed. This provides the possibility that larger numbers of functional RNAs may be found in addition to the several thousand known ones. The precepts of genes and genetic inheritance may have to change to include RNA genes and their transcripts and this would represent a starling change in the principles of molecular genetics.

This special issue of IJMS will be devoted to original papers and reviews of properties and mechanism of action of regulatory non-coding RNAs and will be organized into prokaryotic and eukaryotic RNAs with separate subtopics involving regulatory ncRNAs in plants and animals. There will be a special emphasis on RNAs in humans and their significance to disease formation and will include roles of ncRNAs in neurodegeneration, cancer, diabetes and other diseases.

Prof. Dr. Nicholas Delihas
Prof. Dr. Constantinos Stathopoulos
Guest Editor

Keywords

  • Regulatory RNA
  • sRNA
  • ncRNA
  • lncRNA
  • miRNA
  • siRNA
  • piRNA
  • CRISPR RNA
  • regulatory small RNA fragments

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Editorial

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Open AccessEditorial Editorial on the Special Issue: Regulation by Non-Coding RNAs
Int. J. Mol. Sci. 2013, 14(11), 21960-21964; doi:10.3390/ijms141121960
Received: 22 September 2013 / Accepted: 31 October 2013 / Published: 6 November 2013
PDF Full-text (154 KB) | HTML Full-text | XML Full-text
Abstract
This Special Issue of IJMS is devoted to regulation by non-coding RNAs and contains both original research and review articles. An attempt is made to provide an up-to-date analysis of this very fast moving field and cover regulatory roles of both microRNAs and
[...] Read more.
This Special Issue of IJMS is devoted to regulation by non-coding RNAs and contains both original research and review articles. An attempt is made to provide an up-to-date analysis of this very fast moving field and cover regulatory roles of both microRNAs and long non-coding RNAs. Multifaceted functions of these RNAs in normal cellular processes, as well as in disease progression, are highlighted. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

Research

Jump to: Editorial, Review

Open AccessArticle The Involvement of miR-23a/APAF1 Regulation Axis in Colorectal Cancer
Int. J. Mol. Sci. 2014, 15(7), 11713-11729; doi:10.3390/ijms150711713
Received: 13 May 2014 / Revised: 2 June 2014 / Accepted: 4 June 2014 / Published: 2 July 2014
Cited by 6 | PDF Full-text (940 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Recent advances in microRNAome have made microRNAs (miRNAs) a compelling novel class of biomarker in cancer biology. In the present study, the role of miR-23a in the carcinogenesis of colorectal cancer (CRC) was investigated. Cell viability, apoptosis, and caspase 3/7 activation analyses were
[...] Read more.
Recent advances in microRNAome have made microRNAs (miRNAs) a compelling novel class of biomarker in cancer biology. In the present study, the role of miR-23a in the carcinogenesis of colorectal cancer (CRC) was investigated. Cell viability, apoptosis, and caspase 3/7 activation analyses were conducted to determine the potentiality of apoptosis resistance function of miR-23a in CRC. Luciferase assay was performed to verify a putative target site of miR-23a in the 3'-UTR of apoptosis protease activating factor 1 (APAF1) mRNA. The expression levels of miR-23a and APAF1 in CRC cell lines (SW480 and SW620) and clinical samples were assessed using reverse transcription-quantitative real-time PCR (RT-qPCR) and Western blot. We found that the inhibition of miR-23a in SW480 and SW620 cell lines resulted in significant reduction of cell viability and promotion of cell apoptosis. Moreover, miR-23a up-regulation was coupled with APAF1 down-regulation in CRC tissue samples. Taken together, miR-23a was identified to regulate apoptosis in CRC. Our study highlights the potential application of miR-23a/APAF1 regulation axis in miRNA-based therapy and prognostication. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Conserved miRNAs and Their Response to Salt Stress in Wild Eggplant Solanum linnaeanum Roots
Int. J. Mol. Sci. 2014, 15(1), 839-849; doi:10.3390/ijms15010839
Received: 12 November 2013 / Revised: 19 November 2013 / Accepted: 30 December 2013 / Published: 9 January 2014
Cited by 11 | PDF Full-text (454 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Solanaceae family includes some important vegetable crops, and they often suffer from salinity stress. Some miRNAs have been identified to regulate gene expression in plant response to salt stress; however, little is known about the involvement of miRNAs in Solanaceae species. To
[...] Read more.
The Solanaceae family includes some important vegetable crops, and they often suffer from salinity stress. Some miRNAs have been identified to regulate gene expression in plant response to salt stress; however, little is known about the involvement of miRNAs in Solanaceae species. To identify salt-responsive miRNAs, high-throughput sequencing was used to sequence libraries constructed from roots of the salt tolerant species, Solanum linnaeanum, treated with and without NaCl. The sequencing identified 98 conserved miRNAs corresponding to 37 families, and some of these miRNAs and their expression were verified by quantitative real-time PCR. Under the salt stress, 11 of the miRNAs were down-regulated, and 3 of the miRNAs were up-regulated. Potential targets of the salt-responsive miRNAs were predicted to be involved in diverse cellular processes in plants. This investigation provides valuable information for functional characterization of miRNAs in S. linnaeanum, and would be useful for developing strategies for the genetic improvement of the Solanaceae crops. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Systems Biology Approach to the Dissection of the Complexity of Regulatory Networks in the S. scrofa Cardiocirculatory System
Int. J. Mol. Sci. 2013, 14(11), 23160-23187; doi:10.3390/ijms141123160
Received: 9 August 2013 / Revised: 23 October 2013 / Accepted: 2 November 2013 / Published: 21 November 2013
Cited by 2 | PDF Full-text (5621 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Genome-wide experiments are routinely used to increase the understanding of the biological processes involved in the development and maintenance of a variety of pathologies. Although the technical feasibility of this type of experiment has improved in recent years, data analysis remains challenging. In
[...] Read more.
Genome-wide experiments are routinely used to increase the understanding of the biological processes involved in the development and maintenance of a variety of pathologies. Although the technical feasibility of this type of experiment has improved in recent years, data analysis remains challenging. In this context, gene set analysis has emerged as a fundamental tool for the interpretation of the results. Here, we review strategies used in the gene set approach, and using datasets for the pig cardiocirculatory system as a case study, we demonstrate how the use of a combination of these strategies can enhance the interpretation of results. Gene set analyses are able to distinguish vessels from the heart and arteries from veins in a manner that is consistent with the different cellular composition of smooth muscle cells. By integrating microRNA elements in the regulatory circuits identified, we find that vessel specificity is maintained through specific miRNAs, such as miR-133a and miR-143, which show anti-correlated expression with their mRNA targets. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Regulation of MIR Genes in Response to Abiotic Stress in Hevea brasiliensis
Int. J. Mol. Sci. 2013, 14(10), 19587-19604; doi:10.3390/ijms141019587
Received: 31 May 2013 / Revised: 6 September 2013 / Accepted: 16 September 2013 / Published: 27 September 2013
Cited by 6 | PDF Full-text (824 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Increasing demand for natural rubber (NR) calls for an increase in latex yield and also an extension of rubber plantations in marginal zones. Both harvesting and abiotic stresses lead to tapping panel dryness through the production of reactive oxygen species. Many microRNAs regulated
[...] Read more.
Increasing demand for natural rubber (NR) calls for an increase in latex yield and also an extension of rubber plantations in marginal zones. Both harvesting and abiotic stresses lead to tapping panel dryness through the production of reactive oxygen species. Many microRNAs regulated during abiotic stress modulate growth and development. The objective of this paper was to study the regulation of microRNAs in response to different types of abiotic stress and hormone treatments in Hevea. Regulation of MIR genes differs depending on the tissue and abiotic stress applied. A negative co-regulation between HbMIR398b with its chloroplastic HbCuZnSOD target messenger is observed in response to salinity. The involvement of MIR gene regulation during latex harvesting and tapping panel dryness (TPD) occurrence is further discussed. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Bicistronic Gene Transfer Tools for Delivery of miRNAs and Protein Coding Sequences
Int. J. Mol. Sci. 2013, 14(9), 18239-18255; doi:10.3390/ijms140918239
Received: 22 July 2013 / Revised: 8 August 2013 / Accepted: 13 August 2013 / Published: 5 September 2013
Cited by 5 | PDF Full-text (2746 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNAs (miRNAs) are a category of small RNAs that modulate levels of proteins via post-transcriptional inhibition. Currently, a standard strategy to overexpress miRNAs is as mature miRNA duplexes, although this method is cumbersome if multiple miRNAs need to be delivered. Many of these
[...] Read more.
MicroRNAs (miRNAs) are a category of small RNAs that modulate levels of proteins via post-transcriptional inhibition. Currently, a standard strategy to overexpress miRNAs is as mature miRNA duplexes, although this method is cumbersome if multiple miRNAs need to be delivered. Many of these miRNAs are found within introns and processed through the RNA polymerase II pathway. We have designed a vector to exploit this naturally-occurring intronic pathway to deliver the three members of the sensory-specific miR-183 family from an artificial intron. In one version of the vector, the downstream exon encodes the reporter (GFP) while another version encodes a fusion protein created between the transcription factor Atoh1 and the hemaglutinin epitope, to distinguish it from endogenous Atoh1. In vitro analysis shows that the miRNAs contained within the artificial intron are processed and bind to their targets with specificity. The genes downstream are successfully translated into protein and identifiable through immunofluorescence. More importantly, Atoh1 is proven functional through in vitro assays. These results suggest that this cassette allows expression of miRNAs and proteins simultaneously, which provides the opportunity for joint delivery of specific translational repressors (miRNA) and possibly transcriptional activators (transcription factors). This ability is attractive for future gene therapy use. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle MicroRNA-143 Downregulates Interleukin-13 Receptor Alpha1 in Human Mast Cells
Int. J. Mol. Sci. 2013, 14(8), 16958-16969; doi:10.3390/ijms140816958
Received: 3 June 2013 / Revised: 8 July 2013 / Accepted: 2 August 2013 / Published: 19 August 2013
Cited by 7 | PDF Full-text (843 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNA-143 (miR-143) was found to be downregulated in allergic rhinitis, and bioinformatics analysis predicted that IL-13Rα1 was a target gene of miR-143. To understand the molecular mechanisms of miR-143 involved in the pathogenesis of allergic inflammation, recombinant miR-143 plasmid vectors were constructed, and
[...] Read more.
MicroRNA-143 (miR-143) was found to be downregulated in allergic rhinitis, and bioinformatics analysis predicted that IL-13Rα1 was a target gene of miR-143. To understand the molecular mechanisms of miR-143 involved in the pathogenesis of allergic inflammation, recombinant miR-143 plasmid vectors were constructed, and human mast cell-1(HMC-1) cells which play a central role in the allergic response were used for study. The plasmids were transfected into HMC-1 cells using a lentiviral vector. Expression of IL-13Rα1 mRNA was then detected by reverse transcriptase polymerase chain reaction (RT-PCR) and Western Blotting. The miR-143 lentiviral vector was successfully stably transfected in HMC-1 cells for target gene expression. Compared to the control, the target gene IL-13Rα1 was less expressed in HMC-1 transfected with miR-143 as determined by RT-PCR and Western Blotting (p < 0.05); this difference in expression was statistically significant and the inhibition efficiency was 71%. It indicates that miR-143 directly targets IL-13Rα1 and suppresses IL-13Rα1 expression in HMC-1 cells. Therefore, miR-143 may be associated with allergic reaction in human mast cells. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Regulation of Huntingtin Gene Expression by miRNA-137, -214, -148a, and Their Respective isomiRs
Int. J. Mol. Sci. 2013, 14(8), 16999-17016; doi:10.3390/ijms140816999
Received: 30 May 2013 / Revised: 6 August 2013 / Accepted: 8 August 2013 / Published: 19 August 2013
Cited by 17 | PDF Full-text (949 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
With the advent of deep sequencing technology, a variety of miRNA length and sequence variants, termed isomiRNAs (isomiRs), have been discovered. However, the functional roles of these commonly detected isomiRs remain unknown. In this paper, we demonstrated that miRNAs regulate the expression of
[...] Read more.
With the advent of deep sequencing technology, a variety of miRNA length and sequence variants, termed isomiRNAs (isomiRs), have been discovered. However, the functional roles of these commonly detected isomiRs remain unknown. In this paper, we demonstrated that miRNAs regulate the expression of the HTT gene, whose mutation leads to Huntington’s disease (HD), a hereditary degenerative disorder. Specifically, we validated the interactions of canonical miRNAs, miR-137, miR-214, and miR-148a, with the HTT 3'UTR using a luciferase assay. Moreover, we applied synthetic miRNA mimics to examine whether a slight shifting of miRNA seed regions might alter the regulation of the HTT transcript. We also examined miR-137, miR-214, and miR-148a isomiRs and showed the activity of these isoforms on reporter constructs bearing appropriate sequences from the HTT 3'UTR. Hence, we demonstrated that certain 5'-end variants of miRNAs might be functional for the regulation of the same targets as canonical miRNAs. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Figures

Open AccessArticle Involvement of miR-20a in Promoting Gastric Cancer Progression by Targeting Early Growth Response 2 (EGR2)
Int. J. Mol. Sci. 2013, 14(8), 16226-16239; doi:10.3390/ijms140816226
Received: 5 June 2013 / Revised: 18 July 2013 / Accepted: 18 July 2013 / Published: 6 August 2013
Cited by 28 | PDF Full-text (329 KB) | HTML Full-text | XML Full-text
Abstract
Gastric cancer (GC) is one of the most common cancers, with high incidences in East Asia. microRNAs (miRNAs) play essential roles in the carcinogenesis of GC. miR-20a was elevated in GC, while the potential function of miR-20a was poorly understood. miR-20a expression was
[...] Read more.
Gastric cancer (GC) is one of the most common cancers, with high incidences in East Asia. microRNAs (miRNAs) play essential roles in the carcinogenesis of GC. miR-20a was elevated in GC, while the potential function of miR-20a was poorly understood. miR-20a expression was examined in GC tissues and cell lines. The effects of miR-20a on the growth, migration, invasion, and chemoresistance of GC cells were examined. Luciferase reporter assay and Western blot were used to screen the target of miR-20a. miR-20a was increased in GC tissues and cell lines. miR-20a promoted the growth, migration and invasion of GC cells, enhanced the chemoresistance of GC cells to cisplatin and docetaxel. Luciferase activity and Western blot confirmed that miR-20a negatively regulated EGR2 expression. Overexpression of EGR2 significantly attenuated the oncogenic effect of miR-20a. miR-20a was involved in the carcinogenesis of GC through modulation of the EGR2 signaling pathway. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle MicroRNA Expression Changes during Interferon-Beta Treatment in the Peripheral Blood of Multiple Sclerosis Patients
Int. J. Mol. Sci. 2013, 14(8), 16087-16110; doi:10.3390/ijms140816087
Received: 8 June 2013 / Revised: 12 July 2013 / Accepted: 26 July 2013 / Published: 5 August 2013
Cited by 36 | PDF Full-text (685 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules acting as post-transcriptional regulators of gene expression. They are involved in many biological processes, and their dysregulation is implicated in various diseases, including multiple sclerosis (MS). Interferon-beta (IFN-beta) is widely used as a first-line immunomodulatory treatment
[...] Read more.
MicroRNAs (miRNAs) are small non-coding RNA molecules acting as post-transcriptional regulators of gene expression. They are involved in many biological processes, and their dysregulation is implicated in various diseases, including multiple sclerosis (MS). Interferon-beta (IFN-beta) is widely used as a first-line immunomodulatory treatment of MS patients. Here, we present the first longitudinal study on the miRNA expression changes in response to IFN-beta therapy. Peripheral blood mononuclear cells (PBMC) were obtained before treatment initiation as well as after two days, four days, and one month, from patients with clinically isolated syndrome (CIS) and patients with relapsing-remitting MS (RRMS). We measured the expression of 651 mature miRNAs and about 19,000 mRNAs in parallel using real-time PCR arrays and Affymetrix microarrays. We observed that the up-regulation of IFN-beta-responsive genes is accompanied by a down-regulation of several miRNAs, including members of the mir-29 family. These differentially expressed miRNAs were found to be associated with apoptotic processes and IFN feedback loops. A network of miRNA-mRNA target interactions was constructed by integrating the information from different databases. Our results suggest that miRNA-mediated regulation plays an important role in the mechanisms of action of IFN-beta, not only in the treatment of MS but also in normal immune responses. miRNA expression levels in the blood may serve as a biomarker of the biological effects of IFN-beta therapy that may predict individual disease activity and progression. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle SnoRNA U50 Levels Are Regulated by Cell Proliferation and rRNA Transcription
Int. J. Mol. Sci. 2013, 14(7), 14923-14935; doi:10.3390/ijms140714923
Received: 28 May 2013 / Revised: 1 July 2013 / Accepted: 2 July 2013 / Published: 17 July 2013
Cited by 8 | PDF Full-text (482 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
rRNA post transcriptional modifications play a role in cancer development by affecting ribosomal function. In particular, the snoRNA U50, mediating the methylation of C2848 in 28S rRNA, has been suggested as a potential tumor suppressor-like gene playing a role in breast and prostate
[...] Read more.
rRNA post transcriptional modifications play a role in cancer development by affecting ribosomal function. In particular, the snoRNA U50, mediating the methylation of C2848 in 28S rRNA, has been suggested as a potential tumor suppressor-like gene playing a role in breast and prostate cancers and B-cell lymphoma. Indeed, we observed the downregulation of U50 in colon cancer cell lines as well as tumors. We then investigated the relationship between U50 and proliferation in lymphocytes stimulated by phytohemagglutinin (PHA) and observed a strong decrease in U50 levels associated with a reduced C2848 methylation. This reduction was due to an alteration of U50 stability and to an increase of its consumption. Indeed, the blockade of ribosome biogenesis induced only an early decrease in U50 followed by a stabilization of U50 levels when ribosome biogenesis was almost completely blocked. Similar results were found with other snoRNAs. Lastly, we observed that U50 modulation affects ribosome efficiency in IRES-mediated translation, demonstrating that changes in the methylation levels of a single specific site on 28S rRNA may alter ribosome function. In conclusion, our results link U50 to the cellular proliferation rate and ribosome biogenesis and these findings may explain why its levels are often greatly reduced in cancers. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Cascading cis-Cleavage on Transcript from trans-Acting siRNA-Producing Locus 3
Int. J. Mol. Sci. 2013, 14(7), 14689-14699; doi:10.3390/ijms140714689
Received: 2 May 2013 / Revised: 24 June 2013 / Accepted: 4 July 2013 / Published: 12 July 2013
Cited by 7 | PDF Full-text (642 KB) | HTML Full-text | XML Full-text
Abstract
The production of small RNAs (sRNAs) from phased positions set by microRNA-directed cleavage of trans-acting-siRNA-producing locus (TAS) transcript has been characterized extensively; however, the production of sRNAs from non-phased positions remains unknown. We report three cis-cleavages that occurred in TAS3 transcripts
[...] Read more.
The production of small RNAs (sRNAs) from phased positions set by microRNA-directed cleavage of trans-acting-siRNA-producing locus (TAS) transcript has been characterized extensively; however, the production of sRNAs from non-phased positions remains unknown. We report three cis-cleavages that occurred in TAS3 transcripts in Vitis vinifera, by combining high-throughput sRNA deep sequencing information with evolutional conservation and genome-wide RNA degradome analysis. The three cis-cleavages can be deciphered to generate an orderly cleavage cascade, and can also produce distinct phasing patterns. Each of the patterns, either upstream or downstream of the cis-cleaved position, had a set of sRNAs arranged in 21-nucleotide increments. Part of the cascading cis-cleavages was also conserved in Arabidopsis thaliana. Our results will enhance the understanding of the production of sRNAs from non-phased positions that are not set by microRNA-directed cleavage. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Identification of MicroRNA 395a in 24-Epibrassinolide-Regulated Root Growth of Arabidopsis thaliana Using MicroRNA Arrays
Int. J. Mol. Sci. 2013, 14(7), 14270-14286; doi:10.3390/ijms140714270
Received: 20 May 2013 / Revised: 18 June 2013 / Accepted: 28 June 2013 / Published: 9 July 2013
Cited by 4 | PDF Full-text (3131 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Brassinosteroids (BRs) are endogenous plant hormones and are essential for normal plant growth and development. MicroRNAs (miRNAs) of Arabidopsis thaliana are involved in mediating cell proliferation in leaves, stress tolerance, and root development. The specifics of BR mechanisms involving miRNAs are unknown. Using
[...] Read more.
Brassinosteroids (BRs) are endogenous plant hormones and are essential for normal plant growth and development. MicroRNAs (miRNAs) of Arabidopsis thaliana are involved in mediating cell proliferation in leaves, stress tolerance, and root development. The specifics of BR mechanisms involving miRNAs are unknown. Using customized miRNA array analysis, we identified miRNAs from A. thaliana ecotype Columbia (Col-0) regulated by 24-epibrassinolide (EBR, a highly active BR). We found that miR395a was significantly up-regulated by EBR treatment and validated its expression under these conditions. miR395a was over expressed in leaf veins and root tissues in EBR-treated miR395a promoter::GUS plants. We integrated bioinformatics methods and publicly available DNA microarray data to predict potential targets of miR395a. GUN5—a multifunctional protein involved in plant metabolic functions such as chlorophyll synthesis and the abscisic acid (ABA) pathway—was identified as a possible target. ABI4 and ABI5, both genes positively regulated by ABA, were down-regulated by EBR treatment. In summary, our results suggest that EBR regulates seedling development and root growth of A. thaliana through miR395a by suppressing GUN5 expression and its downstream signal transduction. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessArticle miR-125b Regulates the Early Steps of ESC Differentiation through Dies1 in a TGF-Independent Manner
Int. J. Mol. Sci. 2013, 14(7), 13482-13496; doi:10.3390/ijms140713482
Received: 30 May 2013 / Revised: 13 June 2013 / Accepted: 19 June 2013 / Published: 27 June 2013
Cited by 8 | PDF Full-text (1725 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Over the past few years, it has become evident that the distinctive pattern of miRNA expression seen in embryonic stem cells (ESCs) contributes to important signals in the choice of the cell fate. Thus, the identification of miRNAs and their targets, whose expression
[...] Read more.
Over the past few years, it has become evident that the distinctive pattern of miRNA expression seen in embryonic stem cells (ESCs) contributes to important signals in the choice of the cell fate. Thus, the identification of miRNAs and their targets, whose expression is linked to a specific step of differentiation, as well as the modulation of these miRNAs, may prove useful in the learning of how ESC potential is regulated. In this context, we have studied the expression profile of miRNAs during neural differentiation of ESCs. We have found that miR-125b is upregulated in the first steps of neural differentiation of ESCs. This miRNA targets the BMP4 co-receptor, Dies1, and, in turn, regulates the balance between BMP4 and Nodal/Activin signaling. The ectopic expression of miR-125b blocks ESC differentiation at the epiblast stage, and this arrest is rescued by restoring the expression of Dies1. Finally, opposite to miR-125a, whose expression is under the control of the BMP4, miR-125b is not directly regulated by Transforming Growth Factor beta (TGFβ) signals. These results highlight a new important role of miR-125b in the regulation of the transition from ESCs to the epiblast stage and add a new level of control on TGFβ signaling in ESCs. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessCommunication Up-Regulation of microRNA* Strands by Their Target Transcripts
Int. J. Mol. Sci. 2013, 14(7), 13231-13240; doi:10.3390/ijms140713231
Received: 27 April 2013 / Revised: 29 May 2013 / Accepted: 17 June 2013 / Published: 26 June 2013
Cited by 11 | PDF Full-text (829 KB) | HTML Full-text | XML Full-text
Abstract
During microRNA (miRNA) biogenesis, one strand of a 21–23 nucleotide RNA duplex is preferentially selected for entry into an RNA-induced silencing complex (RISC). The other strand, known as the miRNA* species, is typically thought to be degraded. Previous studies have provided miRNA* selection
[...] Read more.
During microRNA (miRNA) biogenesis, one strand of a 21–23 nucleotide RNA duplex is preferentially selected for entry into an RNA-induced silencing complex (RISC). The other strand, known as the miRNA* species, is typically thought to be degraded. Previous studies have provided miRNA* selection models, but it remains unclear how the dominance of one arm arises during the biogenesis of miRNA. Using miRNA sponge-like methods, we cloned four tandem target sequences (artificial target) of miR-7b* and then measured miR-7b* expression levels after transfection of the artificial target. miR-7b* levels were found to significantly increase after transfection of the artificial target. We postulate that the abundance of target transcripts drives miRNA arm selection. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessArticle Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1
Int. J. Mol. Sci. 2013, 14(6), 12273-12296; doi:10.3390/ijms140612273
Received: 29 March 2013 / Revised: 14 May 2013 / Accepted: 22 May 2013 / Published: 7 June 2013
Cited by 13 | PDF Full-text (1094 KB) | HTML Full-text | XML Full-text
Abstract
The human polycistronic miRNA cluster miR-17-92 is frequently overexpressed in hematopoietic malignancies and cancers. Its transcription is in part controlled by an E2F-regulated host gene promoter. An intronic A/T-rich region directly upstream of the miRNA coding region also contributes to cluster expression. Our
[...] Read more.
The human polycistronic miRNA cluster miR-17-92 is frequently overexpressed in hematopoietic malignancies and cancers. Its transcription is in part controlled by an E2F-regulated host gene promoter. An intronic A/T-rich region directly upstream of the miRNA coding region also contributes to cluster expression. Our deletion analysis of the A/T-rich region revealed a strong dependence on c-Myc binding to the functional E3 site. Yet, constructs lacking the 5'-proximal ~1.3 kb or 3'-distal ~0.1 kb of the 1.5 kb A/T-rich region still retained residual specific promoter activity, suggesting multiple transcription start sites (TSS) in this region. Furthermore, the protooncogenic kinase, Pim-1, its phosphorylation target HP1γ and c-Myc colocalize to the E3 region, as inferred from chromatin immunoprecipitation. Analysis of pri-miR-17-92 expression levels in K562 and HeLa cells revealed that silencing of E2F3, c-Myc or Pim-1 negatively affects cluster expression, with a synergistic effect caused by c-Myc/Pim-1 double knockdown in HeLa cells. Thus, we show, for the first time, that the protooncogene Pim-1 is part of the network that regulates transcription of the human miR-17-92 cluster. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle MicroRNA-Regulated Protein-Protein Interaction Networks and Their Functions in Breast Cancer
Int. J. Mol. Sci. 2013, 14(6), 11560-11606; doi:10.3390/ijms140611560
Received: 17 April 2013 / Revised: 21 May 2013 / Accepted: 22 May 2013 / Published: 30 May 2013
Cited by 16 | PDF Full-text (1768 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNAs, which are small endogenous RNA regulators, have been associated with various types of cancer. Breast cancer is a major health threat for women worldwide. Many miRNAs were reported to be associated with the progression and carcinogenesis of breast cancer. In this study,
[...] Read more.
MicroRNAs, which are small endogenous RNA regulators, have been associated with various types of cancer. Breast cancer is a major health threat for women worldwide. Many miRNAs were reported to be associated with the progression and carcinogenesis of breast cancer. In this study, we aimed to discover novel breast cancer-related miRNAs and to elucidate their functions. First, we identified confident miRNA-target pairs by combining data from miRNA target prediction databases and expression profiles of miRNA and mRNA. Then, miRNA-regulated protein interaction networks (PINs) were constructed with confident pairs and known interaction data in the human protein reference database (HPRD). Finally, the functions of miRNA-regulated PINs were elucidated by functional enrichment analysis. From the results, we identified some previously reported breast cancer-related miRNAs and functions of the PINs, e.g., miR-125b, miR-125a, miR-21, and miR-497. Some novel miRNAs without known association to breast cancer were also found, and the putative functions of their PINs were also elucidated. These include miR-139 and miR-383. Furthermore, we validated our results by receiver operating characteristic (ROC) curve analysis using our miRNA expression profile data, gene expression-based outcome for breast cancer online (GOBO) survival analysis, and a literature search. Our results may provide new insights for research in breast cancer-associated miRNAs. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessArticle Fluctuation of Global Gene Expression by Endogenous miRNA Response to the Introduction of an Exogenous miRNA
Int. J. Mol. Sci. 2013, 14(6), 11171-11189; doi:10.3390/ijms140611171
Received: 21 March 2013 / Revised: 15 April 2013 / Accepted: 6 May 2013 / Published: 27 May 2013
Cited by 3 | PDF Full-text (6221 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Most of the intracellular endogenous microRNAs (endo-miRNAs) are considered to be saturated in Argonaute (Ago) proteins in the RNA-induced silencing complexes (RISCs). When exogenous miRNAs (exo-miRNAs) are introduced into cells, endo-miRNAs in the RISC may be replaced with exo-miRNAs or exo-miRNAs, and endo-miRNAs
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Most of the intracellular endogenous microRNAs (endo-miRNAs) are considered to be saturated in Argonaute (Ago) proteins in the RNA-induced silencing complexes (RISCs). When exogenous miRNAs (exo-miRNAs) are introduced into cells, endo-miRNAs in the RISC may be replaced with exo-miRNAs or exo-miRNAs, and endo-miRNAs might also compete for the position in the newly synthesized RISC with each other. This would lead to the fluctuation of global gene expression not only by repression of exo-miRNA target gene expression, but also by the increase of the endo-miRNA target gene expression. In the present study, we quantified the changes in the expression levels of target genes of exo-miRNA and endo-miRNA in the cells transfected with fifteen different exo-miRNAs by microarray experiments. Different exo-miRNAs increased ratios of expression levels of target genes of a given endo-miRNA to different extents, suggesting that the replacement efficiencies might differ according to the exo-miRNA types. However, the increased ratios in the expression levels of each endo-miRNA target genes by the transfection of any particular exo-miRNA were mostly equivalent, suggesting that the endo-miRNAs present in the RISC might be replaced with excessive exo-miRNAs at similar levels, probably because they exist in single-stranded forms in the RISC. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Angiotensin II Regulates microRNA-132/-212 in Hypertensive Rats and Humans
Int. J. Mol. Sci. 2013, 14(6), 11190-11207; doi:10.3390/ijms140611190
Received: 21 March 2013 / Revised: 25 April 2013 / Accepted: 15 May 2013 / Published: 27 May 2013
Cited by 40 | PDF Full-text (1866 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNAs (miRNAs), a group of small non-coding RNAs that fine tune translation of multiple target mRNAs, are emerging as key regulators in cardiovascular development and disease. MiRNAs are involved in cardiac hypertrophy, heart failure and remodeling following cardiac infarction; however, miRNAs involved in
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MicroRNAs (miRNAs), a group of small non-coding RNAs that fine tune translation of multiple target mRNAs, are emerging as key regulators in cardiovascular development and disease. MiRNAs are involved in cardiac hypertrophy, heart failure and remodeling following cardiac infarction; however, miRNAs involved in hypertension have not been thoroughly investigated. We have recently reported that specific miRNAs play an integral role in Angiotensin II receptor (AT1R) signaling, especially after activation of the Gαq signaling pathway. Since AT1R blockers are widely used to treat hypertension, we undertook a detailed analysis of potential miRNAs involved in Angiotensin II (AngII) mediated hypertension in rats and hypertensive patients, using miRNA microarray and qPCR analysis. The miR-132 and miR-212 are highly increased in the heart, aortic wall and kidney of rats with hypertension (159 ± 12 mm Hg) and cardiac hypertrophy following chronic AngII infusion. In addition, activation of the endothelin receptor, another Gαq coupled receptor, also increased miR-132 and miR-212. We sought to extend these observations using human samples by reasoning that AT1R blockers may decrease miR-132 and miR-212. We analyzed tissue samples of mammary artery obtained from surplus arterial tissue after coronary bypass operations. Indeed, we found a decrease in expression levels of miR-132 and miR-212 in human arteries from bypass-operated patients treated with AT1R blockers, whereas treatment with β-blockers had no effect. Taken together, these data suggest that miR-132 and miR-212 are involved in AngII induced hypertension, providing a new perspective in hypertensive disease mechanisms. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle MicroRNA Transcriptomes Relate Intermuscular Adipose Tissue to Metabolic Risk
Int. J. Mol. Sci. 2013, 14(4), 8611-8624; doi:10.3390/ijms14048611
Received: 20 March 2013 / Revised: 15 April 2013 / Accepted: 17 April 2013 / Published: 22 April 2013
Cited by 5 | PDF Full-text (833 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Intermuscular adipose tissue is located between the muscle fiber bundles in skeletal muscles, and has similar metabolic features to visceral adipose tissue, which has been found to be related to a number of obesity-related diseases. Although various miRNAs are known to play crucial
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Intermuscular adipose tissue is located between the muscle fiber bundles in skeletal muscles, and has similar metabolic features to visceral adipose tissue, which has been found to be related to a number of obesity-related diseases. Although various miRNAs are known to play crucial roles in adipose deposition and adipogenesis, the microRNA transcriptome of intermuscular adipose tissue has not, until now, been studied. Here, we sequenced the miRNA transcriptomes of porcine intermuscular adipose tissue by small RNA-sequencing and compared it to a representative subcutaneous adipose tissue. We found that the inflammation- and diabetes-related miRNAs were significantly enriched in the intermuscular rather than in the subcutaneous adipose tissue. A functional enrichment analysis of the genes predicted to be targeted by the enriched miRNAs also indicated that intermuscular adipose tissue was associated mainly with immune and inflammation responses. Our results suggest that the intermuscular adipose tissue should be recognized as a potential metabolic risk factor of obesity. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessArticle Prevention of Tendon Adhesions by ERK2 Small Interfering RNAs
Int. J. Mol. Sci. 2013, 14(2), 4361-4371; doi:10.3390/ijms14024361
Received: 21 November 2012 / Revised: 6 January 2013 / Accepted: 7 January 2013 / Published: 21 February 2013
Cited by 6 | PDF Full-text (1721 KB) | HTML Full-text | XML Full-text
Abstract
Tendon adhesions are one of the most concerning complications after surgical repair of flexor tendon injury. Extracellular signal-regulated kinase (ERK) 2 plays crucial roles in fibroblast proliferation and collagen expression which contributes to the formation of tendon adhesions after flexor tendon surgery. Using
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Tendon adhesions are one of the most concerning complications after surgical repair of flexor tendon injury. Extracellular signal-regulated kinase (ERK) 2 plays crucial roles in fibroblast proliferation and collagen expression which contributes to the formation of tendon adhesions after flexor tendon surgery. Using a chicken model, we have examined the effects of a small interfering RNA (siRNA) targeting ERK2 delivered by a lentiviral system on tendon adhesion formation with an adhesion scoring system, histological assessment, and biomechanical evaluation. It was found that ERK2 siRNA effectively suppressed the increase of fibroblasts and the formation of tendon adhesions (p < 0.05 compared with the control group). Moreover, no statistically significant reduction in breaking force was detected between the ERK2 siRNA group and the control group. These results show that the lentiviral-mediated siRNA system is effective in preventing tendon adhesion formation but not to tendon healing, and may be used for tendon repair after confirmation and improvement by future detailed studies. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessArticle Downregulation of miR-17~92 Expression Increase Paclitaxel Sensitivity in Human Ovarian Carcinoma SKOV3-TR30 Cells via BIM Instead of PTEN
Int. J. Mol. Sci. 2013, 14(2), 3802-3816; doi:10.3390/ijms14023802
Received: 24 December 2012 / Revised: 23 January 2013 / Accepted: 4 February 2013 / Published: 8 February 2013
Cited by 4 | PDF Full-text (657 KB) | HTML Full-text | XML Full-text
Abstract
To better understand the molecular mechanisms of paclitaxel resistance in ovarian carcinoma, we evaluated the expression of miRNAs using miRNA microarray between human ovarian carcinoma SKOV3 cells and paclitaxel resistant SKOV3-TR30 cells. Results showed that 69 miRNAs were upregulated while 102 miRNAs were
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To better understand the molecular mechanisms of paclitaxel resistance in ovarian carcinoma, we evaluated the expression of miRNAs using miRNA microarray between human ovarian carcinoma SKOV3 cells and paclitaxel resistant SKOV3-TR30 cells. Results showed that 69 miRNAs were upregulated while 102 miRNAs were downregulated in SKOV3-TR30 cells. Using real-time PCR, we further clarified that miR-17~92 was overexpressed in SKOV3-TR30 cells compared with that in SKOV3 cells. We then established stable virally transduced SKOV3-TR30-m-PTIP-Sponge all SKOV3-TR30 cells and its vector-only control SKOV3-TR30-m-PTIP-GFP cells. Real time-PCR revealed that SKOV3-TR30-m-PTIP-Sponge all cells expressed approximately 6.18-fold lower levels of miR-17~92 compared with the control group. Decreased expression of miR-17~92 resulted in cell cycle arrest in the G2/M phase and growth inhibition. After the transduction, the BIM protein level was increased in SKOV3-TR30 cells and luciferase reporter assays revealed that miR-17~92 binds directly to the 3'-UTR of BIM. Results of luciferase reporter assays accompanied with Western Blot showed that although miR-17~92 binds directly to the 3'-UTR of PTEN, the PTEN protein expression level was upregulated slightly while the result is of no statistical significance. Our results showed that miR-17~92 could be a causal factor of the downregulation of BIM in SKOV3-TR30 cells and thus induce the paclitaxel resistance in SKOV3-TR30 cells. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Open AccessReview ADAR Enzyme and miRNA Story: A Nucleotide that Can Make the Difference
Int. J. Mol. Sci. 2013, 14(11), 22796-22816; doi:10.3390/ijms141122796
Received: 8 October 2013 / Revised: 4 November 2013 / Accepted: 5 November 2013 / Published: 19 November 2013
Cited by 12 | PDF Full-text (615 KB) | HTML Full-text | XML Full-text
Abstract
Adenosine deaminase acting on RNA (ADAR) enzymes convert adenosine (A) to inosine (I) in double-stranded (ds) RNAs. Since Inosine is read as Guanosine, the biological consequence of ADAR enzyme activity is an A/G conversion within RNA molecules. A-to-I editing events can occur on
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Adenosine deaminase acting on RNA (ADAR) enzymes convert adenosine (A) to inosine (I) in double-stranded (ds) RNAs. Since Inosine is read as Guanosine, the biological consequence of ADAR enzyme activity is an A/G conversion within RNA molecules. A-to-I editing events can occur on both coding and non-coding RNAs, including microRNAs (miRNAs), which are small regulatory RNAs of ~20–23 nucleotides that regulate several cell processes by annealing to target mRNAs and inhibiting their translation. Both miRNA precursors and mature miRNAs undergo A-to-I RNA editing, affecting the miRNA maturation process and activity. ADARs can also edit 3' UTR of mRNAs, further increasing the interplay between mRNA targets and miRNAs. In this review, we provide a general overview of the ADAR enzymes and their mechanisms of action as well as miRNA processing and function. We then review the more recent findings about the impact of ADAR-mediated activity on the miRNA pathway in terms of biogenesis, target recognition, and gene expression regulation. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Arabidopsis Non-Coding RNA Regulation in Abiotic Stress Responses
Int. J. Mol. Sci. 2013, 14(11), 22642-22654; doi:10.3390/ijms141122642
Received: 15 October 2013 / Revised: 31 October 2013 / Accepted: 31 October 2013 / Published: 18 November 2013
Cited by 15 | PDF Full-text (259 KB) | HTML Full-text | XML Full-text
Abstract
Plant growth and productivity are largely affected by environmental stresses. Therefore, plants have evolved unique adaptation mechanisms to abiotic stresses through fine-tuned adjustment of gene expression and metabolism. Recent advanced technologies, such as genome-wide transcriptome analysis, have revealed that a vast amount of
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Plant growth and productivity are largely affected by environmental stresses. Therefore, plants have evolved unique adaptation mechanisms to abiotic stresses through fine-tuned adjustment of gene expression and metabolism. Recent advanced technologies, such as genome-wide transcriptome analysis, have revealed that a vast amount of non-coding RNAs (ncRNAs) apart from the well-known housekeeping ncRNAs such as rRNAs, tRNAs, small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) are expressed under abiotic stress conditions. These various types of ncRNAs are involved in chromatin regulation, modulation of RNA stability and translational repression during abiotic stress response. In this review, we summarize recent progress that has been made on ncRNA research in plant abiotic stress response. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview An Emerging Role for Long Non-Coding RNA Dysregulation in Neurological Disorders
Int. J. Mol. Sci. 2013, 14(10), 20427-20442; doi:10.3390/ijms141020427
Received: 14 June 2013 / Revised: 18 September 2013 / Accepted: 25 September 2013 / Published: 14 October 2013
Cited by 12 | PDF Full-text (284 KB) | HTML Full-text | XML Full-text
Abstract
A novel class of transcripts, long non coding RNAs (lncRNAs), has recently emerged as key players in several biological processes, including dosage compensation, genomic imprinting, chromatin regulation, embryonic development and segmentation, stem cell pluripotency, cell fate determination and potentially many other biological processes,
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A novel class of transcripts, long non coding RNAs (lncRNAs), has recently emerged as key players in several biological processes, including dosage compensation, genomic imprinting, chromatin regulation, embryonic development and segmentation, stem cell pluripotency, cell fate determination and potentially many other biological processes, which still are to be elucidated. LncRNAs are pervasively transcribed in the genome and several lines of evidence correlate dysregulation of different lncRNAs to human diseases including neurological disorders. Although their mechanisms of action are yet to be fully elucidated, evidence suggests lncRNA contributions to the pathogenesis of a number of diseases. In this review, the current state of knowledge linking lncRNAs to different neurological disorders is discussed and potential future directions are considered. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Non-Coding RNAs: The “Dark Matter” of Cardiovascular Pathophysiology
Int. J. Mol. Sci. 2013, 14(10), 19987-20018; doi:10.3390/ijms141019987
Received: 4 July 2013 / Revised: 12 September 2013 / Accepted: 16 September 2013 / Published: 9 October 2013
Cited by 20 | PDF Full-text (1299 KB) | HTML Full-text | XML Full-text
Abstract
Large-scale analyses of mammalian transcriptomes have identified a significant number of different RNA molecules that are not translated into protein. In fact, the use of new sequencing technologies has identified that most of the genome is transcribed, producing a heterogeneous population of RNAs
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Large-scale analyses of mammalian transcriptomes have identified a significant number of different RNA molecules that are not translated into protein. In fact, the use of new sequencing technologies has identified that most of the genome is transcribed, producing a heterogeneous population of RNAs which do not encode for proteins (ncRNAs). Emerging data suggest that these transcripts influence the development of cardiovascular disease. The best characterized non-coding RNA family is represented by short highly conserved RNA molecules, termed microRNAs (miRNAs), which mediate a process of mRNA silencing through transcript degradation or translational repression. These microRNAs (miRNAs) are expressed in cardiovascular tissues and play key roles in many cardiovascular pathologies, such as coronary artery disease (CAD) and heart failure (HF). Potential links between other ncRNAs, like long non-coding RNA, and cardiovascular disease are intriguing but the functions of these transcripts are largely unknown. Thus, the functional characterization of ncRNAs is essential to improve the overall understanding of cellular processes involved in cardiovascular diseases in order to define new therapeutic strategies. This review outlines the current knowledge of the different ncRNA classes and summarizes their role in cardiovascular development and disease. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessReview Non-Coding RNAs in Muscle Dystrophies
Int. J. Mol. Sci. 2013, 14(10), 19681-19704; doi:10.3390/ijms141019681
Received: 5 August 2013 / Revised: 5 September 2013 / Accepted: 9 September 2013 / Published: 30 September 2013
Cited by 10 | PDF Full-text (287 KB) | HTML Full-text | XML Full-text
Abstract
ncRNAs are the most recently identified class of regulatory RNAs with vital functions in gene expression regulation and cell development. Among the variety of roles they play, their involvement in human diseases has opened new avenues of research towards the discovery and development
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ncRNAs are the most recently identified class of regulatory RNAs with vital functions in gene expression regulation and cell development. Among the variety of roles they play, their involvement in human diseases has opened new avenues of research towards the discovery and development of novel therapeutic approaches. Important data come from the field of hereditary muscle dystrophies, like Duchenne muscle dystrophy and Myotonic dystrophies, rare diseases affecting 1 in 7000–15,000 newborns and is characterized by severe to mild muscle weakness associated with cardiac involvement. Novel therapeutic approaches are now ongoing for these diseases, also based on splicing modulation. In this review we provide an overview about ncRNAs and their behavior in muscular dystrophy and explore their links with diagnosis, prognosis and treatments, highlighting the role of regulatory RNAs in these pathologies. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Long Non-Coding RNAs and Complex Human Diseases
Int. J. Mol. Sci. 2013, 14(9), 18790-18808; doi:10.3390/ijms140918790
Received: 20 June 2013 / Revised: 28 August 2013 / Accepted: 3 September 2013 / Published: 12 September 2013
Cited by 31 | PDF Full-text (211 KB) | HTML Full-text | XML Full-text
Abstract
Long non-coding RNAs (lncRNAs) are a heterogeneous class of RNAs that are generally defined as non-protein-coding transcripts longer than 200 nucleotides. Recently, an increasing number of studies have shown that lncRNAs can be involved in various critical biological processes, such as chromatin remodeling,
[...] Read more.
Long non-coding RNAs (lncRNAs) are a heterogeneous class of RNAs that are generally defined as non-protein-coding transcripts longer than 200 nucleotides. Recently, an increasing number of studies have shown that lncRNAs can be involved in various critical biological processes, such as chromatin remodeling, gene transcription, and protein transport and trafficking. Moreover, lncRNAs are dysregulated in a number of complex human diseases, including coronary artery diseases, autoimmune diseases, neurological disorders, and various cancers, which indicates their important roles in these diseases. Here, we reviewed the current understanding of lncRNAs, including their definition and subclassification, regulatory functions, and potential roles in different types of complex human diseases. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Noncoding RNA in Oncogenesis: A New Era of Identifying Key Players
Int. J. Mol. Sci. 2013, 14(9), 18319-18349; doi:10.3390/ijms140918319
Received: 8 July 2013 / Revised: 23 August 2013 / Accepted: 30 August 2013 / Published: 5 September 2013
Cited by 35 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
New discoveries and accelerating progresses in the field of noncoding RNAs (ncRNAs) continuously challenges our deep-rooted doctrines in biology and sometimes our imagination. A growing body of evidence indicates that ncRNAs are important players in oncogenesis. While a stunning list of ncRNAs has
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New discoveries and accelerating progresses in the field of noncoding RNAs (ncRNAs) continuously challenges our deep-rooted doctrines in biology and sometimes our imagination. A growing body of evidence indicates that ncRNAs are important players in oncogenesis. While a stunning list of ncRNAs has been discovered, only a small portion of them has been examined for their biological activities and very few have been characterized for the molecular mechanisms of their action. To date, ncRNAs have been shown to regulate a wide range of biological processes, including chromatin remodeling, gene transcription, mRNA translation and protein function. Dysregulation of ncRNAs contributes to the pathogenesis of a variety of cancers and aberrant ncRNA expression has a high potential to be prognostic in some cancers. Thus, a new cancer research era has begun to identify novel key players of ncRNAs in oncogenesis. In this review, we will first discuss the function and regulation of miRNAs, especially focusing on the interplay between miRNAs and several key cancer genes, including p53, PTEN and c-Myc. We will then summarize the research of long ncRNAs (lncRNAs) in cancers. In this part, we will discuss the lncRNAs in four categories based on their activities, including regulating gene expression, acting as miRNA decoys, mediating mRNA translation, and modulating protein activities. At the end, we will also discuss recently unraveled activities of circular RNAs (circRNAs). Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Emerging Roles of Small Epstein-Barr Virus Derived Non-Coding RNAs in Epithelial Malignancy
Int. J. Mol. Sci. 2013, 14(9), 17378-17409; doi:10.3390/ijms140917378
Received: 8 July 2013 / Revised: 1 August 2013 / Accepted: 13 August 2013 / Published: 23 August 2013
Cited by 21 | PDF Full-text (2420 KB) | HTML Full-text | XML Full-text
Abstract
Latent Epstein-Barr virus (EBV) infection is an etiological factor in the progression of several human epithelial malignancies such as nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma. Reports have shown that EBV produces several viral oncoproteins, yet their pathological roles in carcinogenesis
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Latent Epstein-Barr virus (EBV) infection is an etiological factor in the progression of several human epithelial malignancies such as nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma. Reports have shown that EBV produces several viral oncoproteins, yet their pathological roles in carcinogenesis are not fully elucidated. Studies on the recently discovered of EBV-encoded microRNAs (ebv-miRNAs) showed that these small molecules function as post-transcriptional gene regulators and may play a role in the carcinogenesis process. In NPC and EBV positive gastric carcinoma (EBVaGC), 22 viral miRNAs which are located in the long alternative splicing EBV transcripts, named BamH1 A rightward transcripts (BARTs), are abundantly expressed. The importance of several miR-BARTs in carcinogenesis has recently been demonstrated. These novel findings enhance our understanding of the oncogenic properties of EBV and may lead to a more effective design of therapeutic regimens to combat EBV-associated malignancies. This article will review the pathological roles of miR-BARTs in modulating the expression of cancer-related genes in both host and viral genomes. The expression of other small non-coding RNAs in NPC and the expression pattern of miR-BARTs in rare EBV-associated epithelial cancers will also be discussed. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Dynamic Nature of Noncoding RNA Regulation of Adaptive Immune Response
Int. J. Mol. Sci. 2013, 14(9), 17347-17377; doi:10.3390/ijms140917347
Received: 1 July 2013 / Revised: 30 July 2013 / Accepted: 12 August 2013 / Published: 22 August 2013
Cited by 12 | PDF Full-text (424 KB) | HTML Full-text | XML Full-text
Abstract
Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases. Recently our understanding of the molecular and cellular networks regulating the immune response,
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Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases. Recently our understanding of the molecular and cellular networks regulating the immune response, and, in particular, adaptive immunity, has improved dramatically. For many years, much of the focus has been on the study of protein regulators; nevertheless, recent evidence points to a fundamental role for specific classes of noncoding RNAs (ncRNAs) in regulating development, activation and homeostasis of the immune system. Although microRNAs (miRNAs) are the most comprehensive and well-studied, a number of reports suggest the exciting possibility that long ncRNAs (lncRNAs) could mediate host response and immune function. Finally, evidence is also accumulating that suggests a role for miRNAs and other small ncRNAs in autocrine, paracrine and exocrine signaling events, thus highlighting an elaborate network of regulatory interactions mediated by different classes of ncRNAs during immune response. This review will explore the multifaceted roles of ncRNAs in the adaptive immune response. In particular, we will focus on the well-established role of miRNAs and on the emerging role of lncRNAs and circulating ncRNAs, which all make indispensable contributions to the understanding of the multilayered modulation of the adaptive immune response. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Non-Coding RNAs and Cancer
Int. J. Mol. Sci. 2013, 14(8), 17085-17110; doi:10.3390/ijms140817085
Received: 5 July 2013 / Revised: 1 August 2013 / Accepted: 8 August 2013 / Published: 19 August 2013
Cited by 16 | PDF Full-text (1556 KB) | HTML Full-text | XML Full-text
Abstract
The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated
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The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated with diagnosis, staging, progression, prognosis, and response to treatment. In this review we will discuss the recent remarkable advancement in the understanding the biological functions of human ncRNAs in cancer, the mechanisms of expression and the therapeutic potential. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective
Int. J. Mol. Sci. 2013, 14(8), 16532-16553; doi:10.3390/ijms140816532
Received: 31 May 2013 / Revised: 22 July 2013 / Accepted: 25 July 2013 / Published: 9 August 2013
Cited by 20 | PDF Full-text (3652 KB) | HTML Full-text | XML Full-text
Abstract
Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis
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Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28’s RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Principles of miRNA-Target Regulation in Metazoan Models
Int. J. Mol. Sci. 2013, 14(8), 16280-16302; doi:10.3390/ijms140816280
Received: 3 June 2013 / Revised: 29 July 2013 / Accepted: 31 July 2013 / Published: 7 August 2013
Cited by 8 | PDF Full-text (1855 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRs) are key post-transcriptional regulators that silence gene expression by direct base pairing to target sites of RNAs. They have a wide variety of tissue expression patterns and are differentially expressed during development and disease. Their activity and abundance is subject to
[...] Read more.
MicroRNAs (miRs) are key post-transcriptional regulators that silence gene expression by direct base pairing to target sites of RNAs. They have a wide variety of tissue expression patterns and are differentially expressed during development and disease. Their activity and abundance is subject to various levels of control ranging from transcription and biogenesis to miR response elements on RNAs, target cellular levels and miR turnover. This review summarizes and discusses current knowledge on the regulation of miR activity and concludes with novel non-canonical functions that have recently emerged. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessReview Non-Coding RNAs: Multi-Tasking Molecules in the Cell
Int. J. Mol. Sci. 2013, 14(8), 16010-16039; doi:10.3390/ijms140816010
Received: 7 June 2013 / Revised: 15 July 2013 / Accepted: 19 July 2013 / Published: 31 July 2013
Cited by 35 | PDF Full-text (456 KB) | HTML Full-text | XML Full-text
Abstract
In the last years it has become increasingly clear that the mammalian transcriptome is highly complex and includes a large number of small non-coding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs). Here we review the biogenesis pathways of the three classes of sncRNAs,
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In the last years it has become increasingly clear that the mammalian transcriptome is highly complex and includes a large number of small non-coding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs). Here we review the biogenesis pathways of the three classes of sncRNAs, namely short interfering RNAs (siRNAs), microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs). These ncRNAs have been extensively studied and are involved in pathways leading to specific gene silencing and the protection of genomes against virus and transposons, for example. Also, lncRNAs have emerged as pivotal molecules for the transcriptional and post-transcriptional regulation of gene expression which is supported by their tissue-specific expression patterns, subcellular distribution, and developmental regulation. Therefore, we also focus our attention on their role in differentiation and development. SncRNAs and lncRNAs play critical roles in defining DNA methylation patterns, as well as chromatin remodeling thus having a substantial effect in epigenetics. The identification of some overlaps in their biogenesis pathways and functional roles raises the hypothesis that these molecules play concerted functions in vivo, creating complex regulatory networks where cooperation with regulatory proteins is necessary. We also highlighted the implications of biogenesis and gene expression deregulation of sncRNAs and lncRNAs in human diseases like cancer. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Impaired Pre-mRNA Processing and Altered Architecture of 3' Untranslated Regions Contribute to the Development of Human Disorders
Int. J. Mol. Sci. 2013, 14(8), 15681-15694; doi:10.3390/ijms140815681
Received: 31 May 2013 / Revised: 21 June 2013 / Accepted: 24 June 2013 / Published: 26 July 2013
Cited by 11 | PDF Full-text (202 KB) | HTML Full-text | XML Full-text
Abstract
The biological fate of each mRNA and consequently, the protein to be synthesised, is highly dependent on the nature of the 3' untranslated region. Despite its non-coding character, the 3' UTR may affect the final mRNA stability, the localisation, the export from the
[...] Read more.
The biological fate of each mRNA and consequently, the protein to be synthesised, is highly dependent on the nature of the 3' untranslated region. Despite its non-coding character, the 3' UTR may affect the final mRNA stability, the localisation, the export from the nucleus and the translation efficiency. The conserved regulatory sequences within 3' UTRs and the specific elements binding to them enable gene expression control at the posttranscriptional level and all these processes reflect the actual state of the cell including proliferation, differentiation, cellular stress or tumourigenesis. Through this article, we briefly outline how the alterations in the establishment and final architecture of 3' UTRs may contribute to the development of various disorders in humans. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview How Can Plant DNA Viruses Evade siRNA-Directed DNA Methylation and Silencing?
Int. J. Mol. Sci. 2013, 14(8), 15233-15259; doi:10.3390/ijms140815233
Received: 13 June 2013 / Revised: 1 July 2013 / Accepted: 1 July 2013 / Published: 24 July 2013
Cited by 24 | PDF Full-text (637 KB) | HTML Full-text | XML Full-text
Abstract
Plants infected with DNA viruses produce massive quantities of virus-derived, 24-nucleotide short interfering RNAs (siRNAs), which can potentially direct viral DNA methylation and transcriptional silencing. However, growing evidence indicates that the circular double-stranded DNA accumulating in the nucleus for Pol II-mediated transcription of
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Plants infected with DNA viruses produce massive quantities of virus-derived, 24-nucleotide short interfering RNAs (siRNAs), which can potentially direct viral DNA methylation and transcriptional silencing. However, growing evidence indicates that the circular double-stranded DNA accumulating in the nucleus for Pol II-mediated transcription of viral genes is not methylated. Hence, DNA viruses most likely evade or suppress RNA-directed DNA methylation. This review describes the specialized mechanisms of replication and silencing evasion evolved by geminiviruses and pararetoviruses, which rescue viral DNA from repressive methylation and interfere with transcriptional and post-transcriptional silencing of viral genes. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Functional Diversity of RNAi-Associated sRNAs in Fungi
Int. J. Mol. Sci. 2013, 14(8), 15348-15360; doi:10.3390/ijms140815348
Received: 30 May 2013 / Revised: 5 July 2013 / Accepted: 9 July 2013 / Published: 24 July 2013
Cited by 9 | PDF Full-text (209 KB) | HTML Full-text | XML Full-text
Abstract
Yeast and filamentous fungi have been essential model systems for unveiling the secrets of RNA interference (RNAi). Research on these organisms has contributed to identifying general mechanisms and conserved eukaryotic RNAi machinery that can be found from fungi to mammals. The development of
[...] Read more.
Yeast and filamentous fungi have been essential model systems for unveiling the secrets of RNA interference (RNAi). Research on these organisms has contributed to identifying general mechanisms and conserved eukaryotic RNAi machinery that can be found from fungi to mammals. The development of deep sequencing technologies has brought on the last wave of studies on RNAi in fungi, which has been focused on the identification of new types of functional small RNAs (sRNAs). These studies have discovered an unexpected diversity of sRNA, biogenesis pathways and new functions that are the focus of this review. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessReview Long Non-Coding RNAs in Haematological Malignancies
Int. J. Mol. Sci. 2013, 14(8), 15386-15422; doi:10.3390/ijms140815386
Received: 31 May 2013 / Revised: 28 June 2013 / Accepted: 9 July 2013 / Published: 24 July 2013
Cited by 10 | PDF Full-text (527 KB) | HTML Full-text | XML Full-text
Abstract
Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. LncRNAs are as diverse as mRNAs and they normally share the same biosynthetic machinery based on RNA polymerase II, splicing and polyadenylation. However, lncRNAs have low coding potential. Compared to
[...] Read more.
Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. LncRNAs are as diverse as mRNAs and they normally share the same biosynthetic machinery based on RNA polymerase II, splicing and polyadenylation. However, lncRNAs have low coding potential. Compared to mRNAs, lncRNAs are preferentially nuclear, more tissue specific and expressed at lower levels. Most of the lncRNAs described to date modulate the expression of specific genes by guiding chromatin remodelling factors; inducing chromosomal loopings; affecting transcription, splicing, translation or mRNA stability; or serving as scaffolds for the organization of cellular structures. They can function in cis, cotranscriptionally, or in trans, acting as decoys, scaffolds or guides. These functions seem essential to allow cell differentiation and growth. In fact, many lncRNAs have been shown to exert oncogenic or tumor suppressor properties in several cancers including haematological malignancies. In this review, we summarize what is known about lncRNAs, the mechanisms for their regulation in cancer and their role in leukemogenesis, lymphomagenesis and hematopoiesis. Furthermore, we discuss the potential of lncRNAs in diagnosis, prognosis and therapy in cancer, with special attention to haematological malignancies. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessReview Detecting and Comparing Non-Coding RNAs in the High-Throughput Era
Int. J. Mol. Sci. 2013, 14(8), 15423-15458; doi:10.3390/ijms140815423
Received: 31 May 2013 / Revised: 16 July 2013 / Accepted: 17 July 2013 / Published: 24 July 2013
Cited by 6 | PDF Full-text (372 KB) | HTML Full-text | XML Full-text
Abstract
In recent years there has been a growing interest in the field of non-coding RNA. This surge is a direct consequence of the discovery of a huge number of new non-coding genes and of the finding that many of these transcripts are involved
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In recent years there has been a growing interest in the field of non-coding RNA. This surge is a direct consequence of the discovery of a huge number of new non-coding genes and of the finding that many of these transcripts are involved in key cellular functions. In this context, accurately detecting and comparing RNA sequences has become important. Aligning nucleotide sequences is a key requisite when searching for homologous genes. Accurate alignments reveal evolutionary relationships, conserved regions and more generally any biologically relevant pattern. Comparing RNA molecules is, however, a challenging task. The nucleotide alphabet is simpler and therefore less informative than that of amino-acids. Moreover for many non-coding RNAs, evolution is likely to be mostly constrained at the structural level and not at the sequence level. This results in very poor sequence conservation impeding comparison of these molecules. These difficulties define a context where new methods are urgently needed in order to exploit experimental results to their full potential. This review focuses on the comparative genomics of non-coding RNAs in the context of new sequencing technologies and especially dealing with two extremely important and timely research aspects: the development of new methods to align RNAs and the analysis of high-throughput data. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview The Role of MicroRNAs in Breast Cancer Stem Cells
Int. J. Mol. Sci. 2013, 14(7), 14712-14723; doi:10.3390/ijms140714712
Received: 30 May 2013 / Revised: 25 June 2013 / Accepted: 2 July 2013 / Published: 15 July 2013
Cited by 36 | PDF Full-text (181 KB) | HTML Full-text | XML Full-text
Abstract
The concept of the existence of a subset of cancer cells with stem cell-like properties, which are thought to play a significant role in tumor formation, metastasis, resistance to anticancer therapies and cancer recurrence, has gained tremendous attraction within the last decade. These
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The concept of the existence of a subset of cancer cells with stem cell-like properties, which are thought to play a significant role in tumor formation, metastasis, resistance to anticancer therapies and cancer recurrence, has gained tremendous attraction within the last decade. These cancer stem cells (CSCs) are relatively rare and have been described by different molecular markers and cellular features in different types of cancers. Ten years ago, a novel class of molecules, small non-protein-coding RNAs, was found to be involved in carcinogenesis. These small RNAs, which are called microRNAs (miRNAs), act as endogenous suppressors of gene expression that exert their effect by binding to the 3'-untranslated region (UTR) of large target messenger RNAs (mRNAs). MicroRNAs trigger either translational repression or mRNA cleavage of target mRNAs. Some studies have shown that putative breast cancer stem cells (BCSCs) exhibit a distinct miRNA expression profile compared to non-tumorigenic breast cancer cells. The deregulated miRNAs may contribute to carcinogenesis and self-renewal of BCSCs via several different pathways and can act either as oncomirs or as tumor suppressive miRNAs. It has also been demonstrated that certain miRNAs play an essential role in regulating the stem cell-like phenotype of BCSCs. Some miRNAs control clonal expansion or maintain the self-renewal and anti-apoptotic features of BCSCs. Others are targeting the specific mRNA of their target genes and thereby contribute to the formation and self-renewal process of BCSCs. Several miRNAs are involved in epithelial to mesenchymal transition, which is often implicated in the process of formation of CSCs. Other miRNAs were shown to be involved in the increased chemotherapeutic resistance of BCSCs. This review highlights the recent findings and crucial role of miRNAs in the maintenance, growth and behavior of BCSCs, thus indicating the potential for novel diagnostic, prognostic and therapeutic miRNA-based strategies. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Long and Short Non-Coding RNAs as Regulators of Hematopoietic Differentiation
Int. J. Mol. Sci. 2013, 14(7), 14744-14770; doi:10.3390/ijms140714744
Received: 3 June 2013 / Revised: 5 July 2013 / Accepted: 9 July 2013 / Published: 15 July 2013
Cited by 13 | PDF Full-text (1055 KB) | HTML Full-text | XML Full-text
Abstract
Genomic analyses estimated that the proportion of the genome encoding proteins corresponds to approximately 1.5%, while at least 66% are transcribed, suggesting that many non-coding DNA-regions generate non-coding RNAs (ncRNAs). The relevance of these ncRNAs in biological, physiological as well as in pathological
[...] Read more.
Genomic analyses estimated that the proportion of the genome encoding proteins corresponds to approximately 1.5%, while at least 66% are transcribed, suggesting that many non-coding DNA-regions generate non-coding RNAs (ncRNAs). The relevance of these ncRNAs in biological, physiological as well as in pathological processes increased over the last two decades with the understanding of their implication in complex regulatory networks. This review particularly focuses on the involvement of two large families of ncRNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of hematopoiesis. To date, miRNAs have been widely studied, leading to a wealth of data about processing, regulation and mechanisms of action and more specifically, their involvement in hematopoietic differentiation. Notably, the interaction of miRNAs with the regulatory network of transcription factors is well documented whereas roles, regulation and mechanisms of lncRNAs remain largely unexplored in hematopoiesis; this review gathers current data about lncRNAs as well as both potential and confirmed roles in normal and pathological hematopoiesis. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Exploiting CRISPR/Cas: Interference Mechanisms and Applications
Int. J. Mol. Sci. 2013, 14(7), 14518-14531; doi:10.3390/ijms140714518
Received: 31 May 2013 / Revised: 26 June 2013 / Accepted: 1 July 2013 / Published: 12 July 2013
Cited by 12 | PDF Full-text (589 KB) | HTML Full-text | XML Full-text
Abstract
The discovery of biological concepts can often provide a framework for the development of novel molecular tools, which can help us to further understand and manipulate life. One recent example is the elucidation of the prokaryotic adaptive immune system, clustered regularly interspaced short
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The discovery of biological concepts can often provide a framework for the development of novel molecular tools, which can help us to further understand and manipulate life. One recent example is the elucidation of the prokaryotic adaptive immune system, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) that protects bacteria and archaea against viruses or conjugative plasmids. The immunity is based on small RNA molecules that are incorporated into versatile multi-domain proteins or protein complexes and specifically target viral nucleic acids via base complementarity. CRISPR/Cas interference machines are utilized to develop novel genome editing tools for different organisms. Here, we will review the latest progress in the elucidation and application of prokaryotic CRISPR/Cas systems and discuss possible future approaches to exploit the potential of these interference machineries. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Regulatory Non-Coding RNAs in Pluripotent Stem Cells
Int. J. Mol. Sci. 2013, 14(7), 14346-14373; doi:10.3390/ijms140714346
Received: 6 May 2013 / Revised: 25 June 2013 / Accepted: 2 July 2013 / Published: 11 July 2013
Cited by 11 | PDF Full-text (1441 KB) | HTML Full-text | XML Full-text
Abstract
The most part of our genome encodes for RNA transcripts are never translated into proteins. These include families of RNA molecules with a regulatory function, which can be arbitrarily subdivided in short (less than 200 nucleotides) and long non-coding RNAs (ncRNAs). MicroRNAs, which
[...] Read more.
The most part of our genome encodes for RNA transcripts are never translated into proteins. These include families of RNA molecules with a regulatory function, which can be arbitrarily subdivided in short (less than 200 nucleotides) and long non-coding RNAs (ncRNAs). MicroRNAs, which act post-transcriptionally to repress the function of target mRNAs, belong to the first group. Included in the second group are multi-exonic and polyadenylated long ncRNAs (lncRNAs), localized either in the nucleus, where they can associate with chromatin remodeling complexes to regulate transcription, or in the cytoplasm, acting as post-transcriptional regulators. Pluripotent stem cells, such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), represent useful systems for modeling normal development and human diseases, as well as promising tools for regenerative medicine. To fully explore their potential, however, a deep understanding of the molecular basis of stemness is crucial. In recent years, increasing evidence of the importance of regulation by ncRNAs in pluripotent cells is accumulating. In this review, we will discuss recent findings pointing to multiple roles played by regulatory ncRNAs in ESC and iPSCs, where they act in concert with signaling pathways, transcriptional regulatory circuitries and epigenetic factors to modulate the balance between pluripotency and differentiation. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessReview Micromanaging Abdominal Aortic Aneurysms
Int. J. Mol. Sci. 2013, 14(7), 14374-14394; doi:10.3390/ijms140714374
Received: 26 April 2013 / Revised: 25 June 2013 / Accepted: 26 June 2013 / Published: 11 July 2013
Cited by 9 | PDF Full-text (298 KB) | HTML Full-text | XML Full-text
Abstract
The contribution of abdominal aortic aneurysm (AAA) disease to human morbidity and mortality has increased in the aging, industrialized world. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of the diseased aorta. This work aims to develop
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The contribution of abdominal aortic aneurysm (AAA) disease to human morbidity and mortality has increased in the aging, industrialized world. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of the diseased aorta. This work aims to develop novel diagnostic and therapeutic strategies to limit AAA expansion and, ultimately, rupture. Contributions from multiple research groups have uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining aortic vascular homeostasis. Recently, novel small noncoding RNAs, called microRNAs, have been identified as important transcriptional and post-transcriptional inhibitors of gene expression. MicroRNAs are thought to “fine tune” the translational output of their target messenger RNAs (mRNAs) by promoting mRNA degradation or inhibiting translation. With the discovery that microRNAs act as powerful regulators in the context of a wide variety of diseases, it is only logical that microRNAs be thoroughly explored as potential therapeutic entities. This current review summarizes interesting findings regarding the intriguing roles and benefits of microRNA expression modulation during AAA initiation and propagation. These studies utilize disease-relevant murine models, as well as human tissue from patients undergoing surgical aortic aneurysm repair. Furthermore, we critically examine future therapeutic strategies with regard to their clinical and translational feasibility. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Intercellular Communication by Exosome-Derived microRNAs in Cancer
Int. J. Mol. Sci. 2013, 14(7), 14240-14269; doi:10.3390/ijms140714240
Received: 2 May 2013 / Revised: 14 June 2013 / Accepted: 17 June 2013 / Published: 9 July 2013
Cited by 76 | PDF Full-text (717 KB) | HTML Full-text | XML Full-text
Abstract
The development of human cancers is a multistep process in which normal cells acquire characteristics that ultimately lead to their conversion into cancer cells. Many obstacles must be overcome for this process to occur; of these obstacles, is the ability to survive an
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The development of human cancers is a multistep process in which normal cells acquire characteristics that ultimately lead to their conversion into cancer cells. Many obstacles must be overcome for this process to occur; of these obstacles, is the ability to survive an inhospitable microenvironment. It is recognized that the intercommunication between tumor cells and their surrounding microenvironment is essential to overcoming this obstacle and for the tumor to progress, metastasize and establish itself at distant sites. Exosomes are membrane-derived vesicles that have recently been recognized as important mediators of intercellular communication, as they carry lipids, proteins, mRNAs and microRNAs that can be transferred to a recipient cell via fusion of the exosome with the target cell membrane. In the context of cancer cells, this process entails the transfer of cancer-promoting cellular contents to surrounding cells within the tumor microenvironment or into the circulation to act at distant sites, thereby enabling cancer progression. In this process, the transfer of exosomal microRNAs to a recipient cell where they can regulate target gene expression is of particular interest, both in understanding the basic biology of cancer progression and for the development of therapeutic approaches. This review discusses the exosome-mediated intercellular communication via microRNAs within the tumor microenvironment in human cancers, with a particular focus on breast cancer exosomes. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Regulation of miRNA Expression by Low-Level Laser Therapy (LLLT) and Photodynamic Therapy (PDT)
Int. J. Mol. Sci. 2013, 14(7), 13542-13558; doi:10.3390/ijms140713542
Received: 31 May 2013 / Revised: 19 June 2013 / Accepted: 20 June 2013 / Published: 27 June 2013
Cited by 11 | PDF Full-text (219 KB) | HTML Full-text | XML Full-text
Abstract
Applications of laser therapy, including low-level laser therapy (LLLT), phototherapy and photodynamic therapy (PDT), have been proven to be beneficial and relatively less invasive therapeutic modalities for numerous diseases and disease conditions. Using specific types of laser irradiation, specific cellular activities can be
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Applications of laser therapy, including low-level laser therapy (LLLT), phototherapy and photodynamic therapy (PDT), have been proven to be beneficial and relatively less invasive therapeutic modalities for numerous diseases and disease conditions. Using specific types of laser irradiation, specific cellular activities can be induced. Because multiple cellular signaling cascades are simultaneously activated in cells exposed to lasers, understanding the molecular responses within cells will aid in the development of laser therapies. In order to understand in detail the molecular mechanisms of LLLT and PDT-related responses, it will be useful to characterize the specific expression of miRNAs and proteins. Such analyses will provide an important source for new applications of laser therapy, as well as for the development of individualized treatments. Although several miRNAs should be up- or down-regulated upon stimulation by LLLT, phototherapy and PDT, very few published studies address the effect of laser therapy on miRNA expression. In this review, we focus on LLLT, phototherapy and PDT as representative laser therapies and discuss the effects of these therapies on miRNA expression. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview The Intertwining of Transposable Elements and Non-Coding RNAs
Int. J. Mol. Sci. 2013, 14(7), 13307-13328; doi:10.3390/ijms140713307
Received: 20 May 2013 / Revised: 5 June 2013 / Accepted: 5 June 2013 / Published: 26 June 2013
Cited by 17 | PDF Full-text (1641 KB) | HTML Full-text | XML Full-text
Abstract
Growing evidence shows a close association of transposable elements (TE) with non-coding RNAs (ncRNA), and a significant number of small ncRNAs originate from TEs. Further, ncRNAs linked with TE sequences participate in a wide-range of regulatory functions. Alu elements in particular are critical
[...] Read more.
Growing evidence shows a close association of transposable elements (TE) with non-coding RNAs (ncRNA), and a significant number of small ncRNAs originate from TEs. Further, ncRNAs linked with TE sequences participate in a wide-range of regulatory functions. Alu elements in particular are critical players in gene regulation and molecular pathways. Alu sequences embedded in both long non-coding RNAs (lncRNA) and mRNAs form the basis of targeted mRNA decay via short imperfect base-pairing. Imperfect pairing is prominent in most ncRNA/target RNA interactions and found throughout all biological kingdoms. The piRNA-Piwi complex is multifunctional, but plays a major role in protection against invasion by transposons. This is an RNA-based genetic immune system similar to the one found in prokaryotes, the CRISPR system. Thousands of long intergenic non-coding RNAs (lincRNAs) are associated with endogenous retrovirus LTR transposable elements in human cells. These TEs can provide regulatory signals for lincRNA genes. A surprisingly large number of long circular ncRNAs have been discovered in human fibroblasts. These serve as “sponges” for miRNAs. Alu sequences, encoded in introns that flank exons are proposed to participate in RNA circularization via Alu/Alu base-pairing. Diseases are increasingly found to have a TE/ncRNA etiology. A single point mutation in a SINE/Alu sequence in a human long non-coding RNA leads to brainstem atrophy and death. On the other hand, genomic clusters of repeat sequences as well as lncRNAs function in epigenetic regulation. Some clusters are unstable, which can lead to formation of diseases such as facioscapulohumeral muscular dystrophy. The future may hold more surprises regarding diseases associated with ncRNAs andTEs. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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Open AccessReview MicroRNA Regulation in Renal Pathophysiology
Int. J. Mol. Sci. 2013, 14(7), 13078-13092; doi:10.3390/ijms140713078
Received: 7 May 2013 / Revised: 5 June 2013 / Accepted: 6 June 2013 / Published: 25 June 2013
Cited by 9 | PDF Full-text (478 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs are small, noncoding RNA molecules that regulate a considerable amount of human genes on the post-transcriptional level, and participate in many key biological processes. MicroRNA deregulation has been found associated with major kidney diseases. Here, we summarize current knowledge on the role
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MicroRNAs are small, noncoding RNA molecules that regulate a considerable amount of human genes on the post-transcriptional level, and participate in many key biological processes. MicroRNA deregulation has been found associated with major kidney diseases. Here, we summarize current knowledge on the role of microRNAs in renal glomerular and tubular pathologies, with emphasis on the mesangial cell and podocyte dysfunction in diabetic nephropathy, the proximal tubular cell survival in acute kidney injury, the transport function of the thick ascending limb in Ca++ imbalance diseases, and the regulation of salt, K+ and blood pressure in the distal tubules. Identification of microRNAs and their target genes provides novel therapeutic candidates for treating these diseases. Manipulation of microRNA function with its sense or antisense oligonucleotide enables coordinated regulation of the entire downstream gene network, which has effectively ameliorated several renal disease phenotypes. The therapeutic potentials of microRNA based treatments, though promising, are confounded by major safety issues related to its target specificity, which remain to be fully elucidated. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview The Role of microRNA in Gastric Malignancy
Int. J. Mol. Sci. 2013, 14(5), 9487-9496; doi:10.3390/ijms14059487
Received: 27 March 2013 / Revised: 19 April 2013 / Accepted: 25 April 2013 / Published: 29 April 2013
Cited by 20 | PDF Full-text (421 KB) | HTML Full-text | XML Full-text
Abstract
Helicobacter pylori (H. pylori) infection is the main cause of gastritis, gastro-duodenal ulcer, and gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs that function as endogenous silencers of numerous target genes. Many miRNA genes are expressed in a tissue-specific manner and
[...] Read more.
Helicobacter pylori (H. pylori) infection is the main cause of gastritis, gastro-duodenal ulcer, and gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs that function as endogenous silencers of numerous target genes. Many miRNA genes are expressed in a tissue-specific manner and play important roles in cell proliferation, apoptosis, and differentiation. Recent discoveries have shed new light on the involvement of miRNAs in gastric malignancy. However, at the same time, several miRNAs have been associated with opposing events, leading to reduced inflammation, inhibition of malignancy, and increased apoptosis of transformed cells. The regulation of miRNA expression could be a novel strategy in the chemoprevention of human gastric malignancy. In this article, the biological importance of miRNAs in gastric malignancy is summarized. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Advances in the Techniques for the Prediction of microRNA Targets
Int. J. Mol. Sci. 2013, 14(4), 8179-8187; doi:10.3390/ijms14048179
Received: 7 January 2013 / Revised: 1 April 2013 / Accepted: 2 April 2013 / Published: 15 April 2013
Cited by 30 | PDF Full-text (155 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs) are small, non-coding, endogenous RNA molecules that play important roles in a variety of normal and diseased biological processes by post-transcriptionally regulating the expression of target genes. They can bind to target messenger RNA (mRNA) transcripts of protein-coding genes and negatively
[...] Read more.
MicroRNAs (miRNAs) are small, non-coding, endogenous RNA molecules that play important roles in a variety of normal and diseased biological processes by post-transcriptionally regulating the expression of target genes. They can bind to target messenger RNA (mRNA) transcripts of protein-coding genes and negatively control their translation or cause mRNA degradation. miRNAs have been found to actively regulate a variety of cellular processes, including cell proliferation, death, and metabolism. Therefore, their study is crucial for the better understanding of cellular functions in eukaryotes. To better understand the mechanisms of miRNA: mRNA interaction and their cellular functions, it is important to identify the miRNA targets accurately. In this paper, we provide a brief review for the advances in the animal miRNA target prediction methods and available resources to facilitate further study of miRNAs and their functions. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
Open AccessReview Long Non-Coding RNA in Cancer
Int. J. Mol. Sci. 2013, 14(3), 4655-4669; doi:10.3390/ijms14034655
Received: 1 November 2012 / Revised: 3 January 2013 / Accepted: 31 January 2013 / Published: 26 February 2013
Cited by 81 | PDF Full-text (250 KB) | HTML Full-text | XML Full-text
Abstract
Long non-coding RNAs (lncRNAs) are pervasively transcribed in the genome and are emerging as new players in tumorigenesis due to their various functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation. LncRNAs are deregulated in a number of cancers, demonstrating both oncogenic
[...] Read more.
Long non-coding RNAs (lncRNAs) are pervasively transcribed in the genome and are emerging as new players in tumorigenesis due to their various functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation. LncRNAs are deregulated in a number of cancers, demonstrating both oncogenic and tumor suppressive roles, thus suggesting their aberrant expression may be a substantial contributor in cancer development. In this review, we will summarize their emerging role in human cancer and discuss their perspectives in diagnostics as potential biomarkers. Full article
(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)
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