Non-Coding RNA — Open Access Journal

Cardiovascular disease (CVD) is a significant cause of morbidity and mortality across the world. A large proportion of CVD deaths are secondary to coronary artery disease (CAD) and myocardial infarction (MI). Even though prevention is the best strategy to reduce risk factors associated with MI, the use of cardioprotective interventions aimed at improving patient outcomes is of great interest. Opioid conditioning has been shown to be effective in reducing myocardial ischemia-reperfusion injury (IRI) and cardiomyocyte death. However, the molecular mechanisms behind these effects are under investigation and could provide the basis for the development of novel therapeutic approaches in the treatment of CVD. Non-coding RNAs (ncRNAs), which are functional RNA molecules that do not translate into proteins, are critical modulators of cardiac gene expression during heart development and disease. Moreover, ncRNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are known to be induced by opioid receptor activation and regulate opioid signaling pathways. Recent advances in experimental and computational tools have accelerated the discovery and functional characterization of ncRNAs. In this study, we review the current understanding of the role of ncRNAs in opioid signaling and opioid-induced cardioprotection. Full article

The landscape of somatic copy-number alterations (SCNAs) affecting long non-coding RNAs (lncRNAs) in human cancers remains largely unexplored. While the majority of lncRNAs remain to be functionally characterized, several have been implicated in cancer development and metastasis. Considering the plethora of lncRNAs genes that have been currently reported, it is conceivable that many more lncRNAs might function as oncogenes or tumor suppressor genes. We devised a strategy to detect focal lncRNA SCNAs using a custom DNA microarray platform probing 10,519 lncRNA genes. By screening a panel of 80 cancer cell lines, we detected numerous focal aberrations targeting one or multiple lncRNAs without affecting neighboring protein-coding genes. These focal aberrations are highly suggestive for a tumor suppressive or oncogenic role of the targeted lncRNA gene. Although functional validation remains an essential step in the further characterization of the involved candidate cancer lncRNAs, our results provide a direct way of prioritizing candidate lncRNAs that are involved in cancer pathogenesis. Full article

Formalin-fixed paraffin embedded (FFPE) tissues are a valuable resource for biomarker discovery in order to understand the etiology of different cancers and many other diseases. Proteins are the biomarkers of interest with respect to FFPE tissues as RNA degradation is the major challenge in these tissue samples. Recently, non-protein coding transcripts, long non-coding RNAs (lncRNAs), have gained significant attention due to their important biological actions and potential involvement in cancer. RNA sequencing (RNA-seq) or quantitative reverse transcription-polymerase chain reaction (qRT-PCR) are the only validated methods to evaluate and study lncRNA expression and neither of them provides visual representation as immunohistochemistry (IHC) provides for proteins. We have standardized and are reporting a sensitive Z probe based in situ hybridization method to visually identify and quantify lncRNA in FFPE tissues. This assay is highly sensitive and identifies transcripts visible within different cell types and tumors. We have detected a scarcely expressed tumor suppressor lncRNA NRON (non-coding repressor of nuclear factor of activated T-cells (NFAT)), a moderately expressed oncogenic lncRNA UCA1 (urothelial cancer associated 1), and a highly studied and expressed lncRNA MALAT1 (metastasis associated lung adenocarcinoma transcript 1) in different cancers. High MALAT1 staining was found in colorectal, breast and pancreatic cancer. Additionally, we have observed an increase in MALAT1 expression in different stages of colorectal cancer. Full article

Many mechanisms of obesity-induced cancers have been proposed. However, it remains unclear whether or not long non-coding RNAs (lncRNAs) play any role in obesity-induced cancers. In this article, we briefly discuss the generally accepted hypotheses explaining the mechanisms of obesity-induced cancers, summarize the latest evidence for the expression of a number of well-known cancer-associated lncRNAs in obese subjects, and propose the potential contribution of lncRNAs to obesity-induced cancers. We hope this review can serve as an inspiration to scientists to further explore the regulatory roles of lncRNAs in the development of obesity-induced cancers. Those findings will be fundamental in the development of effective therapeutics or interventions to combat this life-threatening adverse effect of obesity. Full article

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions ranging from hepatic steatosis to inflammation (nonalcoholic steatohepatitis or NASH) with or without fibrosis, in the absence of significant alcohol consumption. The presence of fibrosis in NASH patients is associated with greater liver-related morbidity and mortality; however, the molecular mechanisms underlying the development of fibrosis and cirrhosis in NAFLD patients remain poorly understood. Long non-coding RNAs (lncRNAs) are emerging as key contributors to biological processes that are underpinning the initiation and progression of NAFLD fibrosis. This review summarizes the experimental findings that have been obtained to date in animal models of liver fibrosis and NAFLD patients with fibrosis. We also discuss the potential applicability of circulating lncRNAs to serve as biomarkers for the diagnosis and prognosis of NAFLD fibrosis. A better understanding of the role played by lncRNAs in NAFLD fibrosis is critical for the identification of novel therapeutic targets for drug development and improved, noninvasive methods for disease diagnosis. Full article

Transcriptomic studies have demonstrated that the vast majority of the genomes of mammals and other complex organisms is expressed in highly dynamic and cell-specific patterns to produce large numbers of intergenic, antisense and intronic long non-protein-coding RNAs (lncRNAs). Despite well characterized examples, their scaling with developmental complexity, and many demonstrations of their association with cellular processes, development and diseases, lncRNAs are still to be widely accepted as major players in gene regulation. This may reflect an underappreciation of the extent and precision of the epigenetic control of differentiation and development, where lncRNAs appear to have a central role, likely as organizational and guide molecules: most lncRNAs are nuclear-localized and chromatin-associated, with some involved in the formation of specialized subcellular domains. I suggest that a reassessment of the conceptual framework of genetic information and gene expression in the 4-dimensional ontogeny of spatially organized multicellular organisms is required. Together with this and further studies on their biology, the key challenges now are to determine the structure–function relationships of lncRNAs, which may be aided by emerging evidence of their modular structure, the role of RNA editing and modification in enabling epigenetic plasticity, and the role of RNA signaling in transgenerational inheritance of experience. Full article

A family of long intergenic noncoding RNA (lincRNA) genes, FAM230 is formed via gene sequence duplication, specifically in human chromosomal low copy repeats (LCR) or segmental duplications. This is the first group of lincRNA genes known to be formed by segmental duplications and is consistent with current views of evolution and the creation of new genes via DNA low copy repeats. It appears to be an efficient way to form multiple lincRNA genes. But as these genes are in a critical chromosomal region with respect to the incidence of abnormal translocations and resulting genetic abnormalities, the 22q11.2 region, and also carry a translocation breakpoint motif, several intriguing questions arise concerning the presence and function of the translocation breakpoint sequence in RNA genes situated in LCR22s. Full article

Small non-coding RNAs are essential for transcription, translation and gene regulation in all cell types, but are particularly important in neurons, with known roles in neurodevelopment, neuroplasticity and neurological disease. Many small non-coding RNAs are directly involved in the post-transcriptional modification of other RNA species, while others are themselves substrates for modification, or are functionally modulated by modification of their target RNAs. In this review, we explore the known and potential functions of several distinct classes of small non-coding RNAs in the mammalian brain, focusing on the newly recognised interplay between the epitranscriptome and the activity of small RNAs. We discuss the potential for this relationship to influence the spatial and temporal dynamics of gene activation in the brain, and predict that further research in the field of epitranscriptomics will identify interactions between small RNAs and RNA modifications which are essential for higher order brain functions such as learning and memory. Full article

Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. It is characterized by the progressive loss of cell-to-cell contacts and actin cytoskeletal rearrangements, leading to filopodia formation and the progressive up-regulation of a mesenchymal gene expression pattern enabling cell migration. Epithelial-to-mesenchymal transition is already observed in early embryonic stages such as gastrulation, when the epiblast undergoes an EMT process and therefore leads to the formation of the third embryonic layer, the mesoderm. Epithelial-to-mesenchymal transition is pivotal in multiple embryonic processes, such as for example during cardiovascular system development, as valve primordia are formed and the cardiac jelly is progressively invaded by endocardium-derived mesenchyme or as the external cardiac cell layer is established, i.e., the epicardium and cells detached migrate into the embryonic myocardial to form the cardiac fibrous skeleton and the coronary vasculature. Strikingly, the most important biological event in which EMT is pivotal is cancer development and metastasis. Over the last years, understanding of the transcriptional regulatory networks involved in EMT has greatly advanced. Several transcriptional factors such as Snail, Slug, Twist, Zeb1 and Zeb2 have been reported to play fundamental roles in EMT, leading in most cases to transcriptional repression of cell–cell interacting proteins such as ZO-1 and cadherins and activation of cytoskeletal markers such as vimentin. In recent years, a fundamental role for non-coding RNAs, particularly microRNAs and more recently long non-coding RNAs, has been identified in normal tissue development and homeostasis as well as in several oncogenic processes. In this study, we will provide a state-of-the-art review of the functional roles of non-coding RNAs, particularly microRNAs, in epithelial-to-mesenchymal transition in both developmental and pathological EMT. Full article

Multifactorial diseases such as cancer, cardiovascular conditions and neurological, immunological and metabolic disorders are a group of diseases caused by the combination of genetic and environmental factors. High-throughput RNA sequencing (RNA-seq) technologies have revealed that less than 2% of the genome corresponds to protein-coding genes, although most of the human genome is transcribed. The other transcripts include a large variety of non-coding RNAs (ncRNAs), and the continuous generation of RNA-seq data shows that ncRNAs are strongly deregulated and may be important players in pathological processes. A specific class of ncRNAs, the long non-coding RNAs (lncRNAs), has been intensively studied in human diseases. For clinical purposes, lncRNAs may have advantages mainly because of their specificity and differential expression patterns, as well as their ideal qualities for diagnosis and therapeutics. Multifactorial diseases are the major cause of death worldwide and many aspects of their development are not fully understood. Recent data about lncRNAs has improved our knowledge and helped risk assessment and prognosis of these pathologies. This review summarizes the involvement of some lncRNAs in the most common multifactorial diseases, with a focus on those with published functional data. Full article

The expansion of long non-coding RNAs (lncRNAs) in organismal genomes has been associated with the emergence of sophisticated regulatory networks that may have contributed to more complex neuronal processes, such as higher-order cognition. In line with the important roles of lncRNAs in the normal functioning of the human brain, dysregulation of lncRNA expression has been implicated in aging and age-related neurodegenerative disorders. In this paper, we discuss the function and expression of known neuronal-associated lncRNAs, their impact on epigenetic changes, the contribution of transposable elements to lncRNA expression, and the implication of lncRNAs in maintaining the 3D nuclear architecture in neurons. Moreover, we discuss how the complex molecular processes that are orchestrated by lncRNAs in the aged brain may contribute to neuronal pathogenesis by promoting protein aggregation and neurodegeneration. Finally, this review explores the possibility that age-related disturbances of lncRNA expression change the genomic and epigenetic regulatory landscape of neurons, which may affect neuronal processes such as neurogenesis and synaptic plasticity. Full article

Schizophrenia is associated with diverse changes in the brain’s transcriptome and proteome. Underlying these changes is the complex dysregulation of gene expression and protein production that varies both spatially across brain regions and temporally with the progression of the illness. The growing body of literature showing changes in non-coding RNA in individuals with schizophrenia offers new insights into the mechanisms causing this dysregulation. A large number of studies have reported that the expression of microRNA (miRNA) is altered in the brains of individuals with schizophrenia. This evidence is complemented by findings that single nucleotide polymorphisms (SNPs) in miRNA host gene sequences can confer an increased risk of developing the disorder. Additionally, recent evidence suggests the expression of other non-coding RNAs, such as small nucleolar RNA and long non-coding RNA, may also be affected in schizophrenia. Understanding how these changes in non-coding RNAs contribute to the development and progression of schizophrenia offers potential avenues for the better treatment and diagnosis of the disorder. This review will focus on the evidence supporting the involvement of non-coding RNA in schizophrenia and its therapeutic potential. Full article

Hypoxia-regulated microRNA-210 (miR-210) is a highly conserved microRNA, known to regulate various processes under hypoxic conditions. Previously we found that miR-210 is also involved in honeybee learning and memory, raising the questions of how neural activity may induce hypoxia-regulated genes and how miR-210 may regulate plasticity in more complex mammalian systems. Using a pull-down approach, we identified 620 unique target genes of miR-210 in humans, among which there was a significant enrichment of age-related neurodegenerative pathways, including Huntington’s, Alzheimer’s, and Parkinson’s diseases. We have also validated that miR-210 directly regulates various identified target genes of interest involved with neuronal plasticity, neurodegenerative diseases, and miR-210-associated cancers. This data suggests a potentially novel mechanism for how metabolic changes may couple plasticity to neuronal activity through hypoxia-regulated genes such as miR-210. Full article

R-loops are evolutionarily conserved three-stranded structures that result from the formation of stable DNA:RNA hybrids in the genome. R-loops have attracted increasing interest in recent years as potent regulators of gene expression and genome stability. In particular, their strong association with severe replication stress makes them potential oncogenic structures. Despite their importance, the rules that govern their formation and their dynamics are still controversial and an in-depth description of their direct impact on chromatin organization and DNA transactions is still lacking. To better understand the diversity of R-loop functions, reliable, accurate, and quantitative mapping techniques, as well as functional assays are required. Here, I review the different approaches that are currently used to do so and to highlight their individual strengths and weaknesses. In particular, I review the advantages and disadvantages of using the S9.6 antibody to map R-loops in vivo in an attempt to propose guidelines for best practices. Full article

The nuclear RNA exosome is an essential and versatile machinery that regulates maturation and degradation of a huge plethora of RNA species. The past two decades have witnessed remarkable progress in understanding the whole picture of its RNA substrates and the structural basis of its functions. In addition to the exosome itself, recent studies focusing on associated co-factors have been elucidating how the exosome is directed towards specific substrates. Moreover, it has been gradually realized that loss-of-function of exosome subunits affect multiple biological processes, such as the DNA damage response, R-loop resolution, maintenance of genome integrity, RNA export, translation, and cell differentiation. In this review, we summarize the current knowledge of the mechanisms of nuclear exosome-mediated RNA metabolism and discuss their physiological significance. Full article

Long non-coding RNAs (lncRNAs) constitute non-protein coding transcripts with a size > than 200 nucleotides. They are involved in many cellular processes, such as chromatin remodelling, transcription, and gene expression. They play a role in the development, progression, and invasion of many human cancers, including osteosarcoma. This rare tumor entity predominantly arises in children and young adults. Treatment consists of polychemotherapy and surgical resection, increasing survival rates up to 60%. In the present review, the role of lncRNAs with prognostic, predictive, therapeutic, and diagnostic significance in osteosarcoma is discussed. Moreover, their potential application in clinical practice is highlighted. Full article

Although developmental regulation by long non-coding RNAs (lncRNAs) appears to be a widespread feature amongst animals, the origin and level of evolutionary conservation of this mode of regulation remain unclear. We have previously demonstrated that the sponge Amphimedon queenslandica—a morphologically-simple animal—developmentally expresses an array of lncRNAs in manner akin to more complex bilaterians (insects + vertebrates). Here, we first show that Amphimedon lncRNAs are expressed in specific cell types in larvae, juveniles and adults. Thus, as in bilaterians, sponge developmental regulation involves the dynamic, cell type- and context-specific regulation of specific lncRNAs. Second, by comparing gene co-expression networks between Amphimedon queenslandica and Sycon ciliatum—a distantly-related calcisponge—we identify several putative co-expression modules that appear to be shared in sponges; these network-embedded sponge lncRNAs have no discernable sequence similarity. Together, these results suggest sponge lncRNAs are developmentally regulated and operate in conserved gene regulatory networks, as appears to be the case in more complex bilaterians. Full article

Micro-RNAs (miRNAs) are small non-coding RNAs that act as negative regulators of the genomic output. Their intrinsic importance within cell biology and human disease is well known. Their mechanism of action based on the base pairing binding to their cognate targets have helped the development not only of many computer applications for the prediction of miRNA target recognition but also of specific applications for functional assessment and analysis. Learning about miRNA function requires practical training in the use of specific computer and web-based applications that are complementary to wet-lab studies. In order to guide the learning process about miRNAs, we have created miRNAtools (http://mirnatools.eu), a web repository of miRNA tools and tutorials. This article compiles tools with which miRNAs and their regulatory action can be analyzed and that function to collect and organize information dispersed on the web. The miRNAtools website contains a collection of tutorials that can be used by students and tutors engaged in advanced training courses. The tutorials engage in analyses of the functions of selected miRNAs, starting with their nomenclature and genomic localization and finishing with their involvement in specific cellular functions. Full article

Undifferentiated large cell lung carcinoma (LCLC) accounts for 2.9–9% of total lung cancers. Recently, RNA-seq based studies have revealed major genomic aberrations in LCLC. In this study, we aim to identify long non-coding RNAs (LncRNAs) expression pattern specific to LCLC. The RNA-seq profile of LCLC and other non-small cell lung carcinoma (NSCLC) was downloaded from Gene Expression Omnibus (GEO) and analyzed. Using 10 LCLC samples, we found that 18% of all the annotated LncRNAs are expressed in LCLC samples. Among 1794 expressed LncRNAs, 11 were overexpressed and 14 were downregulated in LCLC compared to normal samples. Based on receiver operating characteristic (ROC) analysis, we showed that the top five differentially expressed LncRNAs were able to differentiate between LCLC and normal samples with high sensitivity and specificity. Guilt by association analysis using genes correlating with differentially expressed LncRNAs identified several cancer-associated pathways, suggesting the role of these deregulated LncRNA in LCLC biology. We also identified the LncRNA differentially expressed in LCLC compared to lung squamous carcinoma (LUSC) and Lung-adenocarcinoma (LUAD). We found that LCLC sample showed more deregulated LncRNA in LUSC than LUAD. Interestingly, LCLC had more downregulated LncRNA compared to LUAD and LUSC. Our study provides novel insight into LncRNA deregulation in LCLC. This study also finds tools to diagnose LCLC and differentiate LCLC with other Non-Small Cell Lung Cancer. Full article