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Sample records for screening non-coding rnas

  1. From structure prediction to genomic screens for novel non-coding RNAs.

    PubMed

    Gorodkin, Jan; Hofacker, Ivo L

    2011-08-01

    Non-coding RNAs (ncRNAs) are receiving more and more attention not only as an abundant class of genes, but also as regulatory structural elements (some located in mRNAs). A key feature of RNA function is its structure. Computational methods were developed early for folding and prediction of RNA structure with the aim of assisting in functional analysis. With the discovery of more and more ncRNAs, it has become clear that a large fraction of these are highly structured. Interestingly, a large part of the structure is comprised of regular Watson-Crick and GU wobble base pairs. This and the increased amount of available genomes have made it possible to employ structure-based methods for genomic screens. The field has moved from folding prediction of single sequences to computational screens for ncRNAs in genomic sequence using the RNA structure as the main characteristic feature. Whereas early methods focused on energy-directed folding of single sequences, comparative analysis based on structure preserving changes of base pairs has been efficient in improving accuracy, and today this constitutes a key component in genomic screens. Here, we cover the basic principles of RNA folding and touch upon some of the concepts in current methods that have been applied in genomic screens for de novo RNA structures in searches for novel ncRNA genes and regulatory RNA structure on mRNAs. We discuss the strengths and weaknesses of the different strategies and how they can complement each other.

  2. lncRNA-screen: an interactive platform for computationally screening long non-coding RNAs in large genomics datasets.

    PubMed

    Gong, Yixiao; Huang, Hsuan-Ting; Liang, Yu; Trimarchi, Thomas; Aifantis, Iannis; Tsirigos, Aristotelis

    2017-06-05

    Long non-coding RNAs (lncRNAs) have emerged as a class of factors that are important for regulating development and cancer. Computational prediction of lncRNAs from ultra-deep RNA sequencing has been successful in identifying candidate lncRNAs. However, the complexity of handling and integrating different types of genomics data poses significant challenges to experimental laboratories that lack extensive genomics expertise. To address this issue, we have developed lncRNA-screen, a comprehensive pipeline for computationally screening putative lncRNA transcripts over large multimodal datasets. The main objective of this work is to facilitate the computational discovery of lncRNA candidates to be further examined by functional experiments. lncRNA-screen provides a fully automated easy-to-run pipeline which performs data download, RNA-seq alignment, assembly, quality assessment, transcript filtration, novel lncRNA identification, coding potential estimation, expression level quantification, histone mark enrichment profile integration, differential expression analysis, annotation with other type of segmented data (CNVs, SNPs, Hi-C, etc.) and visualization. Importantly, lncRNA-screen generates an interactive report summarizing all interesting lncRNA features including genome browser snapshots and lncRNA-mRNA interactions based on Hi-C data. lncRNA-screen provides a comprehensive solution for lncRNA discovery and an intuitive interactive report for identifying promising lncRNA candidates. lncRNA-screen is available as open-source software on GitHub.

  3. Non-coding RNAs as antibiotic targets.

    PubMed

    Colameco, Savannah; Elliot, Marie A

    2016-12-22

    Antibiotics inhibit a wide range of essential processes in the bacterial cell, including replication, transcription, translation and cell wall synthesis. In many instances, these antibiotics exert their effects through association with non-coding RNAs. This review highlights many classical antibiotic targets (e.g. rRNAs and the ribosome), explores a number of emerging targets (e.g. tRNAs, RNase P, riboswitches and small RNAs), and discusses the future directions and challenges associated with non-coding RNAs as antibiotic targets.

  4. Genome-scale deletion screening of human long non-coding RNAs using a paired-guide RNA CRISPR-Cas9 library.

    PubMed

    Zhu, Shiyou; Li, Wei; Liu, Jingze; Chen, Chen-Hao; Liao, Qi; Xu, Ping; Xu, Han; Xiao, Tengfei; Cao, Zhongzheng; Peng, Jingyu; Yuan, Pengfei; Brown, Myles; Liu, Xiaole Shirley; Wei, Wensheng

    2016-12-01

    CRISPR-Cas9 screens have been widely adopted to analyze coding-gene functions, but high-throughput screening of non-coding elements using this method is more challenging because indels caused by a single cut in non-coding regions are unlikely to produce a functional knockout. A high-throughput method to produce deletions of non-coding DNA is needed. We report a high-throughput genomic deletion strategy to screen for functional long non-coding RNAs (lncRNAs) that is based on a lentiviral paired-guide RNA (pgRNA) library. Applying our screening method, we identified 51 lncRNAs that can positively or negatively regulate human cancer cell growth. We validated 9 of 51 lncRNA hits using CRISPR-Cas9-mediated genomic deletion, functional rescue, CRISPR activation or inhibition and gene-expression profiling. Our high-throughput pgRNA genome deletion method will enable rapid identification of functional mammalian non-coding elements.

  5. Non-coding RNAs: An Introduction.

    PubMed

    Yang, Jennifer X; Rastetter, Raphael H; Wilhelm, Dagmar

    2016-01-01

    For many years the main role of RNA, it addition to the housekeeping functions of for example tRNAs and rRNAs, was believed to be a messenger between the genes encoded on the DNA and the functional units of the cell, the proteins. This changed drastically with the identification of the first small non-coding RNA, termed microRNA, some 20 years ago. This discovery opened the field of regulatory RNAs with no or little protein-coding potential. Since then many new classes of regulatory non-coding RNAs, including endogenous small interfering RNAs (endo-siRNAs), PIWI-associated RNAs (piRNAs), and long non-coding RNAs, have been identified and we have made amazing progress in elucidating their expression, biogenesis, mechanisms and mode of action, and function in many, if not all, biological processes. In this chapter we provide an introduction about the current knowledge of the main classes of non-coding RNAs, what is know about their biogenesis and mechanism of function.

  6. The non-coding RNAs as riboregulators.

    PubMed

    Erdmann, V A; Barciszewska, M Z; Szymanski, M; Hochberg, A; de Groot, N; Barciszewski, J

    2001-01-01

    The non-coding RNAs database (http://biobases.ibch.poznan.pl/ncRNA/) contains currently available data on RNAs, which do not have long open reading frames and act as riboregulators. Non-coding RNAs are involved in the specific recognition of cellular nucleic acid targets through complementary base pairing to control cell growth and differentiation. Some of them are connected with several well known developmental and neuro-behavioral disorders. We have divided them into four groups. This paper is a short introduction to the database and presents its latest, updated edition.

  7. Non-coding RNAs in cardiac hypertrophy.

    PubMed

    Ottaviani, Lara; da Costa Martins, Paula A

    2017-02-23

    Heart Failure is one of the largest contributors to disease burden and healthcare outflow in the Western world. Despite significant progress in the treatment of heart failure, disease prognosis remains very poor with the only curative therapy still being heart transplantation. To counteract the current situation, efforts have been made to better understand the underlying molecular pathways in the progression of cardiac disease towards heart failure, and to link the disease to novel therapeutic targets such as non-coding RNAs. The non-coding part of the genome has gained prominence over the last couple of decades by opening a completely new research field and having established different non-coding RNAs species as fundamental regulators of cellular functions. Not surprisingly, their dysregulation is increasingly being linked to pathology, including to cardiac disease. Pre-clinically, non-coding RNAs have been shown to be of great value as therapeutic targets in pathological cardiac remodelling and also as diagnostic/prognostic biomarkers for heart failure. Therefore, it is to expect that non-coding RNA-based therapeutic strategies will reach the bedside in the future and provide new and more efficient treatments for heart failure. Here, we review recent discoveries linking the function and molecular interactions of non-coding RNAs with the pathophysiology of cardiac hypertrophy and heart failure. This article is protected by copyright. All rights reserved.

  8. Non-coding RNAs and gastric cancer

    PubMed Central

    Li, Pei-Fei; Chen, Sheng-Can; Xia, Tian; Jiang, Xiao-Ming; Shao, Yong-Fu; Xiao, Bing-Xiu; Guo, Jun-Ming

    2014-01-01

    Non-coding RNAs (ncRNAs) play key roles in development, proliferation, differentiation and apoptosis. Altered ncRNA expression is associated with gastric cancer occurrence, invasion, and metastasis. Moreover, aberrant expression of microRNAs (miRNAs) is significantly related to gastric cancer tumor stage, size, differentiation and metastasis. MiRNAs interrupt cellular signaling pathways, inhibit the activity of tumor suppressor genes, and affect the cell cycle in gastric cancer cells. Some miRNAs, including miR-21, miR-106a and miR-421, could be potential markers for the diagnosis of gastric cancer. Long non-coding RNAs (lncRNAs), a new research hotspot among cancer-associated ncRNAs, play important roles in epigenetic, transcriptional and post-transcriptional regulation. Several gastric cancer-associated lncRNAs, such as CCAT1, GACAT1, H19, and SUMO1P3, have been explored. In addition, Piwi-interacting RNAs, another type of small ncRNA that is recognized by gastroenterologists, are involved in gastric carcinogenesis, and piR-651/823 represents an efficient diagnostic biomarker of gastric cancer that can be detected in the blood and gastric juice. Small interfering RNAs also function in post-transcriptional regulation in gastric cancer and might be useful in gastric cancer treatment. PMID:24833871

  9. Screening of crucial long non-coding RNAs in oral epithelial dysplasia by serial analysis of gene expression.

    PubMed

    Han, X; Wei, Y B; Tian, G; Tang, Z; Gao, J Y; Xu, X G

    2015-10-02

    Oral epithelial dysplasia (OED) is a premalignant lesion of the oral mucosa. Considering the poor 5-year survival rate of oral cancer, further investigation is needed in order to determine the pathogenesis of OED. In the present study, serial analysis of gene expression (SAGE) data from patients with OED were compared to normal controls to identify differentially expressed genes (DEGs). SAGE data were obtained from the Gene Expression Omnibus, and included samples from patients with mild, moderate, or severe dysplasia. The DEGs were identified using the edgeR software package and functional-enrichment analysis was performed with the DAVID (https://david.ncifcrf.gov/) software program. The co-expression network was constructed using the CoExpress software and target genes of long non-coding RNAs (lncRNAs) were predicted according to the proximity between the lncRNAs and mRNAs in the genome. A total of 517 DEGs were identified, including 409 mRNAs and 108 lncRNAs. Functional-enrichment analysis showed that mRNAs and lncRNAs involved in epithelial cell differentiation, epithelium development, and epidermal cell differentiation were significantly enriched in the DEGs. Thirty-eight potential regulatory relationships were unveiled between lncRNAs and mRNAs, and two subnetworks were discovered by analyzing the topological properties of the co-expression network. In conclusion, we have identified key mRNAs and lncRNAs in OED, and these findings may aid in understanding the pathogenesis of OED and advance potential future treatments.

  10. Non-coding RNAs and atherosclerosis

    PubMed Central

    Fernández-Hernando, Carlos

    2014-01-01

    Non-coding RNAs (ncRNAs) represent a class of RNA molecules that typically do not code for proteins. Emerging data suggest that ncRNAs play an important role in several physiological and pathological conditions such as cancer and cardiovascular diseases (CVDs) including atherosclerosis. The best-characterized ncRNAs are the microRNAs (miRNAs), which are small, ~22 nucleotide (nt) sequences of RNA that regulate gene expression at the posttranscriptional level through transcript degradation or translational repression. MiRNAs control several aspects of atherosclerosis including endothelial cell, vascular smooth cell, and macrophage functions as well as lipoprotein metabolism. Apart from miRNAs, recently ncRNAs, especially long ncRNAs (lncRNAs), have emerged as important potential regulators of the progression of atherosclerosis. However, the molecular mechanism of their regulation and function as well as significance of other ncRNAs such as small nucleolar RNAs (snoRNAs) during atherogenesis is largely unknown. In this review, we summarize the recent findings in the field, highlighting the importance of ncRNAs in atherosclerosis and discuss their potential use as therapeutic targets in CVDs. PMID:24623179

  11. Dysregulation of non-coding RNAs in gastric cancer

    PubMed Central

    Yang, Qing; Zhang, Ren-Wen; Sui, Peng-Cheng; He, Hai-Tao; Ding, Lei

    2015-01-01

    Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC. PMID:26494954

  12. Non-coding RNAs in cardiovascular ageing.

    PubMed

    Gupta, Shashi Kumar; Piccoli, Maria Teresa; Thum, Thomas

    2014-09-01

    The increasing burden of ageing populations and their healthcare expenditure is a major challenge worldwide. Ageing is a complex disorder and can be defined as progressive decline in function with time leading to increased incidence of various cardiovascular, neurological and immunological diseases. The human genome comprises of many protein coding and even more non-coding RNA genes. MicroRNAs, a class of non-coding RNA, regulate the expression of multiple messenger RNAs post-transcriptionally and are reported to be involved in crucial aspects of cell biology encompassing ageing. Recently, several studies have reported the regulation of microRNAs with ageing and microRNAs like miR-34 have emerged as critical regulator of ageing extending from Caenorhabditis elegans to mammals. Here, we summarize the reported role of microRNAs as well as long noncoding RNAs (lncRNAs) in the process of ageing with a special emphasis on cardiovascular ageing. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Non-coding RNAs in Mammary Gland Development and Disease.

    PubMed

    Sandhu, Gurveen K; Milevskiy, Michael J G; Wilson, Wesley; Shewan, Annette M; Brown, Melissa A

    2016-01-01

    Non-coding RNAs (ncRNAs) are untranslated RNA molecules that function to regulate the expression of numerous genes and associated biochemical pathways and cellular functions. NcRNAs include small interfering RNAs (siRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and long non-coding RNAs (lncRNAs). They participate in the regulation of all developmental processes and are frequently aberrantly expressed or functionally defective in disease. This Chapter will focus on the role of ncRNAs, in particular miRNAs and lncRNAs, in mammary gland development and disease.

  14. Non-coding RNAs in lung cancer

    PubMed Central

    Ricciuti, Biagio; Mecca, Carmen; Crinò, Lucio; Baglivo, Sara; Cenci, Matteo; Metro, Giulio

    2014-01-01

    The discovery that protein-coding genes represent less than 2% of all human genome, and the evidence that more than 90% of it is actively transcribed, changed the classical point of view of the central dogma of molecular biology, which was always based on the assumption that RNA functions mainly as an intermediate bridge between DNA sequences and protein synthesis machinery. Accumulating data indicates that non-coding RNAs are involved in different physiological processes, providing for the maintenance of cellular homeostasis. They are important regulators of gene expression, cellular differentiation, proliferation, migration, apoptosis, and stem cell maintenance. Alterations and disruptions of their expression or activity have increasingly been associated with pathological changes of cancer cells, this evidence and the prospect of using these molecules as diagnostic markers and therapeutic targets, make currently non-coding RNAs among the most relevant molecules in cancer research. In this paper we will provide an overview of non-coding RNA function and disruption in lung cancer biology, also focusing on their potential as diagnostic, prognostic and predictive biomarkers. PMID:25593996

  15. Functional roles of non-coding Y RNAs.

    PubMed

    Kowalski, Madzia P; Krude, Torsten

    2015-09-01

    Non-coding RNAs are involved in a multitude of cellular processes but the biochemical function of many small non-coding RNAs remains unclear. The family of small non-coding Y RNAs is conserved in vertebrates and related RNAs are present in some prokaryotic species. Y RNAs are also homologous to the newly identified family of non-coding stem-bulge RNAs (sbRNAs) in nematodes, for which potential physiological functions are only now emerging. Y RNAs are essential for the initiation of chromosomal DNA replication in vertebrates and, when bound to the Ro60 protein, they are involved in RNA stability and cellular responses to stress in several eukaryotic and prokaryotic species. Additionally, short fragments of Y RNAs have recently been identified as abundant components in the blood and tissues of humans and other mammals, with potential diagnostic value. While the number of functional roles of Y RNAs is growing, it is becoming increasingly clear that the conserved structural domains of Y RNAs are essential for distinct cellular functions. Here, we review the biochemical functions associated with these structural RNA domains, as well as the functional conservation of Y RNAs in different species. The existing biochemical and structural evidence supports a domain model for these small non-coding RNAs that has direct implications for the modular evolution of functional non-coding RNAs.

  16. Perspectives of Long Non-Coding RNAs in Cancer Diagnostics

    PubMed Central

    Reis, Eduardo M.; Verjovski-Almeida, Sergio

    2012-01-01

    Long non-coding RNAs (lncRNAs) transcribed from intergenic and intronic regions of the human genome constitute a broad class of cellular transcripts that are under intensive investigation. While only a handful of lncRNAs have been characterized, their involvement in fundamental cellular processes that control gene expression highlights a central role in cell homeostasis. Not surprisingly, aberrant expression of regulatory lncRNAs has been increasingly documented in different types of cancer, where they can mediate both oncogenic or tumor suppressor effects. Interaction with chromatin remodeling complexes that promote silencing of specific genes or modulation of splicing factor proteins seem to be two general modes of lncRNA regulation, but it is conceivable that additional mechanisms of action are yet to be unveiled. LncRNAs show greater tissue specificity compared to protein-coding mRNAs making them attractive in the search of novel diagnostics/prognostics cancer biomarkers in body fluid samples. In fact, lncRNA prostate cancer antigen 3 can be detected in urine samples and has been shown to improve diagnosis of prostate cancer. We suggest that an unbiased screening of the presence of RNAs in easily accessible body fluids such as serum and urine might reveal novel circulating lncRNAs as potential biomarkers in many types of cancer. Annotation and functional characterization of the lncRNA complement of the cancer transcriptome will conceivably provide new venues for early diagnosis and treatment of the disease. PMID:22408643

  17. Role of Long Non-Coding RNAs in Prostate Cancer

    DTIC Science & Technology

    2013-09-01

    other non-coding RNAs such as long non-coding RNAs (>200 bases) ( lncRNAs ), which could account for 4-9% of transcripts in human genome. In this...application we proposed to test whether lncRNAs are dysregulated in prostate cancer. We demonstrated that lncRNA GAS5 is a direct target for miR-21...Together, our study suggests that lncRNAs are important players in prostate cancer biology, and further characterization of these lncRNAs will provide a

  18. Long non-coding RNAs in cancer metabolism.

    PubMed

    Xiao, Zhen-Dong; Zhuang, Li; Gan, Boyi

    2016-10-01

    Altered cellular metabolism is an emerging hallmark of cancer. Accumulating recent evidence links long non-coding RNAs (lncRNAs), a still poorly understood class of non-coding RNAs, to cancer metabolism. Here we review the emerging findings on the functions of lncRNAs in cancer metabolism, with particular emphasis on how lncRNAs regulate glucose and glutamine metabolism in cancer cells, discuss how lncRNAs regulate various aspects of cancer metabolism through their cross-talk with other macromolecules, explore the mechanistic conceptual framework of lncRNAs in reprogramming metabolism in cancers, and highlight the challenges in this field. A more in-depth understanding of lncRNAs in cancer metabolism may enable the development of novel and effective therapeutic strategies targeting cancer metabolism.

  19. Non-coding RNAs in chromatin disease involving neurological defects

    PubMed Central

    Della Ragione, Floriana; Gagliardi, Miriam; D'Esposito, Maurizio; Matarazzo, Maria R.

    2014-01-01

    Novel classes of small and long non-coding RNAs (ncRNAs) are increasingly becoming apparent, being engaged in diverse structural, functional and regulatory activities. They take part in target gene silencing, play roles in transcriptional, post-transcriptional and epigenetic processes, such as chromatin remodeling, nuclear reorganization with the formation of silent compartments and fine-tuning of gene recruitment into them. Among their functions, non-coding RNAs are thought to act either as guide or scaffold for epigenetic modifiers that write, erase, and read the epigenetic signature over the genome. Studies on human disorders caused by defects in epigenetic modifiers and involving neurological phenotypes highlight the disruption of diverse classes of non-coding RNAs. Noteworthy, these molecules mediate a wide spectrum of neuronal functions, including brain development, and synaptic plasticity. These findings imply a significant contribution of ncRNAs in pathophysiology of the aforesaid diseases and provide new concepts for potential therapeutic applications. PMID:24616662

  20. Decoding the function of nuclear long non-coding RNAs.

    PubMed

    Chen, Ling-Ling; Carmichael, Gordon G

    2010-06-01

    Long non-coding RNAs (lncRNAs) are mRNA-like, non-protein-coding RNAs that are pervasively transcribed throughout eukaryotic genomes. Rather than silently accumulating in the nucleus, many of these are now known or suspected to play important roles in nuclear architecture or in the regulation of gene expression. In this review, we highlight some recent progress in how lncRNAs regulate these important nuclear processes at the molecular level. Copyright 2010 Elsevier Ltd. All rights reserved.

  1. Genome-wide screening and characterization of long non-coding RNAs involved in flowering development of trifoliate orange (Poncirus trifoliata L. Raf.)

    PubMed Central

    Wang, Chen-Yang; Liu, Sheng-Rui; Zhang, Xiao-Yu; Ma, Yu-Jiao; Hu, Chun-Gen; Zhang, Jin-Zhi

    2017-01-01

    Long non-coding RNAs (lncRNAs) have been demonstrated to play critical regulatory roles in post-transcriptional and transcriptional regulation in Arabidopsis. However, lncRNAs and their functional roles remain poorly characterized in woody plants, including citrus. To identify lncRNAs and investigate their role in citrus flowering, paired-end strand-specific RNA sequencing was performed for precocious trifoliate orange and its wild-type counterpart. A total of 6,584 potential lncRNAs were identified, 51.6% of which were from intergenic regions. Additionally, 555 lncRNAs were significantly up-regulated and 276 lncRNAs were down-regulated in precocious trifoliate orange, indicating that lncRNAs could be involved in the regulation of trifoliate orange flowering. Comparisons between lncRNAs and coding genes indicated that lncRNAs tend to have shorter transcripts and lower expression levels and that they display significant expression specificity. More importantly, 59 and 7 lncRNAs were identified as putative targets and target mimics of citrus miRNAs, respectively. In addition, the targets of Pt-miR156 and Pt-miR396 were confirmed using the regional amplification reverse-transcription polymerase chain reaction method. Furthermore, overexpression of Pt-miR156a1 and Pt-miR156a1 in Arabidopsis resulted in an extended juvenile phase, short siliques, and smaller leaves in transgenic plants compared with control plants. These findings provide important insight regarding citrus lncRNAs, thus enabling in-depth functional analyses. PMID:28233798

  2. Long Non-coding RNAs in the Cytoplasm.

    PubMed

    Rashid, Farooq; Shah, Abdullah; Shan, Ge

    2016-04-01

    An enormous amount of long non-coding RNAs (lncRNAs) transcribed from eukaryotic genome are important regulators in different aspects of cellular events. Cytoplasm is the residence and the site of action for many lncRNAs. The cytoplasmic lncRNAs play indispensable roles with multiple molecular mechanisms in animal and human cells. In this review, we mainly talk about functions and the underlying mechanisms of lncRNAs in the cytoplasm. We highlight relatively well-studied examples of cytoplasmic lncRNAs for their roles in modulating mRNA stability, regulating mRNA translation, serving as competing endogenous RNAs, functioning as precursors of microRNAs, and mediating protein modifications. We also elaborate the perspectives of cytoplasmic lncRNA studies. Copyright © 2016 Beijing Institute of Genomics, Chinese Academy of Sciences and Genetics Society of China. Production and hosting by Elsevier Ltd.. All rights reserved.

  3. IRNdb: the database of immunologically relevant non-coding RNAs

    PubMed Central

    Denisenko, Elena; Ho, Daniel; Tamgue, Ousman; Ozturk, Mumin; Suzuki, Harukazu; Brombacher, Frank; Guler, Reto; Schmeier, Sebastian

    2016-01-01

    MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs) and other functional non-coding RNAs (ncRNAs) have emerged as pivotal regulators involved in multiple biological processes. Recently, ncRNA control of gene expression has been identified as a critical regulatory mechanism in the immune system. Despite the great efforts made to discover and characterize ncRNAs, the functional role for most remains unknown. To facilitate discoveries in ncRNA regulation of immune system-related processes, we developed the database of immunologically relevant ncRNAs and target genes (IRNdb). We integrated mouse data on predicted and experimentally supported ncRNA-target interactions, ncRNA and gene annotations, biological pathways and processes and experimental data in a uniform format with a user-friendly web interface. The current version of IRNdb documents 12 930 experimentally supported miRNA-target interactions between 724 miRNAs and 2427 immune-related mouse targets. In addition, we recorded 22 453 lncRNA-immune target and 377 PIWI-interacting RNA-immune target interactions. IRNdb is a comprehensive searchable data repository which will be of help in studying the role of ncRNAs in the immune system. Database URL: http://irndb.org

  4. Functions of plants long non-coding RNAs.

    PubMed

    Shafiq, Sarfraz; Li, Jingrui; Sun, Qianwen

    2016-01-01

    Long non-coding RNAs (lncRNAs) have been emerged as important players for various biological pathways, including dosage compensation, genomic imprinting, chromatin regulation, alternative splicing and nuclear organization. A large number of lncRNAs had already been identified by different approaches in plants, while the functions of only a few of them have been investigated. This review will summarize our current understanding of a wide range of plant lncRNAs functions, and highlight their roles in the regulation of diverse pathways in plants. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa.

  5. Cell cycle regulation by long non-coding RNAs.

    PubMed

    Kitagawa, Masatoshi; Kitagawa, Kyoko; Kotake, Yojiro; Niida, Hiroyuki; Ohhata, Tatsuya

    2013-12-01

    The mammalian cell cycle is precisely controlled by cyclin-dependent kinases (CDKs) and related pathways such as the RB and p53 pathways. Recent research on long non-coding RNAs (lncRNAs) indicates that many lncRNAs are involved in the regulation of critical cell cycle regulators such as the cyclins, CDKs, CDK inhibitors, pRB, and p53. These lncRNAs act as epigenetic regulators, transcription factor regulators, post-transcription regulators, and protein scaffolds. These cell cycle-regulated lncRNAs mainly control cellular levels of cell cycle regulators via various mechanisms, and may provide diversity and reliability to the general cell cycle. Interestingly, several lncRNAs are induced by DNA damage and participate in cell cycle arrest or induction of apoptosis as DNA damage responses. Therefore, deregulations of these cell cycle regulatory lncRNAs may be involved in tumorigenesis, and they are novel candidate molecular targets for cancer therapy and diagnosis.

  6. Long Non-coding RNAs and Drug Resistance.

    PubMed

    Pan, Jing-Jing; Xie, Xiao-Juan; Li, Xu; Chen, Wei

    2015-01-01

    Long non-coding RNAs (lncRNAs) are emerging as key players in gene expression that govern cell developmental processes, and thus contributing to diseases, especially cancers. Many studies have suggested that aberrant expression of lncRNAs is responsible for drug resistance, a substantial obstacle for cancer therapy. Drug resistance not only results from individual variations in patients, but also from genetic and epigenetic differences in tumors. It is reported that drug resistance is tightly modulated by lncRNAs which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, and drug metabolism. In this review, we summarize recent advances in research on lncRNAs associated with drug resistance and underlying molecular or cellular mechanisms, which may contribute helpful approaches for the development of new therapeutic strategies to overcome treatment failure.

  7. Biocomputational prediction of small non-coding RNAs in Streptomyces

    PubMed Central

    Pánek, Josef; Bobek, Jan; Mikulík, Karel; Basler, Marek; Vohradský, Jiří

    2008-01-01

    Background The first systematic study of small non-coding RNAs (sRNA, ncRNA) in Streptomyces is presented. Except for a few exceptions, the Streptomyces sRNAs, as well as the sRNAs in other genera of the Actinomyces group, have remained unstudied. This study was based on sequence conservation in intergenic regions of Streptomyces, localization of transcription termination factors, and genomic arrangement of genes flanking the predicted sRNAs. Results Thirty-two potential sRNAs in Streptomyces were predicted. Of these, expression of 20 was detected by microarrays and RT-PCR. The prediction was validated by a structure based computational approach. Two predicted sRNAs were found to be terminated by transcription termination factors different from the Rho-independent terminators. One predicted sRNA was identified computationally with high probability as a Streptomyces 6S RNA. Out of the 32 predicted sRNAs, 24 were found to be structurally dissimilar from known sRNAs. Conclusion Streptomyces is the largest genus of Actinomyces, whose sRNAs have not been studied. The Actinomyces is a group of bacterial species with unique genomes and phenotypes. Therefore, in Actinomyces, new unique bacterial sRNAs may be identified. The sequence and structural dissimilarity of the predicted Streptomyces sRNAs demonstrated by this study serve as the first evidence of the uniqueness of Actinomyces sRNAs. PMID:18477385

  8. The roles of non-coding RNAs in Parkinson's disease.

    PubMed

    Majidinia, Maryam; Mihanfar, Aynaz; Rahbarghazi, Reza; Nourazarian, Alireza; Bagca, BakiyeGoker; Avci, Çığır Biray

    2016-11-01

    Parkinson's disease (PD) is considered as a high prevalence neurodegenerative disorders worldwide. Pathologically, the demise of dopamine-producing cells, in large part due to an abnormal accumulation of the α-synuclein in the substantia nigra, is one of the main causes of the disease. Up until now, many de novo investigations have been conducted to disclose the mechanisms underlying in PD. Among them, impacts of non-coding RNAs (ncRNAs) on the pathogenesis and/or progression of PD need to be highlighted. microRNAs (miRNAs) and long ncRNAs (lncRNAs) are more noteworthy in this context. miRNAs are small ncRNAs (with 18-25 nucleotide in length) that control the expression of multiple genes at post-transcriptional level, while lncRNAs have longer size (over 200 nucleotides) and are involved in some key biological processes through various mechanisms. Involvement of miRNAs has been well documented in the development of PD, particularly gene expression. Hence, in this current review, we will discuss the impacts of miRNAs in regulation of the expression of PD-related genes and the role of lncRNAs in the pathogenesis of PD.

  9. Non-coding RNAs in Uterine Development, Function and Disease

    PubMed Central

    2016-01-01

    The major function of the uterus is to accept and provide a suitable environment for an embryo, ultimately leading the birth of offspring and successful propagation of the species. For this occur, there must be precise coordination of hormonal signalling within both the endometrial and myometrial components of this organ. Non-coding RNAs, specifically, microRNAs (miRNAs) have been shown to be essential for normal uterine development and function. Within this organ, miRNAs are proposed to fine-tune the actions of the female steroid hormones estradiol and progesterone. Not surprising, mis-expression of miRNAs has been documented in diseases of the endometrium and myometrium such as endometriosis and leiomyomas, respectively. In this chapter, I will review the current understanding on the role, regulation and function of non-coding RNAs focusing on miRNAs in both the normal physiology of the endometrium and myometrium as well as in pathologies of these tissues, namely endometriosis and leiomyomas. PMID:26659492

  10. Non-coding Y RNAs as tethers and gates

    PubMed Central

    Wolin, Sandra L; Belair, Cedric; Boccitto, Marco; Chen, Xinguo; Sim, Soyeong; Taylor, David W; Wang, Hong-Wei

    2013-01-01

    Non-coding RNAs (ncRNAs) called Y RNAs are abundant components of both animal cells and a variety of bacteria. In all species examined, these ~100 nt RNAs are bound to the Ro 60 kDa (Ro60) autoantigen, a ring-shaped protein that also binds misfolded ncRNAs in some vertebrate nuclei. Although the function of Ro60 RNPs has been mysterious, we recently reported that a bacterial Y RNA tethers Ro60 to the 3′ to 5′ exoribonuclease polynucleotide phosphorylase (PNPase) to form RYPER (Ro60/Y RNA/PNPase Exoribonuclease RNP), a new RNA degradation machine. PNPase is a homotrimeric ring that degrades single-stranded RNA, and Y RNA-mediated tethering of Ro60 increases the effectiveness of PNPase in degrading structured RNAs. Single particle electron microscopy of RYPER suggests that RNA threads through the Ro60 ring into the PNPase cavity. Further studies indicate that Y RNAs may also act as gates to regulate entry of RNA substrates into the Ro60 channel. These findings reveal novel functions for Y RNAs and raise questions about how the bacterial findings relate to the roles of these ncRNAs in animal cells. Here we review the literature on Y RNAs, highlighting their close relationship with Ro60 proteins and the hypothesis that these ncRNAs function generally to tether Ro60 rings to diverse RNA-binding proteins. PMID:24036917

  11. Non-coding RNAs in cancer brain metastasis.

    PubMed

    Wu, Kerui; Sharma, Sambad; Venkat, Suresh; Liu, Keqin; Zhou, Xiaobo; Watabe, Kounosuke

    2016-01-01

    More than 90% of cancer death is attributed to metastatic disease, and the brain is one of the major metastatic sites of melanoma, colon, renal, lung and breast cancers. Despite the recent advancement of targeted therapy for cancer, the incidence of brain metastasis is increasing. One reason is that most therapeutic drugs can't penetrate blood-brain-barrier and tumor cells find the brain as sanctuary site. In this review, we describe the pathophysiology of brain metastases to introduce the latest understandings of metastatic brain malignancies. This review also particularly focuses on non-coding RNAs and their roles in cancer brain metastasis. Furthermore, we discuss the roles of the extracellular vesicles as they are known to transport information between cells to initiate cancer cell-microenvironment communication. The potential clinical translation of non-coding RNAs as a tool for diagnosis and for treatment is also discussed in this review. At the end, the computational aspects of non-coding RNA detection, the sequence and structure calculation and epigenetic regulation of non-coding RNA in brain metastasis are discussed.

  12. Transcription control by long non-coding RNAs

    PubMed Central

    Faust, Tyler

    2012-01-01

    Non-coding RNAs have been found to regulate many cellular processes and thus expand the functional genetic repertoire contained within the genome. With the recent advent of genomic tools, it is now evident that these RNA molecules play central regulatory roles in many transcriptional programs. Here we discuss how they are targeted to promoters in several cases and how they operate at specific points in the transcription cycle to precisely control gene expression. PMID:22414755

  13. Non-Coding RNAs in Stroke and Neuroprotection

    PubMed Central

    Saugstad, Julie A.

    2015-01-01

    This review will focus on the current state of knowledge regarding non-coding RNAs (ncRNA) in stroke and neuroprotection. There will be a brief introduction to microRNAs (miRNA), long ncRNAs (lncRNA), and piwi-interacting RNAs (piRNA), followed by evidence for the regulation of ncRNAs in ischemia. This review will also discuss the effect of neuroprotection induced by a sublethal duration of ischemia or other stimuli given before a stroke (preconditioning) on miRNA expression and the role of miRNAs in preconditioning-induced neuroprotection. Experimental manipulation of miRNAs and/or their targets to induce pre- or post-stroke protection will also be presented, as well as discussion on miRNA responses to current post-stroke therapies. This review will conclude with a brief discussion of future directions for ncRNAs studies in stroke, such as new approaches to model complex ncRNA datasets, challenges in ncRNA studies, and the impact of extracellular RNAs on human diseases such as stroke. PMID:25821444

  14. Non-Coding RNAs in Neural Networks, REST-Assured

    PubMed Central

    Rossbach, Michael

    2011-01-01

    In the nervous system, several key steps in cellular complexity and development are regulated by non-coding RNAs (ncRNAs) and the repressor element-1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF). REST recruits gene regulatory complexes to regulatory sequences, among them the repressor element-1/neuron-restrictive silencer element, and mediates developmental stage-specific gene expression or repression, chromatin (re-)organization or silencing for protein-coding genes as well as for several ncRNAs like microRNAs, short interfering RNAs or long ncRNAs. NcRNAs are far from being just transcriptional noise and are involved in chromatin accessibility, transcription and post-transcriptional processing, trafficking, or RNA editing. REST and its cofactor CoREST are both highly regulated through various ncRNAs. The importance of the correct regulation within the ncRNA network, the ncRNAome, is demonstrated when it comes to a deregulation of REST and/or ncRNAs associated with molecular pathophysiology underlying diverse disorders including neurodegenerative diseases or brain tumors. PMID:22303307

  15. Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance

    PubMed Central

    Ayers, Duncan; Vandesompele, Jo

    2017-01-01

    Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology. PMID:28273813

  16. Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance.

    PubMed

    Ayers, Duncan; Vandesompele, Jo

    2017-03-03

    Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology.

  17. Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: An update and review

    PubMed Central

    Huang, Ya-Kai; Yu, Jian-Chun

    2015-01-01

    Gastric cancer (GC) is the fourth most common cancer and the third leading cause of cancer mortality worldwide. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most popular non-coding RNAs in cancer research. To date, the roles of miRNAs and lncRNAs have been extensively studied in GC, suggesting that miRNAs and lncRNAs represent a vital component of tumor biology. Furthermore, circulating miRNAs and lncRNAs are found to be dysregulated in patients with GC compared with healthy individuals. Circulating miRNAs and lncRNAs may function as promising biomarkers to improve the early detection of GC. Multiple possibilities for miRNA secretion have been elucidated, including active secretion by microvesicles, exosomes, apoptotic bodies, high-density lipoproteins and protein complexes as well as passive leakage from cells. However, the mechanism underlying lncRNA secretion and the functions of circulating miRNAs and lncRNAs have not been fully illuminated. Concurrently, to standardize results of global investigations of circulating miRNAs and lncRNAs biomarker studies, several recommendations for pre-analytic considerations are put forward. In this review, we summarize the known circulating miRNAs and lncRNAs for GC diagnosis. The possible mechanism of miRNA and lncRNA secretion as well as methodologies for identification of circulating miRNAs and lncRNAs are also discussed. The topics covered here highlight new insights into GC diagnosis and screening. PMID:26379393

  18. Decoding the non-coding RNAs in Alzheimer's disease.

    PubMed

    Schonrock, Nicole; Götz, Jürgen

    2012-11-01

    Non-coding RNAs (ncRNAs) are integral components of biological networks with fundamental roles in regulating gene expression. They can integrate sequence information from the DNA code, epigenetic regulation and functions of multimeric protein complexes to potentially determine the epigenetic status and transcriptional network in any given cell. Humans potentially contain more ncRNAs than any other species, especially in the brain, where they may well play a significant role in human development and cognitive ability. This review discusses their emerging role in Alzheimer's disease (AD), a human pathological condition characterized by the progressive impairment of cognitive functions. We discuss the complexity of the ncRNA world and how this is reflected in the regulation of the amyloid precursor protein and Tau, two proteins with central functions in AD. By understanding this intricate regulatory network, there is hope for a better understanding of disease mechanisms and ultimately developing diagnostic and therapeutic tools.

  19. Long non-coding RNAs in normal and malignant hematopoiesis

    PubMed Central

    Nobili, Lucia; Lionetti, Marta; Neri, Antonino

    2016-01-01

    Long non-coding RNAs (lncRNAs) are defined as ncRNAs of more than 200 nt in length. They are involved in a large spectrum of biological processes, such as maintenance of genome integrity, genomic imprinting, cell differentiation, and development by means of mechanisms that remain to be fully elucidated. Besides their role in normal cellular physiology, accumulating evidence has linked lncRNA expression and functions to cancer development and progression. In this review, we summarize and discuss what is known about their expression and roles in hematopoiesis with a particular focus on their cell-type specificity, functional interactions, and involvement in the pathobiology of hematological malignancies. PMID:27177333

  20. Long non-coding RNAs in colorectal cancer.

    PubMed

    Xie, Xia; Tang, Bo; Xiao, Yu-Feng; Xie, Rui; Li, Bo-Sheng; Dong, Hui; Zhou, Jian-Yun; Yang, Shi-Ming

    2016-02-02

    Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Despite substantial progress in understanding the molecular mechanisms and treatment of CRC in recent years, the overall survival rate of CRC patients has not improved dramatically. The development of CRC is multifactor and multistep processes, in which abnormal gene expression may play an important role. With the advance of human tumor molecular biology, a series of studies have highlighted the role of long non-coding RNAs (lncRNAs) in the development of CRC. CRC-related lncRNAs have been demonstrated to regulate the genes by various mechanisms, including epigenetic modifications, lncRNA-miRNA and lncRNA-protein interactions, and by their actions as miRNA precursors or pseudogenes. Since some lncRNAs can be detected in human body fluid and have good specificity and accessibility, they have been suggested to be used as novel potential biomarkers for CRC diagnosis and prognosis as well as in the prediction of the response to therapy. Therefore, in this review, we will focus on lncRNAs in CRC development, the mechanisms and biomarkers of lncRNAs in CRC.

  1. CANTATAdb: A Collection of Plant Long Non-Coding RNAs

    PubMed Central

    Szcześniak, Michał W.; Rosikiewicz, Wojciech; Makałowska, Izabela

    2016-01-01

    Long non-coding RNAs (lncRNAs) represent a class of potent regulators of gene expression that are found in a wide array of eukaryotes; however, our knowledge about these molecules in plants is still very limited. In particular, a number of model plant species still lack comprehensive data sets of lncRNAs and their annotations, and very little is known about their biological roles. To meet these shortcomings, we created an online database of lncRNAs in 10 model plant species. The lncRNAs were identified computationally using dozens of publicly available RNA sequencing (RNA-Seq) libraries. Expression values, coding potential, sequence alignments as well as other types of data provide annotation for the identified lncRNAs. In order to better characterize them, we investigated their potential roles in splicing modulation and deregulation of microRNA functions. The data are freely available for searching, browsing and downloading from an online database called CANTATAdb (http://cantata.amu.edu.pl, http://yeti.amu.edu.pl/CANTATA/). PMID:26657895

  2. Non-Coding RNAs: New Players in Skin Wound Healing

    PubMed Central

    Herter, Eva K.; Xu Landén, Ning

    2017-01-01

    Significance: Wound healing is a basic physiological process that is utilized to keep the integrity of the skin. Impaired wound repair, such as chronic wounds and pathological scars, presents a major health and economic burden worldwide. To date, efficient targeted treatment for these wound disorders is still lacking, which is largely due to our limited understanding of the biological mechanisms underlying these diseases. Research driven around discovering new therapies for these complications is, therefore, an urgent need. Recent Advances: The vast majority of the human genome is transcribed to RNAs that lack protein-coding capacity. Intensive research in the recent decade has revealed that these non-coding RNAs (ncRNAs) function as important regulators of cellular physiology and pathology, which makes them promising therapeutic and diagnostic entities. Critical Issues: A class of short ncRNAs, microRNAs, has been found to be indispensable for all the phases of skin wound healing and plays important roles in the pathogenesis of wound complications. The role of long ncRNAs (lncRNA) in skin wound healing remains largely unexplored. Recent studies revealed the essential role of lncRNAs in epidermal differentiation and stress response, indicating their potential importance for skin wound healing, which warrants future research. Future Directions: An investigation of ncRNAs will add new layers of complexity to our understanding of normal skin wound healing as well as to the pathogenesis of wound disorders. Development of ncRNA-based biomarkers and treatments is an interesting and important avenue for future research on wound healing. PMID:28289554

  3. Non-Coding RNAs: New Players in Skin Wound Healing.

    PubMed

    Herter, Eva K; Xu Landén, Ning

    2017-03-01

    Significance: Wound healing is a basic physiological process that is utilized to keep the integrity of the skin. Impaired wound repair, such as chronic wounds and pathological scars, presents a major health and economic burden worldwide. To date, efficient targeted treatment for these wound disorders is still lacking, which is largely due to our limited understanding of the biological mechanisms underlying these diseases. Research driven around discovering new therapies for these complications is, therefore, an urgent need. Recent Advances: The vast majority of the human genome is transcribed to RNAs that lack protein-coding capacity. Intensive research in the recent decade has revealed that these non-coding RNAs (ncRNAs) function as important regulators of cellular physiology and pathology, which makes them promising therapeutic and diagnostic entities. Critical Issues: A class of short ncRNAs, microRNAs, has been found to be indispensable for all the phases of skin wound healing and plays important roles in the pathogenesis of wound complications. The role of long ncRNAs (lncRNA) in skin wound healing remains largely unexplored. Recent studies revealed the essential role of lncRNAs in epidermal differentiation and stress response, indicating their potential importance for skin wound healing, which warrants future research. Future Directions: An investigation of ncRNAs will add new layers of complexity to our understanding of normal skin wound healing as well as to the pathogenesis of wound disorders. Development of ncRNA-based biomarkers and treatments is an interesting and important avenue for future research on wound healing.

  4. Novel classes of non-coding RNAs and cancer

    PubMed Central

    2012-01-01

    For the many years, the central dogma of molecular biology has been that RNA functions mainly as an informational intermediate between a DNA sequence and its encoded protein. But one of the great surprises of modern biology was the discovery that protein-coding genes represent less than 2% of the total genome sequence, and subsequently the fact that at least 90% of the human genome is actively transcribed. Thus, the human transcriptome was found to be more complex than a collection of protein-coding genes and their splice variants. Although initially argued to be spurious transcriptional noise or accumulated evolutionary debris arising from the early assembly of genes and/or the insertion of mobile genetic elements, recent evidence suggests that the non-coding RNAs (ncRNAs) may play major biological roles in cellular development, physiology and pathologies. NcRNAs could be grouped into two major classes based on the transcript size; small ncRNAs and long ncRNAs. Each of these classes can be further divided, whereas novel subclasses are still being discovered and characterized. Although, in the last years, small ncRNAs called microRNAs were studied most frequently with more than ten thousand hits at PubMed database, recently, evidence has begun to accumulate describing the molecular mechanisms by which a wide range of novel RNA species function, providing insight into their functional roles in cellular biology and in human disease. In this review, we summarize newly discovered classes of ncRNAs, and highlight their functioning in cancer biology and potential usage as biomarkers or therapeutic targets. PMID:22613733

  5. cncRNAs: Bi-functional RNAs with protein coding and non-coding functions.

    PubMed

    Kumari, Pooja; Sampath, Karuna

    2015-12-01

    For many decades, the major function of mRNA was thought to be to provide protein-coding information embedded in the genome. The advent of high-throughput sequencing has led to the discovery of pervasive transcription of eukaryotic genomes and opened the world of RNA-mediated gene regulation. Many regulatory RNAs have been found to be incapable of protein coding and are hence termed as non-coding RNAs (ncRNAs). However, studies in recent years have shown that several previously annotated non-coding RNAs have the potential to encode proteins, and conversely, some coding RNAs have regulatory functions independent of the protein they encode. Such bi-functional RNAs, with both protein coding and non-coding functions, which we term as 'cncRNAs', have emerged as new players in cellular systems. Here, we describe the functions of some cncRNAs identified from bacteria to humans. Because the functions of many RNAs across genomes remains unclear, we propose that RNAs be classified as coding, non-coding or both only after careful analysis of their functions.

  6. Long Non-Coding RNAs in Endometrial Carcinoma

    PubMed Central

    Smolle, Maria A.; Bullock, Marc D.; Ling, Hui; Pichler, Martin; Haybaeck, Johannes

    2015-01-01

    Endometrial carcinoma (EC), the second most common form of gynaecological malignancy, can be divided into two distinct sub-types: Type I tumours arise from hyperplastic endometrium and typically effect women around the time of menopause, whereas type II tumours arise in postmenopausal women from atrophic endometrium. Long non-coding RNAs (lncRNAs) are a novel class of non-protein coding molecules that have recently been implicated in the pathogenesis of many types of cancer including gynaecological tumours. Although they play critical physiological roles in cellular metabolism, their expression and function are deregulated in EC compared with paired normal tissue, indicating that they may also participate in tumour initiation and progression. For instance, the lncRNA MALAT-1 is down-regulated in EC samples compared to normal or hyperplastic endometrium, whereas the lncRNA OVAL is down-regulated in type II disease but up-regulated in type I disease. Other notatble lncRNAs such as HOTAIR, H19 and SRA become up-regulated with increasing EC tumour grade and other features associated with poor prognosis. In the current review, we will examine the growing body of evidence linking deregulated lncRNAs with specific biological functions of tumour cells in EC, we will highlight associations between lncRNAs and the molecular pathways implicated in EC tumourigenesis and we will identify critical knowledge gaps that remain to be addressed. PMID:26556343

  7. Non-coding RNAs and complex distributed genetic networks

    NASA Astrophysics Data System (ADS)

    Zhdanov, Vladimir P.

    2011-08-01

    In eukaryotic cells, the mRNA-protein interplay can be dramatically influenced by non-coding RNAs (ncRNAs). Although this new paradigm is now widely accepted, an understanding of the effect of ncRNAs on complex genetic networks is lacking. To clarify what may happen in this case, we propose a mean-field kinetic model describing the influence of ncRNA on a complex genetic network with a distributed architecture including mutual protein-mediated regulation of many genes transcribed into mRNAs. ncRNA is considered to associate with mRNAs and inhibit their translation and/or facilitate degradation. Our results are indicative of the richness of the kinetics under consideration. The main complex features are found to be bistability and oscillations. One could expect to find kinetic chaos as well. The latter feature has however not been observed in our calculations. In addition, we illustrate the difference in the regulation of distributed networks by mRNA and ncRNA.

  8. Viroids: the minimal non-coding RNAs with autonomous replication.

    PubMed

    Flores, Ricardo; Delgado, Sonia; Gas, María-Eugenia; Carbonell, Alberto; Molina, Diego; Gago, Selma; De la Peña, Marcos

    2004-06-01

    Viroids are small (246-401 nucleotides), non-coding, circular RNAs able to replicate autonomously in certain plants. Viroids are classified into the families Pospiviroidae and Avsunviroidae, whose members replicate in the nucleus and chloroplast, respectively. Replication occurs by an RNA-based rolling-circle mechanism in three steps: (1). synthesis of longer-than-unit strands catalyzed by host DNA-dependent RNA polymerases forced to transcribe RNA templates, (2). processing to unit-length, which in family Avsunviroidae is mediated by hammerhead ribozymes, and (3). circularization either through an RNA ligase or autocatalytically. Disease induction might result from the accumulation of viroid-specific small interfering RNAs that, via RNA silencing, could interfere with normal developmental pathways.

  9. Non-coding RNAs: the architects of eukaryotic complexity.

    PubMed

    Mattick, J S

    2001-11-01

    Around 98% of all transcriptional output in humans is non-coding RNA. RNA-mediated gene regulation is widespread in higher eukaryotes and complex genetic phenomena like RNA interference, co-suppression, transgene silencing, imprinting, methylation, and possibly position-effect variegation and transvection, all involve intersecting pathways based on or connected to RNA signaling. I suggest that the central dogma is incomplete, and that intronic and other non-coding RNAs have evolved to comprise a second tier of gene expression in eukaryotes, which enables the integration and networking of complex suites of gene activity. Although proteins are the fundamental effectors of cellular function, the basis of eukaryotic complexity and phenotypic variation may lie primarily in a control architecture composed of a highly parallel system of trans-acting RNAs that relay state information required for the coordination and modulation of gene expression, via chromatin remodeling, RNA-DNA, RNA-RNA and RNA-protein interactions. This system has interesting and perhaps informative analogies with small world networks and dataflow computing.

  10. Kinetic models of gene expression including non-coding RNAs

    NASA Astrophysics Data System (ADS)

    Zhdanov, Vladimir P.

    2011-03-01

    In cells, genes are transcribed into mRNAs, and the latter are translated into proteins. Due to the feedbacks between these processes, the kinetics of gene expression may be complex even in the simplest genetic networks. The corresponding models have already been reviewed in the literature. A new avenue in this field is related to the recognition that the conventional scenario of gene expression is fully applicable only to prokaryotes whose genomes consist of tightly packed protein-coding sequences. In eukaryotic cells, in contrast, such sequences are relatively rare, and the rest of the genome includes numerous transcript units representing non-coding RNAs (ncRNAs). During the past decade, it has become clear that such RNAs play a crucial role in gene expression and accordingly influence a multitude of cellular processes both in the normal state and during diseases. The numerous biological functions of ncRNAs are based primarily on their abilities to silence genes via pairing with a target mRNA and subsequently preventing its translation or facilitating degradation of the mRNA-ncRNA complex. Many other abilities of ncRNAs have been discovered as well. Our review is focused on the available kinetic models describing the mRNA, ncRNA and protein interplay. In particular, we systematically present the simplest models without kinetic feedbacks, models containing feedbacks and predicting bistability and oscillations in simple genetic networks, and models describing the effect of ncRNAs on complex genetic networks. Mathematically, the presentation is based primarily on temporal mean-field kinetic equations. The stochastic and spatio-temporal effects are also briefly discussed.

  11. MicroRNAs and other non-coding RNAs as targets for anticancer drug development

    PubMed Central

    Ling, Hui; Fabbri, Muller; Calin, George A.

    2015-01-01

    With the first cancer-targeted microRNA drug, MRX34, a liposome-based miR-34 mimic, entering phase I clinical trial in patients with advanced hepatocellular carcinoma in April 2013, miRNA therapeutics are attracting special attention from both academia and biotechnology companies. Although to date the most studied non-coding RNAs (ncRNAs) are miRNAs, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. Here we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges. PMID:24172333

  12. Neighboring gene regulation by antisense long non-coding RNAs.

    PubMed

    Villegas, Victoria E; Zaphiropoulos, Peter G

    2015-02-03

    Antisense transcription, considered until recently as transcriptional noise, is a very common phenomenon in human and eukaryotic transcriptomes, operating in two ways based on whether the antisense RNA acts in cis or in trans. This process can generate long non-coding RNAs (lncRNAs), one of the most diverse classes of cellular transcripts, which have demonstrated multifunctional roles in fundamental biological processes, including embryonic pluripotency, differentiation and development. Antisense lncRNAs have been shown to control nearly every level of gene regulation--pretranscriptional, transcriptional and posttranscriptional--through DNA-RNA, RNA-RNA or protein-RNA interactions. This review is centered on functional studies of antisense lncRNA-mediated regulation of neighboring gene expression. Specifically, it addresses how these transcripts interact with other biological molecules, nucleic acids and proteins, to regulate gene expression through chromatin remodeling at the pretranscriptional level and modulation of transcriptional and post-transcriptional processes by altering the sense mRNA structure or the cellular compartmental distribution, either in the nucleus or the cytoplasm.

  13. [Epigenetics of plant vernalization regulated by non-coding RNAs].

    PubMed

    Zhang, Shao-Feng; Li, Xiao-Rong; Sun, Chuan-Bao; He, Yu-Ke

    2012-07-01

    Many higher plants must experience a period of winter cold to accomplish the transition from vegetative to reproductive growth. This biological process is called vernalization. Some crops such as wheat (Triticum aestivum L.) and oilseed rape (Brassica napus L.) produce seeds as edible organs, and therefore special measures of rotation and cultivation are necessary for plants to go through an early vernalization for flower differentiation and development, whereas the other crops such as Chinese cabbage (B rapa ssp. pekinenesis) and cabbage (Brassica napus L.) produce leafy heads as edible organs, and additional practice should be taken to avoid vernalization for a prolonged and fully vegetative growth. Before vernalization, flowering is repressed by the action of a gene called Flowering Locus C (FLC). This paper reviewed the function of non-coding RNAs and some proteins including VRN1, VRN2, and VIN3 in epigenetic regulation of FLC during vernalization.

  14. Prioritization of non-coding disease-causing variants and long non-coding RNAs in liver cancer

    PubMed Central

    Li, Hua; He, Zekun; Gu, Yang; Fang, Lin; Lv, Xin

    2016-01-01

    There are multiple bioinformatics tools available for the detection of coding driver mutations in cancers. However, the prioritization of pathogenic non-coding variants remains a challenging and demanding task. The present study was performed to discriminate non-coding disease-causing mutations and prioritize potential cancer-implicated long non-coding RNAs (lncRNAs) in liver cancer using a logistic regression model. A logistic regression model was constructed by combining 19,153 disease-associated ClinVar and human gene mutation database pathogenic variants as the response variable and non-coding features as the predictor variable. Genome-wide association study (GWAS) disease or trait-associated variants and recurrent somatic mutations were used to validate the model. Non-coding gene features with the highest fractions of load were characterized and potential cancer-associated lncRNA candidates were prioritized by combining the fraction of high-scoring regions and average score predicted by the logistic regression model. H3K9me3 and conserved regions were the most negatively and positively informative for the model, respectively. The area under the receiver operating characteristic curve of the model was 0.92. The average score of GWAS disease-associated variants was significantly increased compared with neutral single nucleotide polymorphisms (5.8642 vs. 5.4707; P<0.001), the average score of recurrent somatic mutations of liver cancer was significantly increased compared with non-recurrent somatic mutations (5.4101 vs. 5.2768; P=0.0125). The present study found regions in lncRNAs and introns/untranslated regions of protein coding genes where mutations are most likely to be damaging. In total, 847 lncRNAs were filtered out from the background. Characterization of this subset of lncRNAs showed that these lncRNAs are more conservative, less mutated and more highly expressed compared with other control lncRNAs. In addition, 23 of these lncRNAs were differentially

  15. Prioritization of non-coding disease-causing variants and long non-coding RNAs in liver cancer.

    PubMed

    Li, Hua; He, Zekun; Gu, Yang; Fang, Lin; Lv, Xin

    2016-11-01

    There are multiple bioinformatics tools available for the detection of coding driver mutations in cancers. However, the prioritization of pathogenic non-coding variants remains a challenging and demanding task. The present study was performed to discriminate non-coding disease-causing mutations and prioritize potential cancer-implicated long non-coding RNAs (lncRNAs) in liver cancer using a logistic regression model. A logistic regression model was constructed by combining 19,153 disease-associated ClinVar and human gene mutation database pathogenic variants as the response variable and non-coding features as the predictor variable. Genome-wide association study (GWAS) disease or trait-associated variants and recurrent somatic mutations were used to validate the model. Non-coding gene features with the highest fractions of load were characterized and potential cancer-associated lncRNA candidates were prioritized by combining the fraction of high-scoring regions and average score predicted by the logistic regression model. H3K9me3 and conserved regions were the most negatively and positively informative for the model, respectively. The area under the receiver operating characteristic curve of the model was 0.92. The average score of GWAS disease-associated variants was significantly increased compared with neutral single nucleotide polymorphisms (5.8642 vs. 5.4707; P<0.001), the average score of recurrent somatic mutations of liver cancer was significantly increased compared with non-recurrent somatic mutations (5.4101 vs. 5.2768; P=0.0125). The present study found regions in lncRNAs and introns/untranslated regions of protein coding genes where mutations are most likely to be damaging. In total, 847 lncRNAs were filtered out from the background. Characterization of this subset of lncRNAs showed that these lncRNAs are more conservative, less mutated and more highly expressed compared with other control lncRNAs. In addition, 23 of these lncRNAs were differentially

  16. Sequence and Structural Analyses for Functional Non-coding RNAs

    NASA Astrophysics Data System (ADS)

    Sakakibara, Yasubumi; Sato, Kengo

    Analysis and detection of functional RNAs are currently important topics in both molecular biology and bioinformatics research. Several computational methods based on stochastic context-free grammars (SCFGs) have been developed for modeling and analysing functional RNA sequences. These grammatical methods have succeeded in modeling typical secondary structures of RNAs and are used for structural alignments of RNA sequences. Such stochastic models, however, are not sufficient to discriminate member sequences of an RNA family from non-members, and hence to detect non-coding RNA regions from genome sequences. Recently, the support vector machine (SVM) and kernel function techniques have been actively studied and proposed as a solution to various problems in bioinformatics. SVMs are trained from positive and negative samples and have strong, accurate discrimination abilities, and hence are more appropriate for the discrimination tasks. A few kernel functions that extend the string kernel to measure the similarity of two RNA sequences from the viewpoint of secondary structures have been proposed. In this article, we give an overview of recent progress in SCFG-based methods for RNA sequence analysis and novel kernel functions tailored to measure the similarity of two RNA sequences and developed for use with support vector machines (SVM) in discriminating members of an RNA family from non-members.

  17. Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events

    PubMed Central

    Ashouri, Arghavan; Sayin, Volkan I.; Van den Eynden, Jimmy; Singh, Simranjit X.; Papagiannakopoulos, Thales; Larsson, Erik

    2016-01-01

    Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers.

  18. Regulation of mammalian cell differentiation by long non-coding RNAs.

    PubMed

    Hu, Wenqian; Alvarez-Dominguez, Juan R; Lodish, Harvey F

    2012-11-06

    Differentiation of specialized cell types from stem and progenitor cells is tightly regulated at several levels, both during development and during somatic tissue homeostasis. Many long non-coding RNAs have been recognized as an additional layer of regulation in the specification of cellular identities; these non-coding species can modulate gene-expression programmes in various biological contexts through diverse mechanisms at the transcriptional, translational or messenger RNA stability levels. Here, we summarize findings that implicate long non-coding RNAs in the control of mammalian cell differentiation. We focus on several representative differentiation systems and discuss how specific long non-coding RNAs contribute to the regulation of mammalian development.

  19. Identifying (non-)coding RNAs and small peptides: challenges and opportunities.

    PubMed

    Pauli, Andrea; Valen, Eivind; Schier, Alexander F

    2015-01-01

    Over the past decade, high-throughput studies have identified many novel transcripts. While their existence is undisputed, their coding potential and functionality have remained controversial. Recent computational approaches guided by ribosome profiling have indicated that translation is far more pervasive than anticipated and takes place on many transcripts previously assumed to be non-coding. Some of these newly discovered translated transcripts encode short, functional proteins that had been missed in prior screens. Other transcripts are translated, but it might be the process of translation rather than the resulting peptides that serves a function. Here, we review annotation studies in zebrafish to discuss the challenges of placing RNAs onto the continuum that ranges from functional protein-encoding mRNAs to potentially non-functional peptide-producing RNAs to non-coding RNAs. As highlighted by the discovery of the novel signaling peptide Apela/ELABELA/Toddler, accurate annotations can give rise to exciting opportunities to identify the functions of previously uncharacterized transcripts.

  20. Genome-wide analyses of small non-coding RNAs in streptococci

    PubMed Central

    Patenge, Nadja; Pappesch, Roberto; Khani, Afsaneh; Kreikemeyer, Bernd

    2015-01-01

    Streptococci represent a diverse group of Gram-positive bacteria, which colonize a wide range of hosts among animals and humans. Streptococcal species occur as commensal as well as pathogenic organisms. Many of the pathogenic species can cause severe, invasive infections in their hosts leading to a high morbidity and mortality. The consequence is a tremendous suffering on the part of men and livestock besides the significant financial burden in the agricultural and healthcare sectors. An environmentally stimulated and tightly controlled expression of virulence factor genes is of fundamental importance for streptococcal pathogenicity. Bacterial small non-coding RNAs (sRNAs) modulate the expression of genes involved in stress response, sugar metabolism, surface composition, and other properties that are related to bacterial virulence. Even though the regulatory character is shared by this class of RNAs, variation on the molecular level results in a high diversity of functional mechanisms. The knowledge about the role of sRNAs in streptococci is still limited, but in recent years, genome-wide screens for sRNAs have been conducted in an increasing number of species. Bioinformatics prediction approaches have been employed as well as expression analyses by classical array techniques or next generation sequencing. This review will give an overview of whole genome screens for sRNAs in streptococci with a focus on describing the different methods and comparing their outcome considering sRNA conservation among species, functional similarities, and relevance for streptococcal infection. PMID:26042151

  1. MicroRNAs and non-coding RNAs in virus-infected cells

    PubMed Central

    Ouellet, Dominique L.; Provost, Patrick

    2010-01-01

    Within the past few years, microRNAs (miRNAs) and other non-coding RNAs (ncRNAs) have emerged as elements with critically high importance in post-transcriptional control of cellular and, more recently, viral processes. Endogenously produced by a component of the miRNA-guided RNA silencing machinery known as Dicer, miRNAs are known to control messenger RNA (mRNA) translation through recognition of specific binding sites usually located in their 3′ untranslated region. Recent evidences indicate that the host miRNA pathway may represent an adapted antiviral defense mechanism that can act either by direct miRNA-mediated modulation of viral gene expression or through recognition and inactivation of structured viral RNA species by the protein components of the RNA silencing machinery, such as Dicer. This latter process, however, is a double-edge sword, as it may yield viral miRNAs exerting gene regulatory properties on both host and viral mRNAs. Our knowledge of the interaction between viruses and host RNA silencing machineries, and how this influences the course of infection, is becoming increasingly complex. This review article aims to summarize our current knowledge about viral miRNAs/ncRNAs and their targets, as well as cellular miRNAs that are modulated by viruses upon infection. PMID:20217543

  2. Non-coding RNAs and Berberine: A new mechanism of its anti-diabetic activities.

    PubMed

    Chang, Wenguang

    2017-01-15

    Type 2 Diabetes (T2D) is a metabolic disease with high mortality and morbidity. Non-coding RNAs, including small and long non-coding RNAs, are a novel class of functional RNA molecules that regulate multiple biological functions through diverse mechanisms. Studies in the last decade have demonstrated that non-coding RNAs may represent compelling therapeutic targets and play important roles in regulating the course of insulin resistance and T2D. Berberine, a plant-based alkaloid, has shown promise as an anti-hyperglycaemic, anti-hyperlipidaemic agent against T2D. Previous studies have primarily focused on a diverse array of efficacy end points of berberine in the pathogenesis of metabolic syndromes and inflammation or oxidative stress. Currently, an increasing number of studies have revealed the importance of non-coding RNAs as regulators of the anti-diabetic effects of berberine. The regulation of non-coding RNAs has been associated with several therapeutic actions of berberine in T2D progression. Thus, this review summarizes the anti-diabetic mechanisms of berberine by focusing on its role in regulating non-coding RNA, thus demonstrating that berberine exerts global anti-diabetic effects by targeting non-coding RNAs and that these effects involve several miRNAs, lncRNAs and multiple signal pathways, which may enhance the current understanding of the anti-diabetic mechanism actions of berberine and provide new pathological targets for the development of berberine-related drugs.

  3. Facts and updates about cardiovascular non-coding RNAs in heart failure.

    PubMed

    Thum, Thomas

    2015-09-01

    About 11% of all deaths include heart failure as a contributing cause. The annual cost of heart failure amounts to US $34,000,000,000 in the United States alone. With the exception of heart transplantation, there is no curative therapy available. Only occasionally there are new areas in science that develop into completely new research fields. The topic on non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, is such a field. In this short review, we will discuss the latest developments about non-coding RNAs in cardiovascular disease. MicroRNAs are short regulatory non-coding endogenous RNA species that are involved in virtually all cellular processes. Long non-coding RNAs also regulate gene and protein levels; however, by much more complicated and diverse mechanisms. In general, non-coding RNAs have been shown to be of great value as therapeutic targets in adverse cardiac remodelling and also as diagnostic and prognostic biomarkers for heart failure. In the future, non-coding RNA-based therapeutics are likely to enter the clinical reality offering a new treatment approach of heart failure.

  4. Non-Coding RNAs as Potential Neuroprotectants against Ischemic Brain Injury.

    PubMed

    Kaur, Prameet; Liu, Fujia; Tan, Jun Rong; Lim, Kai Ying; Sepramaniam, Sugunavathi; Karolina, Dwi Setyowati; Armugam, Arunmozhiarasi; Jeyaseelan, Kandiah

    2013-03-20

    Over the past decade, scientific discoveries have highlighted new roles for a unique class of non-coding RNAs. Transcribed from the genome, these non-coding RNAs have been implicated in determining the biological complexity seen in mammals by acting as transcriptional and translational regulators. Non-coding RNAs, which can be sub-classified into long non-coding RNAs, microRNAs, PIWI-interacting RNAs and several others, are widely expressed in the nervous system with roles in neurogenesis, development and maintenance of the neuronal phenotype. Perturbations of these non-coding transcripts have been observed in ischemic preconditioning as well as ischemic brain injury with characterization of the mechanisms by which they confer toxicity. Their dysregulation may also confer pathogenic conditions in neurovascular diseases. A better understanding of their expression patterns and functions has uncovered the potential use of these riboregulators as neuroprotectants to antagonize the detrimental molecular events taking place upon ischemic-reperfusion injury. In this review, we discuss the various roles of non-coding RNAs in brain development and their mechanisms of gene regulation in relation to ischemic brain injury. We will also address the future directions and open questions for identifying promising non-coding RNAs that could eventually serve as potential neuroprotectants against ischemic brain injury.

  5. The Role and Molecular Mechanism of Non-Coding RNAs in Pathological Cardiac Remodeling

    PubMed Central

    Gao, Jinning; Xu, Wenhua; Wang, Jianxun; Wang, Kun; Li, Peifeng

    2017-01-01

    Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Studies show that ncRNAs are not only involved in cell proliferation, apoptosis, differentiation, metabolism and other physiological processes, but also involved in the pathogenesis of diseases. Cardiac remodeling is the main pathological basis of a variety of cardiovascular diseases. Many studies have shown that the occurrence and development of cardiac remodeling are closely related with the regulation of ncRNAs. Recent research of ncRNAs in heart disease has achieved rapid development. Thus, we summarize here the latest research progress and mainly the molecular mechanism of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), in cardiac remodeling, aiming to look for new targets for heart disease treatment. PMID:28287427

  6. Non-coding RNAs and LRRFIP1 Regulate TNF Expression1

    PubMed Central

    Shi, Lihua; Song, Li; Fitzgerald, Michael; Maurer, Kelly; Bagashev, Asen; Sullivan, Kathleen E.

    2014-01-01

    Non-coding RNAs have been implicated in the regulation of expression of numerous genes, however, the mechanism is not fully understood. We identified bidirectional, long non-coding RNAs upstream of the TNF gene using five different methods. They arose in a region where the repressors LRRFIP1, EZH2, and SUZ12 were demonstrated to bind, suggesting a role in repression. The non-coding RNAs were polyadenylated, capped, and chromatin-associated. Knock-down of the non-coding RNAs was associated with de-repression of TNF mRNA and diminished binding of LRRFIP1 to both RNA targets and chromatin. Over-expression of the non-coding RNAs led to diminished expression of TNF and recruitment of repressor proteins to the locus. One repressor protein, LRRFIP1, bound directly to the non-coding RNAs. These data place the non-coding RNAs upstream of TNF gene as central to the transcriptional regulation. They appear to serve as a platform for the assembly of a repressive complex. PMID:24567534

  7. Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs

    PubMed Central

    Zebisch, Armin; Hatzl, Stefan; Pichler, Martin; Wölfler, Albert; Sill, Heinz

    2016-01-01

    Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still succumbs to chemoresistant disease. Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA fragments and act as key players in the regulation of both physiologic and pathologic gene expression profiles. Aberrant expression of various non-coding RNAs proved to be of seminal importance in the pathogenesis of AML, as well in the development of resistance to chemotherapy. In this review, we discuss the role of miRNAs and lncRNAs with respect to sensitivity and resistance to treatment regimens currently used in AML and provide an outlook on potential therapeutic targets emerging thereof. PMID:27973410

  8. Non-coding RNAs: an emerging player in DNA damage response.

    PubMed

    Zhang, Chunzhi; Peng, Guang

    2015-01-01

    Non-coding RNAs play a crucial role in maintaining genomic stability which is essential for cell survival and preventing tumorigenesis. Through an extensive crosstalk between non-coding RNAs and the canonical DNA damage response (DDR) signaling pathway, DDR-induced expression of non-coding RNAs can provide a regulatory mechanism to accurately control the expression of DNA damage responsive genes in a spatio-temporal manner. Mechanistically, DNA damage alters expression of a variety of non-coding RNAs at multiple levels including transcriptional regulation, post-transcriptional regulation, and RNA degradation. In parallel, non-coding RNAs can directly regulate cellular processes involved in DDR by altering expression of their targeting genes, with a particular emphasis on miRNAs and lncRNAs. MiRNAs are required for almost every aspect of cellular responses to DNA damage, including sensing DNA damage, transducing damage signals, repairing damaged DNA, activating cell cycle checkpoints, and inducing apoptosis. As for lncRNAs, they control transcription of DDR relevant gene by four different regulatory models, including signal, decoy, guide, and scaffold. In addition, we also highlight potential clinical applications of non-coding RNAs as biomarkers and therapeutic targets for anti-cancer treatments using DNA-damaging agents including radiation and chemotherapy. Although tremendous advances have been made to elucidate the role of non-coding RANs in genome maintenance, many key questions remain to be answered including mechanistically how non-coding RNA pathway and DNA damage response pathway is coordinated in response to genotoxic stress. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Identification and characterization of long non-coding RNAs in rainbow trout eggs

    USDA-ARS?s Scientific Manuscript database

    Long non-coding RNAs (lncRNAs) are in general considered as a diverse class of transcripts longer than 200 nucleotides that structurally resemble mRNAs but do not encode proteins. Recent advances in RNA sequencing (RNA-Seq) and bioinformatics methods have provided an opportunity to indentify and ana...

  10. Developmentally regulated long non-coding RNAs in Xenopus tropicalis.

    PubMed

    Forouzmand, Elmira; Owens, Nick D L; Blitz, Ira L; Paraiso, Kitt D; Khokha, Mustafa K; Gilchrist, Michael J; Xie, Xiaohui; Cho, Ken W Y

    2017-06-15

    Advances in RNA sequencing technologies have led to the surprising discovery that a vast number of transcripts emanate from regions of the genome that are not part of coding genes. Although some of the smaller ncRNAs such as microRNAs have well-characterized functions, the majority of long ncRNA (lncRNA) functions remain poorly understood. Understanding the significance of lncRNAs is an important challenge facing biology today. A powerful approach to uncovering the function of lncRNAs is to explore temporal and spatial expression profiling. This may be particularly useful for classes of lncRNAs that have developmentally important roles as the expression of such lncRNAs will be expected to be both spatially and temporally regulated during development. Here, we take advantage of our ultra-high frequency (temporal) sampling of Xenopus embryos to analyze gene expression trajectories of lncRNA transcripts over the first 3 days of development. We computationally identify 5689 potential single- and multi-exon lncRNAs. These lncRNAs demonstrate clear dynamic expression patterns. A subset of them displays highly correlative temporal expression profiles with respect to those of the neighboring genes. We also identified spatially localized lncRNAs in the gastrula stage embryo. These results suggest that lncRNAs have regulatory roles during early embryonic development. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Small non-coding RNAs as novel therapeutics.

    PubMed

    Rossbach, M

    2010-06-01

    RNA interference (RNAi), an evolutionarily conserved sequence-specific post-transcriptional gene silencing mechanism, is triggered by double-stranded RNA (dsRNA) that results in the degradation of homologous mRNA or in the inhibition of mRNA translation. The naturally occurring triggers for the RNAi pathway are small regulatory RNAs, including small interfering RNAs (siRNAs), processed from longer dsRNAs by the RNAse III enzyme Dicer, and microRNAs (miRNAs), generated in a regulated multistep process from endogenous primary transcripts (pri-miRNA). These primary transcripts are capped, polyadenylated and spliced, thus resembling conventional mRNAs. It is estimated that miRNAs regulate more than one third of all cellular mRNAs, and bioinformatic data indicate that each miRNA can control hundreds of gene targets. Thus, there are likely to be few biological processes not regulated by miRNAs. Although the biological functions of miRNAs are not completely revealed, there is growing evidence that miRNA pathways are a new mechanism of gene regulation in both normal and diseased conditions. Recent evidence has shown that miRNA mutations or aberrant expression patterns correlate with various diseases, such as cancer, viral infections, cardiovascular or neurodegenerative diseases and indicates that miRNAs can function as tumor suppressors and oncogenes. MiRNAs have not only emerged as a powerful tool for gene regulation studies but also for the development of novel drugs. Since they do not encode proteins, they are not traditional therapeutic targets of small-molecule inhibitors and thus comprise a novel class of therapeutics. This article will focus on the current progress in drug discovery using the miRNA strategy.

  12. Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer

    PubMed Central

    Smolle, Maria A.; Bauernhofer, Thomas; Pummer, Karl; Calin, George A.; Pichler, Martin

    2017-01-01

    The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs can promote castration resistance, cell proliferation, invasion, and metastatic spread. Expression patterns of lncRNAs often change during tumour progression; their expression levels may constantly rise (e.g., HOX transcript antisense RNA, HOTAIR), or steadily decrease (e.g., downregulated RNA in cancer, DRAIC). In prostate cancer, lncRNAs likewise have diagnostic (e.g., prostate cancer antigen 3, PCA3), prognostic (e.g., second chromosome locus associated with prostate-1, SChLAP1), and predictive (e.g., metastasis-associated lung adenocarcinoma transcript-1, MALAT-1) functions. Considering their dynamic role in prostate cancer, lncRNAs may also serve as therapeutic targets, helping to prevent development of castration resistance, maintain stable disease, and prohibit metastatic spread. PMID:28241429

  13. Non-coding RNAs as emerging molecular targets of gallbladder cancer.

    PubMed

    Tekcham, Dinesh Singh; Tiwari, Pramod Kumar

    2016-08-15

    Gallbladder cancer is one of the most common cancers of biliary tract with aggressive pathophysiology, now emerging as a global health issue. Although minority of gallbladder cancer patients could receive such curative resection due to late diagnosis, this increases the survival rate. Lack of potential target molecule (s) for early diagnosis, better prognosis and effective therapy of gallbladder cancer has triggered investigators to look for novel technological or high throughput approaches to identify potential biomarker for gallbladder cancer. Intervention of non-coding RNAs in gallbladder cancer has been revealed recently. Non-coding RNAs are now widely implicated in cancer. Recent reports have revealed association of non-coding RNAs (microRNAs or miRNAs and long non-coding RNAs or lncRNAs) with gallbladder cancer. Here, we present an updated overview on the biogenesis, mechanism of action, role of non-coding RNAs, the identified cellular functions in gallbladder tumorigenesis, their prognostic & therapeutic potentials (efficacies) and future significance in developing effective biomarker(s), in future, for gallbladder. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Standing your Ground to Exoribonucleases: Function of Flavivirus Long Non-coding RNAs

    PubMed Central

    Charley, Phillida A.; Wilusz, Jeffrey

    2015-01-01

    Members of the Flaviviridae (e.g. Dengue virus, West Nile virus, and Hepatitis C virus) contain a positive-sense RNA genome that encodes a large polyprotein. It is now also clear most if not all of these viruses also produce an abundant subgenomic long non-coding RNA. These non-coding RNAs, which are called subgenomicflavivirus RNAs (sfRNAs) or Xrn1-resistant RNAs (xrRNAs), are stable decay intermediates generated from the viral genomic RNA through the stalling of the cellular exoribonuclease Xrn1 at highly structured regions. Several functions of these flavivirus long non-coding RNAs have been revealed in recent years. The generation of these sfRNAs/xrRNAs from viral transcripts results in the repression of Xrn1 and the dysregulation of cellular mRNA stability. The abundant sfRNAs also serve directly as a decoy for important cellular protein regulators of the interferon and RNA interference antiviral pathways. Thus the generation of long non-coding RNAs from flaviviruses, hepaciviruses and pestiviruses likely disrupts aspects of innate immunity and may directly contribute to viral replication, cytopathology and pathogenesis. PMID:26368052

  15. Long non-coding RNAs in innate and adaptive immunity

    PubMed Central

    Aune, Thomas M.; Spurlock, Charles F.

    2015-01-01

    Long noncoding RNAs (lncRNAs) represent a newly discovered class of regulatory molecules that impact a variety of biological processes in cells and organ systems. In humans, it is estimated that there may be more than twice as many lncRNA genes than protein-coding genes. However, only a handful of lncRNAs have been analyzed in detail. In this review, we describe expression and functions of lncRNAs that have been demonstrated to impact innate and adaptive immunity. These emerging paradigms illustrate remarkably diverse mechanisms that lncRNAs utilize to impact the transcriptional programs of immune cells required to fight against pathogens and maintain normal health and homeostasis. PMID:26166759

  16. Emerging roles of non-coding RNAs in gastric cancer: Pathogenesis and clinical implications

    PubMed Central

    Xie, Shan-Shan; Jin, Juan; Xu, Xiao; Zhuo, Wei; Zhou, Tian-Hua

    2016-01-01

    Gastric cancer is a leading cause of cancer-related deaths. However, the mechanisms underlying gastric carcinogenesis remain largely unclear. The association of non-coding RNAs (ncRNAs) with cancer has been widely studied during the past decade. In general, ncRNAs have been classified as small ncRNAs, including microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). Emerging evidence shows that miRNAs and lncRNAs play key roles in the formation and progression of many cancers. In this review, we focus on the regulation of miRNAs and lncRNAs in gastric cancer. miRNAs and lncRNAs appear to be involved in gastric tumor growth, invasion, and metastasis and in establishment of the gastric tumor microenvironment through various mechanisms. Furthermore, we also discuss the possibilities of establishing miRNAs and lncRNAs as potential biomarkers and therapeutic targets for gastric cancer. Taken together, we summarize the emerging roles of ncRNAs in gastric cancer development and their possible clinical significance. PMID:26811659

  17. Regulation of mammalian cell differentiation by long non-coding RNAs

    PubMed Central

    Hu, Wenqian; Alvarez-Dominguez, Juan R; Lodish, Harvey F

    2012-01-01

    Differentiation of specialized cell types from stem and progenitor cells is tightly regulated at several levels, both during development and during somatic tissue homeostasis. Many long non-coding RNAs have been recognized as an additional layer of regulation in the specification of cellular identities; these non-coding species can modulate gene-expression programmes in various biological contexts through diverse mechanisms at the transcriptional, translational or messenger RNA stability levels. Here, we summarize findings that implicate long non-coding RNAs in the control of mammalian cell differentiation. We focus on several representative differentiation systems and discuss how specific long non-coding RNAs contribute to the regulation of mammalian development. PMID:23070366

  18. Pathophysiology and Clinical Utility of Non-coding RNAs in Epilepsy.

    PubMed

    Shao, Yiye; Chen, Yinghui

    2017-01-01

    Epilepsy is a common neurologic disorder. The underlying pathological processes include synaptic strength, inflammation, ion channels, and apoptosis. Acting as epigenetic factors, non-coding RNAs (ncRNAs) participate in the regulation of pathophysiologic processes of epilepsy and are dysregulated during epileptogenesis. Aberrant expression of ncRNAs are observed in epilepsy patients and animal models of epilepsy. Furthermore, ncRNAs might also be used as biomarkers for diagnosis and the prognosis of treatment response in epilepsy. In this review, we will summarize the role of ncRNAs in the pathophysiology of epilepsy and the putative utilization of ncRNAs as diagnostic biomarkers and therapeutic targets.

  19. Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer

    PubMed Central

    Fang, Yiwen; Fullwood, Melissa J.

    2016-01-01

    Long non-coding RNAs (lncRNAs) play important roles in cancer. They are involved in chromatin remodeling, as well as transcriptional and post-transcriptional regulation, through a variety of chromatin-based mechanisms and via cross-talk with other RNA species. lncRNAs can function as decoys, scaffolds, and enhancer RNAs. This review summarizes the characteristics of lncRNAs, including their roles, functions, and working mechanisms, describes methods for identifying and annotating lncRNAs, and discusses future opportunities for lncRNA-based therapies using antisense oligonucleotides. PMID:26883671

  20. Structure based approaches for targeting non-coding RNAs with small molecules

    PubMed Central

    Shortridge, Matthew D.; Varani, Gabriele

    2015-01-01

    The increasing appreciation of the central role of non-coding RNAs (miRNAs and long non coding RNAs) in chronic and degenerative human disease makes them attractive therapeutic targets. This would not be unprecedented: the bacterial ribosomal RNA is a mainstay for antibacterial treatment, while the conservation and functional importance of viral RNA regulatory elements has long suggested they would constitute attractive targets for new antivirals. Oligonucleotide-based chemistry has obvious appeals but also considerable pharmacological limitations that are yet to be addressed satisfactorily. Recent studies identifying small molecules targeting non-coding RNAs may provide an alternative approach to oligonucleotide methods. Here we review recent work investigating new structural and chemical principles for targeting RNA with small molecules. PMID:25687935

  1. Aberrant Expression of Long Non-Coding RNAs in Schizophrenia Patients

    PubMed Central

    Chen, Shengdong; Sun, Xinyang; Niu, Wei; Kong, Lingming; He, Mingjun; Li, Wanshuai; Zhong, Aifang; Lu, Jim; Zhang, Liyi

    2016-01-01

    Background Dysfunction of long non-coding RNAs (lncRNAs) has been demonstrated to be involved in psychiatric diseases. However, the expression patterns and functions of the regulatory lncRNAs in schizophrenia (SZ) patients have rarely been systematically reported. Material/Methods The lncRNAs in peripheral blood mononuclear cells (PBMCs) were screened and compared between the SZ patients and demographically-matched healthy controls using microarray analysis, and then were validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) method. Three verified significantly dysregulated lncRNAs of PBMCs were selected and then measured in SZ patients before and after the antipsychotic treatment. SZ symptomatology improvement was measured by Positive And Negative Syndrome Scale (PANSS) scores. Results One hundred and twenty-five lncRNAs were significantly differentially expressed in SZ patients compared with healthy controls, of which 62 were up-regulated and 63 were down-regulated. Concurrent with the significant decrease of the PANSS scores of patients after the treatment, the PBMC levels of lncRNA NONHSAT089447 and NONHSAT041499 were strikingly decreased (P<0.05). Down-regulation of PBMC expression of NONHSAT041499 was significantly correlated to the improvement of positive and activity symptoms of patients (r=−0.444 and −0.423, respectively, P<0.05, accounting for 16.9% and 15.1%, respectively), and was also significantly associated with better outcomes (odds ratio 2.325 for positive symptom and 12.340 for activity symptom). Conclusions LncRNA NONHSAT089447 and NONHSAT041499 might be involved in the pathogenesis and development of SZ, and the PBMC level of NONHSAT041499 is significantly associated with the treatment outcomes of SZ. PMID:27650396

  2. Involvement of Host Non-Coding RNAs in the Pathogenesis of the Influenza Virus

    PubMed Central

    Ma, Yanmei; Ouyang, Jing; Wei, Jingyun; Maarouf, Mohamed; Chen, Ji-Long

    2016-01-01

    Non-coding RNAs (ncRNAs) are a new type of regulators that play important roles in various cellular processes, including cell growth, differentiation, survival, and apoptosis. ncRNAs, including small non-coding RNAs (e.g., microRNAs, small interfering RNAs) and long non-coding RNAs (lncRNAs), are pervasively transcribed in human and mammalian cells. Recently, it has been recognized that these ncRNAs are critically implicated in the virus–host interaction as key regulators of transcription or post-transcription during viral infection. Influenza A virus (IAV) is still a major threat to human health. Hundreds of ncRNAs are differentially expressed in response to infection with IAV, such as infection by pandemic H1N1 and highly pathogenic avian strains. There is increasing evidence demonstrating functional involvement of these regulatory microRNAs, vault RNAs (vtRNAs) and lncRNAs in pathogenesis of influenza virus, including a variety of host immune responses. For example, it has been shown that ncRNAs regulate activation of pattern recognition receptor (PRR)-associated signaling and transcription factors (nuclear factor κ-light-chain-enhancer of activated B cells, NF-κB), as well as production of interferons (IFNs) and cytokines, and expression of critical IFN-stimulated genes (ISGs). The vital functions of IAV-regulated ncRNAs either to against defend viral invasion or to promote progeny viron production are summarized in this review. In addition, we also highlight the potentials of ncRNAs as therapeutic targets and diagnostic biomarkers. PMID:28035991

  3. Genome-Wide Discovery of Long Non-Coding RNAs in Rainbow Trout

    PubMed Central

    Al-Tobasei, Rafet; Paneru, Bam; Salem, Mohamed

    2016-01-01

    The ENCODE project revealed that ~70% of the human genome is transcribed. While only 1–2% of the RNAs encode for proteins, the rest are non-coding RNAs. Long non-coding RNAs (lncRNAs) form a diverse class of non-coding RNAs that are longer than 200nt. Emerging evidence indicates that lncRNAs play critical roles in various cellular processes including regulation of gene expression. LncRNAs show low levels of gene expression and sequence conservation, which make their computational identification in genomes difficult. In this study, more than two billion Illumina sequence reads were mapped to the genome reference using the TopHat and Cufflinks software. Transcripts shorter than 200nt, with more than 83–100 amino acids ORF, or with significant homologies to the NCBI nr-protein database were removed. In addition, a computational pipeline was used to filter the remaining transcripts based on a protein-coding-score test. Depending on the filtering stringency conditions, between 31,195 and 54,503 lncRNAs were identified, with only 421 matching known lncRNAs in other species. A digital gene expression atlas revealed 2,935 tissue-specific and 3,269 ubiquitously-expressed lncRNAs. This study annotates the lncRNA rainbow trout genome and provides a valuable resource for functional genomics research in salmonids. PMID:26895175

  4. Genome-Wide Discovery of Long Non-Coding RNAs in Rainbow Trout.

    PubMed

    Al-Tobasei, Rafet; Paneru, Bam; Salem, Mohamed

    2016-01-01

    The ENCODE project revealed that ~70% of the human genome is transcribed. While only 1-2% of the RNAs encode for proteins, the rest are non-coding RNAs. Long non-coding RNAs (lncRNAs) form a diverse class of non-coding RNAs that are longer than 200 nt. Emerging evidence indicates that lncRNAs play critical roles in various cellular processes including regulation of gene expression. LncRNAs show low levels of gene expression and sequence conservation, which make their computational identification in genomes difficult. In this study, more than two billion Illumina sequence reads were mapped to the genome reference using the TopHat and Cufflinks software. Transcripts shorter than 200 nt, with more than 83-100 amino acids ORF, or with significant homologies to the NCBI nr-protein database were removed. In addition, a computational pipeline was used to filter the remaining transcripts based on a protein-coding-score test. Depending on the filtering stringency conditions, between 31,195 and 54,503 lncRNAs were identified, with only 421 matching known lncRNAs in other species. A digital gene expression atlas revealed 2,935 tissue-specific and 3,269 ubiquitously-expressed lncRNAs. This study annotates the lncRNA rainbow trout genome and provides a valuable resource for functional genomics research in salmonids.

  5. Non-coding RNAs: Functions and applications in endocrine-related cancer.

    PubMed

    Venkatesh, Thejaswini; Suresh, Padmanaban S; Tsutsumi, Rie

    2015-11-15

    A significant fraction of the human genome is transcribed as non-coding RNAs (ncRNAs). This non-coding transcriptome has challenged the notion of the central dogma and its involvement in transcriptional and post-transcriptional regulation of gene expression is well established. Interestingly, several ncRNAs are dysregulated in cancer and current non-coding transcriptome research aims to use our increasing knowledge of these ncRNAs for the development of cancer biomarkers and anti-cancer drugs. In endocrine-related cancers, for which survival rates can be relatively low, there is a need for such advancements. In this review, we aimed to summarize the roles and clinical implications of recently discovered ncRNAs, including long ncRNAs, PIWI-interacting RNAs, tRNA- and Y RNA-derived ncRNAs, and small nucleolar RNAs, in endocrine-related cancers affecting both sexes. We focus on recent studies highlighting discoveries in ncRNA biology and expression in cancer, and conclude with a discussion on the challenges and future directions, including clinical application. ncRNAs show great promise as diagnostic tools and therapeutic targets, but further work is necessary to realize the potential of these unconventional transcripts.

  6. There is a world beyond protein mutations: the role of non-coding RNAs in melanomagenesis.

    PubMed

    Swoboda, Rolf K; Herlyn, Meenhard

    2013-05-01

    Until recently, the general perception has been that mutations in protein-coding genes are responsible for tumorigenesis. With the discovery of (V600E)BRAF in about 50% of cutaneous melanomas, there was an increased effort to find additional mutations. However, mutations characterized in melanoma to date cannot account for the development of all melanomas. With the discovery of microRNAs as important players in melanomagenesis, protein mutations are no longer considered the sole drivers of tumors. Recent research findings have expanded the view for tumor initiation and progression to additional non-coding RNAs. The data suggest that tumorigenesis is likely an interplay between mutated proteins and deregulation of non-coding RNAs in the cell with an additional role of the tumor environment. With the exception of microRNAs, our knowledge of the role of non-coding RNAs in melanoma is in its infancy. Using few examples, we will summarize some of the roles of non-coding RNAs in tumorigenesis. Thus, there is a whole world beyond protein-coding sequences and microRNAs, which can cause melanoma.

  7. Small non-coding RNAs in plant-pathogenic Xanthomonas spp.

    PubMed

    Abendroth, Ulrike; Schmidtke, Cornelius; Bonas, Ulla

    2014-01-01

    The genus Xanthomonas comprises a large group of plant-pathogenic bacteria. The infection and bacterial multiplication in the plant tissue depends on the type III secretion system and other virulence determinants. Recent studies revealed that bacterial virulence is also controlled at the post-transcriptional level by small non-coding RNAs (sRNAs). In this review, we highlight our current knowledge about sRNAs and RNA-binding proteins in Xanthomonas species.

  8. Computational analysis identifies a sponge interaction network between long non-coding RNAs and messenger RNAs in human breast cancer

    PubMed Central

    2014-01-01

    Background Non-coding RNAs (ncRNAs) are emerging as key regulators of many cellular processes in both physiological and pathological states. Moreover, the constant discovery of new non-coding RNA species suggests that the study of their complex functions is still in its very early stages. This variegated class of RNA species encompasses the well-known microRNAs (miRNAs) and the most recently acknowledged long non-coding RNAs (lncRNAs). Interestingly, in the last couple of years, a few studies have shown that some lncRNAs can act as miRNA sponges, i.e. as competing endogenous RNAs (ceRNAs), able to reduce the amount of miRNAs available to target messenger RNAs (mRNAs). Results We propose a computational approach to explore the ability of lncRNAs to act as ceRNAs by protecting mRNAs from miRNA repression. A seed match analysis was performed to validate the underlying regression model. We built normal and cancer networks of miRNA-mediated sponge interactions (MMI-networks) using breast cancer expression data provided by The Cancer Genome Atlas. Conclusions Our study highlights a marked rewiring in the ceRNA program between normal and pathological breast tissue, documented by its “on/off” switch from normal to cancer, and vice-versa. This mutually exclusive activation confers an interesting character to ceRNAs as potential oncosuppressive, or oncogenic, protagonists in cancer. At the heart of this phenomenon is the lncRNA PVT1, as illustrated by both the width of its antagonist mRNAs in normal-MMI-network, and the relevance of the latter in breast cancer. Interestingly, PVT1 revealed a net binding preference towards the mir-200 family as the bone of contention with its rival mRNAs. PMID:25033876

  9. The Mix of Two Worlds: Non-Coding RNAs and Hormones

    PubMed Central

    Shah, Maitri Y.

    2013-01-01

    The recent discovery of functional cell-free circulating microRNAs (miRNAs) in human body fluids has opened new avenues for the application of non-coding RNAs (ncRNAs) as noninvasive, specific and sensitive biomarkers for cancers and other human diseases. In this review, we explore the concept of circulating miRNAs as hormones, and discuss their potential functions in cellular communication and transferring of signals. We also provide a brief overview of their identification, processing, and potential functions and applications in human diseases. PMID:23051203

  10. The mix of two worlds: non-coding RNAs and hormones.

    PubMed

    Shah, Maitri Y; Calin, George A

    2013-02-01

    The recent discovery of functional cell-free circulating microRNAs (miRNAs) in human body fluids has opened new avenues for the application of non-coding RNAs (ncRNAs) as noninvasive, specific and sensitive biomarkers for cancers and other human diseases. In this review, we explore the concept of circulating miRNAs as hormones, and discuss their potential functions in cellular communication and transferring of signals. We also provide a brief overview of their identification, processing, and potential functions and applications in human diseases.

  11. Non-coding RNAs in pluripotency and neural differentiation of human pluripotent stem cells

    PubMed Central

    Lukovic, Dunja; Moreno-Manzano, Victoria; Klabusay, Martin; Stojkovic, Miodrag; Bhattacharya, Shomi S.; Erceg, Slaven

    2014-01-01

    Several studies have demonstrated the important role of non-coding RNAs as regulators of posttranscriptional processes, including stem cells self-renewal and neural differentiation. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (ihPSCs) show enormous potential in regenerative medicine due to their capacity to differentiate to virtually any type of cells of human body. Deciphering the role of non-coding RNAs in pluripotency, self-renewal and neural differentiation will reveal new molecular mechanisms involved in induction and maintenances of pluripotent state as well as triggering these cells toward clinically relevant cells for transplantation. In this brief review we will summarize recently published studies which reveal the role of non-coding RNAs in pluripotency and neural differentiation of hESCs and ihPSC. PMID:24860598

  12. The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease.

    PubMed

    Gomes, Clarissa P C; Spencer, Helen; Ford, Kerrie L; Michel, Lauriane Y M; Baker, Andrew H; Emanueli, Costanza; Balligand, Jean-Luc; Devaux, Yvan

    2017-09-15

    The popularization of genome-wide analyses and RNA sequencing led to the discovery that a large part of the human genome, while effectively transcribed, does not encode proteins. Long non-coding RNAs have emerged as critical regulators of gene expression in both normal and disease states. Studies of long non-coding RNAs expressed in the heart, in combination with gene association studies, revealed that these molecules are regulated during cardiovascular development and disease. Some long non-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potential therapeutic targets. Here, we review the current knowledge of the function of long non-coding RNAs in the cardiovascular system, with an emphasis on cardiovascular development and biology, focusing on hypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure. We discuss potential therapeutic implications and the challenges of long non-coding RNA research, with directions for future research and translational focus. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  13. MicroRNAs: Non-coding fine tuners of receptor tyrosine kinase signalling in cancer.

    PubMed

    Donzelli, Sara; Cioce, Mario; Muti, Paola; Strano, Sabrina; Yarden, Yosef; Blandino, Giovanni

    2016-02-01

    Emerging evidence point to a crucial role for non-coding RNAs in modulating homeostatic signaling under physiological and pathological conditions. MicroRNAs, the best-characterized non-coding RNAs to date, can exquisitely integrate spatial and temporal signals in complex networks, thereby confer specificity and sensitivity to tissue response to changes in the microenvironment. MicroRNAs appear as preferential partners for Receptor Tyrosine Kinases (RTKs) in mediating signaling under stress conditions. Stress signaling can be especially relevant to disease. Here we focus on the ability of microRNAs to mediate RTK signaling in cancer, by acting as both tumor suppressors and oncogenes. We will provide a few general examples of microRNAs modulating specific tumorigenic functions downstream of RTK signaling and integrate oncogenic signals from multiple RTKs. A special focus will be devoted to epidermal growth factor receptor (EGFR) signaling, a system offering relatively rich information. We will explore the role of selected microRNAs as bidirectional modulators of EGFR functions in cancer cells. In addition, we will present the emerging evidence for microRNAs being specifically modulated by oncogenic EGFR mutants and we will discuss how this impinges on EGFRmut driven chemoresistance, which fits into the tumor heterogeneity-driven cancer progression. Finally, we discuss how other non-coding RNA species are emerging as important modulators of cancer progression and why the scenario depicted herein is destined to become increasingly complex in the future.

  14. Non-coding RNAs deregulation in oral squamous cell carcinoma: advances and challenges.

    PubMed

    Yu, T; Li, C; Wang, Z; Liu, K; Xu, C; Yang, Q; Tang, Y; Wu, Y

    2016-05-01

    Oral squamous cell carcinoma (OSCC) is a common cause of cancer death. Despite decades of improvements in exploring new treatments and considerable advance in multimodality treatment, satisfactory curative rates have not yet been reached. The difficulty of early diagnosis and the high prevalence of metastasis associated with OSCC contribute to its dismal prognosis. In the last few decades the emerging data from both tumor biology and clinical trials led to growing interest in the research for predictive biomarkers. Non-coding RNAs (ncRNAs) are promising biomarkers. Among numerous kinds of ncRNAs, short ncRNAs, such as microRNAs (miRNAs), have been extensively investigated with regard to their biogenesis, function, and importance in carcinogenesis. In contrast to miRNAs, long non-coding RNAs (lncRNAs) are much less known concerning their functions in human cancers especially in OSCC. The present review highlighted the roles of miRNAs and newly discovered lncRNAs in oral tumorigenesis, metastasis, and their clinical implication.

  15. Role of Non-Coding RNAs in the Transgenerational Epigenetic Transmission of the Effects of Reprotoxicants

    PubMed Central

    Larriba, Eduardo; del Mazo, Jesús

    2016-01-01

    Non-coding RNAs (ncRNAs) are regulatory elements of gene expression and chromatin structure. Both long and small ncRNAs can also act as inductors and targets of epigenetic programs. Epigenetic patterns can be transmitted from one cell to the daughter cell, but, importantly, also through generations. Diversity of ncRNAs is emerging with new and surprising roles. Functional interactions among ncRNAs and between specific ncRNAs and structural elements of the chromatin are drawing a complex landscape. In this scenario, epigenetic changes induced by environmental stressors, including reprotoxicants, can explain some transgenerationally-transmitted phenotypes in non-Mendelian ways. In this review, we analyze mechanisms of action of reprotoxicants upon different types of ncRNAs and epigenetic modifications causing transgenerationally transmitted characters through germ cells but affecting germ cells and reproductive systems. A functional model of epigenetic mechanisms of transgenerational transmission ncRNAs-mediated is also proposed. PMID:27023531

  16. Role of Non-Coding RNAs in the Transgenerational Epigenetic Transmission of the Effects of Reprotoxicants.

    PubMed

    Larriba, Eduardo; del Mazo, Jesús

    2016-03-25

    Non-coding RNAs (ncRNAs) are regulatory elements of gene expression and chromatin structure. Both long and small ncRNAs can also act as inductors and targets of epigenetic programs. Epigenetic patterns can be transmitted from one cell to the daughter cell, but, importantly, also through generations. Diversity of ncRNAs is emerging with new and surprising roles. Functional interactions among ncRNAs and between specific ncRNAs and structural elements of the chromatin are drawing a complex landscape. In this scenario, epigenetic changes induced by environmental stressors, including reprotoxicants, can explain some transgenerationally-transmitted phenotypes in non-Mendelian ways. In this review, we analyze mechanisms of action of reprotoxicants upon different types of ncRNAs and epigenetic modifications causing transgenerationally transmitted characters through germ cells but affecting germ cells and reproductive systems. A functional model of epigenetic mechanisms of transgenerational transmission ncRNAs-mediated is also proposed.

  17. Long antisense non-coding RNAs and the epigenetic regulation of gene expression.

    PubMed

    Vadaie, Nadia; Morris, Kevin V

    2013-08-01

    Shortly after the completion of the human genome project in 2003, the Encode project was launched. The project was set out to identify the functional elements in the human genome, and unexpectedly it was found that >80% of the genome is transcribed. The Encode project identified those transcribed regions of the genome to be encoded by non-coding RNAs (ncRNAs). With only 2% of the genome carrying gene-encoding proteins, the conundrum was then, what is the function, if any, of these non-coding regions of the genome? These ncRNAs included both short and long RNAs. The focus of this review will be on antisense long non-coding RNAs (lncRNAs), as these transcripts have been observed to play a role in gene expression of protein-coding genes. Some lncRNAs have been found to regulate protein-coding gene transcription at the epigenetic level, whereby they suppress transcription through the recruitment of protein complexes to target loci in the genome. Conversely, there are lncRNAs that have a positive role in gene expression with less known about mechanism, and some lncRNAs have been shown to be involved in post-transcriptional processes. Additionally, lncRNAs have been observed to regulate their own expression in a positive feedback loop by functioning as a decoy. The biological significance of lncRNAs is only just now becoming evident, with many lncRNAs found to play a significant role in several human diseases.

  18. Characterization of Sus scrofa small non-coding RNAs present in both female and male gonads.

    PubMed

    Kowalczykiewicz, Dorota; Świercz, Aleksandra; Handschuh, Luiza; Leśniak, Katarzyna; Figlerowicz, Marek; Wrzesinski, Jan

    2014-01-01

    Small non-coding RNAs (sncRNAs) are indispensable for proper germ cell development, emphasizing the need for greater elucidation of the mechanisms of germline development and regulation of this process by sncRNAs. We used deep sequencing to characterize three families of small non-coding RNAs (piRNAs, miRNAs, and tRFs) present in Sus scrofa gonads and focused on the small RNA fraction present in both male and female gonads. Although similar numbers of reads were obtained from both types of gonads, the number of unique RNA sequences in the ovaries was several times lower. Of the sequences detected in the testes, 2.6% of piRNAs, 9% of miRNAs, and 10% of tRFs were also present in the ovaries. Notably, the majority of the shared piRNAs mapped to ribosomal RNAs and were derived from clustered loci. In addition, the most abundant miRNAs present in the ovaries and testes are conserved and are involved in many biological processes such as the regulation of homeobox genes, the control of cell proliferation, and carcinogenesis. Unexpectedly, we detected a novel sncRNA type, the tRFs, which are 30-36-nt RNA fragments derived from tRNA molecules, in gonads. Analysis of S. scrofa piRNAs show that testes specific piRNAs are biased for 5' uracil but both testes and ovaries specific piRNAs are not biased for adenine at the 10th nucleotide position. These observations indicate that adult porcine piRNAs are predominantly produced by a primary processing pathway or other mechanisms and secondary piRNAs generated by ping-pong mechanism are absent.

  19. The underlying mechanisms of non-coding RNAs in the chemoresistance of pancreatic cancer.

    PubMed

    Xiong, Guangbing; Feng, Mengyu; Yang, Gang; Zheng, Suli; Song, Xujun; Cao, Zhe; You, Lei; Zheng, Lianfang; Hu, Ya; Zhang, Taiping; Zhao, Yupei

    2017-07-01

    Pancreatic cancer, which is often asymptomatic, is currently one of the most common causes of cancer-related death. This phenomenon is most likely due to a lack of early diagnosis, a high metastasis rate and a disappointing chemotherapy outcome. Thus, improving treatment outcomes by overcoming chemotherapy resistance may be a useful strategy in pancreatic cancer. Various underlying mechanisms involved in the chemoresistance of pancreatic cancer have been investigated. Notably, non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a pivotal role in regulating sensitivity to chemotherapy in pancreatic cancer. In this review, we highlight recent evidence regarding the role of miRNAs and lncRNAs in the chemoresistance of pancreatic cancer, including their expression levels, targets, biological functions and the regulation of chemoresistance, and discuss the potential clinical application of miRNAs and lncRNAs in the treatment of pancreatic cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Computational identification of human long intergenic non-coding RNAs using a GA-SVM algorithm.

    PubMed

    Wang, Yanqiu; Li, Yang; Wang, Qi; Lv, Yingli; Wang, Shiyuan; Chen, Xi; Yu, Xuexin; Jiang, Wei; Li, Xia

    2014-01-01

    Long intergenic non-coding RNAs (lincRNAs) are a new type of non-coding RNAs and are closely related with the occurrence and development of diseases. In previous studies, most lincRNAs have been identified through next-generation sequencing. Because lincRNAs exhibit tissue-specific expression, the reproducibility of lincRNA discovery in different studies is very poor. In this study, not including lincRNA expression, we used the sequence, structural and protein-coding potential features as potential features to construct a classifier that can be used to distinguish lincRNAs from non-lincRNAs. The GA-SVM algorithm was performed to extract the optimized feature subset. Compared with several feature subsets, the five-fold cross validation results showed that this optimized feature subset exhibited the best performance for the identification of human lincRNAs. Moreover, the LincRNA Classifier based on Selected Features (linc-SF) was constructed by support vector machine (SVM) based on the optimized feature subset. The performance of this classifier was further evaluated by predicting lincRNAs from two independent lincRNA sets. Because the recognition rates for the two lincRNA sets were 100% and 99.8%, the linc-SF was found to be effective for the prediction of human lincRNAs.

  1. The RNA-centred view of the synapse: non-coding RNAs and synaptic plasticity

    PubMed Central

    Smalheiser, Neil R.

    2014-01-01

    If mRNAs were the only RNAs made by a neuron, there would be a simple mapping of mRNAs to proteins. However, microRNAs and other non-coding RNAs (ncRNAs; endo-siRNAs, piRNAs, BC1, BC200, antisense and long ncRNAs, repeat-related transcripts, etc.) regulate mRNAs via effects on protein translation as well as transcriptional and epigenetic mechanisms. Not only are genes ON or OFF, but their ability to be translated can be turned ON or OFF at the level of synapses, supporting an enormous increase in information capacity. Here, I review evidence that ncRNAs are expressed pervasively within dendrites in mammalian brain; that some are activity-dependent and highly enriched near synapses; and that synaptic ncRNAs participate in plasticity responses including learning and memory. Ultimately, ncRNAs can be viewed as the post-it notes of the neuron. They have no literal meaning of their own, but derive their functions from where (and to what) they are stuck. This may explain, in part, why ncRNAs differ so dramatically from protein-coding genes, both in terms of the usual indicators of functionality and in terms of evolutionary constraints. ncRNAs do not appear to be direct mediators of synaptic transmission in the manner of neurotransmitters or receptors, yet they orchestrate synaptic plasticity—and may drive species-specific changes in cognition. PMID:25135965

  2. Mammalian hibernation and regulation of lipid metabolism: a focus on non-coding RNAs.

    PubMed

    Lang-Ouellette, D; Richard, T G; Morin, P

    2014-11-01

    Numerous species will confront severe environmental conditions by undergoing significant metabolic rate reduction. Mammalian hibernation is one such natural model of hypometabolism. Hibernators experience considerable physiological, metabolic, and molecular changes to survive the harsh challenges associated with winter. Whether as fuel source or as key signaling molecules, lipids are of primary importance for a successful bout of hibernation and their careful regulation throughout this process is essential. In recent years, a plethora of non-coding RNAs has emerged as potential regulators of targets implicated in lipid metabolism in diverse models. In this review, we introduce the general characteristics associated with mammalian hibernation, present the importance of lipid metabolism prior to and during hibernation, as well as discuss the potential relevance of non-coding RNAs such as miRNAs and lncRNAs during this process.

  3. Long non-coding RNAs act as regulators of cell autophagy in diseases

    PubMed Central

    Xu, Zhijie; Yan, Yuanliang; Qian, Long; Gong, Zhicheng

    2017-01-01

    Identification of long non-coding RNAs (lncRNAs) has provided a substantial increase in our understanding of the non-coding transcriptome. Studies have revealed a crucial function of lncRNAs in the modulation of cell autophagy in vitro and in vivo, further contributing to the hallmarks of disease phenotypes. These findings have profoundly altered our understanding of disease pathobiology, and may lead to the emergence of new biological concepts underlying autophagy-associated diseases, such as the carcinomas. Studies on the molecular mechanism of the lncRNA-autophagy axis may offer additional avenues for therapeutic intervention and biomarker assessment. In this review, we discuss recent findings on the multiple molecular roles of regulatory lncRNAs in the signaling pathways of cell autophagy. The emerging knowledge in this rapidly advancing field will offer novel insights into human diseases, especially cancers. PMID:28184916

  4. Non-coding RNAs: Epigenetic regulators of bone development and homeostasis.

    PubMed

    Hassan, Mohammad Q; Tye, Coralee E; Stein, Gary S; Lian, Jane B

    2015-12-01

    Non-coding RNAs (ncRNAs) have evolved in eukaryotes as epigenetic regulators of gene expression. The most abundant regulatory ncRNAs are the 20-24 nt small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs, <200 nt). Each class of ncRNAs operates through distinct mechanisms, but their pathways to regulating gene expression are interrelated in ways that are just being recognized. While the importance of lncRNAs in epigenetic control of transcription, developmental processes and human traits is emerging, the identity of lncRNAs in skeletal biology is scarcely known. However, since the first profiling studies of miRNA at stages during osteoblast and osteoclast differentiation, over 1100 publications related to bone biology and pathologies can be found, as well as many recent comprehensive reviews summarizing miRNA in skeletal cells. Delineating the activities and targets of specific miRNAs regulating differentiation of osteogenic and resorptive bone cells, coupled with in vivo gain- and loss-of-function studies, discovered unique mechanisms that support bone development and bone homeostasis in adults. We present here "guiding principles" for addressing biological control of bone tissue formation by ncRNAs. This review emphasizes recent advances in understanding regulation of the process of miRNA biogenesis that impact on osteogenic lineage commitment, transcription factors and signaling pathways. Also discussed are the approaches to be pursued for an understanding of the role of lncRNAs in bone and the challenges in addressing their multiple and complex functions. Based on new knowledge of epigenetic control of gene expression to be gained for ncRNA regulation of the skeleton, new directions for translating the miRNAs and lncRNAs into therapeutic targets for skeletal disorders are possible. This article is part of a Special Issue entitled Epigenetics and Bone. Published by Elsevier Inc.

  5. Emerging Roles for Non-Coding RNAs in Male Reproductive Development in Flowering Plants.

    PubMed

    Grant-Downton, Robert; Rodriguez-Enriquez, Josefina

    2012-12-04

    Knowledge of sexual reproduction systems in flowering plants is essential to humankind, with crop fertility vitally important for food security. Here, we review rapidly emerging new evidence for the key importance of non-coding RNAs in male reproductive development in flowering plants. From the commitment of somatic cells to initiating reproductive development through to meiosis and the development of pollen-containing the male gametes (sperm cells)-in the anther, there is now overwhelming data for a diversity of non-coding RNAs and emerging evidence for crucial roles for them in regulating cellular events at these developmental stages. A particularly exciting development has been the association of one example of cytoplasmic male sterility, which has become an unparalleled breeding tool for producing new crop hybrids, with a non-coding RNA locus.

  6. Emerging Roles for Non-Coding RNAs in Male Reproductive Development in Flowering Plants

    PubMed Central

    Grant-Downton, Robert; Rodriguez-Enriquez, Josefina

    2012-01-01

    Knowledge of sexual reproduction systems in flowering plants is essential to humankind, with crop fertility vitally important for food security. Here, we review rapidly emerging new evidence for the key importance of non-coding RNAs in male reproductive development in flowering plants. From the commitment of somatic cells to initiating reproductive development through to meiosis and the development of pollen—containing the male gametes (sperm cells)—in the anther, there is now overwhelming data for a diversity of non-coding RNAs and emerging evidence for crucial roles for them in regulating cellular events at these developmental stages. A particularly exciting development has been the association of one example of cytoplasmic male sterility, which has become an unparalleled breeding tool for producing new crop hybrids, with a non-coding RNA locus. PMID:24970151

  7. Expression signatures of long non-coding RNAs in early brain injury following experimental subarachnoid hemorrhage.

    PubMed

    Zheng, Bingjie; Liu, Huailei; Wang, Ruke; Xu, Shancai; Liu, Yaohua; Wang, Kaikai; Hou, Xu; Shen, Chen; Wu, Jianing; Chen, Xin; Wu, Pei; Zhang, Guang; Ji, Zhiyong; Wang, Hongyu; Xiao, Yao; Han, Jianyi; Shi, Huaizhang; Zhao, Shiguang

    2015-07-01

    Subarachnoid hemorrhage (SAH) is an important cause of mortality in stroke patients. Long non-coding RNAs (LncRNAs) have important functions in brain disease, however their expression profiles in SAH remain to be elucidated. The present study aimed to investigate the expression signatures of LncRNAs and mRNAs in early brain injury (EBI) following SAH in a rat model. Male Wistar rats were randomly divided into an SAH group and a sham operation group. The expression signatures of the LncRNAs and mRNAs in the temporal lobe cortex were investigated using a rat LncRNAs array following experimental SAH. The results revealed that there were 144 downregulated and 64 upregulated LncRNAs and 181 downregulated and 221 upregulated mRNAs following SAH. Additionally, two upregulated (BC092207, MRuc008hvl) and three downregulated (XR_006756, MRAK038897, MRAK017168) LncRNAs were confirmed using reverse transcription quantitative polymerase chain reaction. The differentially expressed mRNAs were further analyzed using the Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The pathway analysis results provided by the KEGG database indicated that eight pathways associated with inflammation were involved in EBI following SAH. In conclusion, these results demonstrated that the expression profiles of the LncRNAs and mRNAs were significantly different between the SAH-induced EBI group and the sham operation group. These differently expressed LncRNAs may be important in EBI following SAH.

  8. New technologies accelerate the exploration of non-coding RNAs in horticultural plants.

    PubMed

    Liu, Degao; Mewalal, Ritesh; Hu, Rongbin; Tuskan, Gerald A; Yang, Xiaohan

    2017-01-01

    Non-coding RNAs (ncRNAs), that is, RNAs not translated into proteins, are crucial regulators of a variety of biological processes in plants. While protein-encoding genes have been relatively well-annotated in sequenced genomes, accounting for a small portion of the genome space in plants, the universe of plant ncRNAs is rapidly expanding. Recent advances in experimental and computational technologies have generated a great momentum for discovery and functional characterization of ncRNAs. Here we summarize the classification and known biological functions of plant ncRNAs, review the application of next-generation sequencing (NGS) technology and ribosome profiling technology to ncRNA discovery in horticultural plants and discuss the application of new technologies, especially the new genome-editing tool clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) systems, to functional characterization of plant ncRNAs.

  9. Long Non-Coding RNAs As Potential Novel Prognostic Biomarkers in Colorectal Cancer

    PubMed Central

    Saus, Ester; Brunet-Vega, Anna; Iraola-Guzmán, Susana; Pegueroles, Cinta; Gabaldón, Toni; Pericay, Carles

    2016-01-01

    Colorectal cancer (CRC) is the fourth most common cause of death worldwide. Surgery is usually the first line of treatment for patients with CRC but many tumors with similar histopathological features show significantly different clinical outcomes. The discovery of robust prognostic biomarkers in patients with CRC is imperative to achieve more effective treatment strategies and improve patient's care. Recent progress in next generation sequencing methods and transcriptome analysis has revealed that a much larger part of the genome is transcribed into RNA than previously assumed. Collectively referred to as non-coding RNAs (ncRNAs), some of these RNA molecules such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been shown to be altered and to play critical roles in tumor biology. This discovery leads to exciting possibilities for personalized cancer diagnosis, and therapy. Many lncRNAs are tissue and cancer-type specific and have already revealed to be useful as prognostic markers. In this review, we focus on recent findings concerning aberrant expression of lncRNAs in CRC tumors and emphasize their prognostic potential in CRC. Further studies focused on the mechanisms of action of lncRNAs will contribute to the development of novel biomarkers for diagnosis and disease progression. PMID:27148353

  10. Comprehensive characterization of cancer subtype associated long non-coding RNAs and their clinical implications.

    PubMed

    Zhao, Weihong; Luo, Jiancheng; Jiao, Shunchang

    2014-10-13

    Long non-coding RNAs (lncRNAs) are a kind of RNAs with regulation that participate fundamental cellular processes via diverse mechanisms. Despite the potential importance of lncRNAs in multiple kinds of cancer has been well studied, no comprehensive survey of cancer subtype associated lncRNAs. Here, we performed an array-based transcriptional survey of lncRNAs across 150 lung cancer samples comprising both adenocarcinoma and squamous cell carcinoma, and 306 breast cancer patients with clear clinical information. In lung cancer, 72 lncRNAs are identified to be associated with tumor subtypes and their functions as well as the associated proteins are predicted by constructing coding-non-coding co-expression network. The results suggest that they are mostly related with epidermis development, cell adhesion and response to stimulus. The validation results show the high concordance and confirmed the robust of the identification results. In breast cancer, we found 3 lncRNA genes are associated with estrogen receptor α (ER) positive and ER negative subtypes and tumor histologic grade. Survival (Kaplan-Meier) analysis results suggest that the expression pattern of the 3 lncRNAs is significantly correlated with clinical outcomes. The current study provides the first large-scale survey of lncRNAs within cancer subtypes, and may offer new targets for their diagnosis, therapy and prognosis.

  11. Current Status of Long Non-Coding RNAs in Human Breast Cancer

    PubMed Central

    Cerk, Stefanie; Schwarzenbacher, Daniela; Adiprasito, Jan Basri; Stotz, Michael; Hutterer, Georg C.; Gerger, Armin; Ling, Hui; Calin, George Adrian; Pichler, Martin

    2016-01-01

    Breast cancer represents a major health burden in Europe and North America, as recently published data report breast cancer as the second leading cause of cancer related death in women worldwide. Breast cancer is regarded as a highly heterogeneous disease in terms of clinical course and biological behavior and can be divided into several molecular subtypes, with different prognosis and treatment responses. The discovery of numerous non-coding RNAs has dramatically changed our understanding of cell biology, especially the pathophysiology of cancer. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts >200 nucleotides in length. Several studies have demonstrated their role as key regulators of gene expression, cell biology and carcinogenesis. Deregulated expression levels of lncRNAs have been observed in various types of cancers including breast cancer. lncRNAs are involved in cancer initiation, progression, and metastases. In this review, we summarize the recent literature to highlight the current status of this class of long non-coding lncRNAs in breast cancer. PMID:27608009

  12. BmncRNAdb: a comprehensive database of non-coding RNAs in the silkworm, Bombyx mori.

    PubMed

    Zhou, Qiu-Zhong; Zhang, Bindan; Yu, Quan-You; Zhang, Ze

    2016-09-13

    Long non-coding RNAs (lncRNAs) may play critical roles in a wide range of developmental processes of higher organisms. Recently, lncRNAs have been widely identified across eukaryotes and many databases of lncRNAs have been developed for human, mouse, fruit fly, etc. However, there is rare information about them in the only completely domesticated insect, silkworm (Bombyx mori). In this study, we systematically scanned lncRNAs using the available silkworm RNA-seq data and public unigenes. Finally, we identified and collected 6281 lncRNAs in the silkworm. Besides, we also collected 1986 microRNAs (miRNAs) from previous studies. Then, we organized them into a comprehensive and web-based database, BmncRNAdb. This database offers a user-friendly interface for data browse and online analysis as well as the three online tools for users to predict the target genes of lncRNA or miRNA. We have systematically identified and collected the silkworm lncRNAs and constructed a comprehensive database of the silkworm lncRNAs and miRNAs. This work gives a glimpse into lncRNAs of the silkworm and lays foundations for the ncRNAs study of the silkworm and other insects in the future. The BmncRNAdb is freely available at http://gene.cqu.edu.cn/BmncRNAdb/index.php .

  13. Developmental programming of long non-coding RNAs during postnatal liver maturation in mice.

    PubMed

    Peng, Lai; Paulson, Ariel; Li, Hua; Piekos, Stephanie; He, Xi; Li, Linheng; Zhong, Xiao-Bo

    2014-01-01

    The liver is a vital organ with critical functions in metabolism, protein synthesis, and immune defense. Most of the liver functions are not mature at birth and many changes happen during postnatal liver development. However, it is unclear what changes occur in liver after birth, at what developmental stages they occur, and how the developmental processes are regulated. Long non-coding RNAs (lncRNAs) are involved in organ development and cell differentiation. Here, we analyzed the transcriptome of lncRNAs in mouse liver from perinatal (day -2) to adult (day 60) by RNA-Sequencing, with an attempt to understand the role of lncRNAs in liver maturation. We found around 15,000 genes expressed, including about 2,000 lncRNAs. Most lncRNAs were expressed at a lower level than coding RNAs. Both coding RNAs and lncRNAs displayed three major ontogenic patterns: enriched at neonatal, adolescent, or adult stages. Neighboring coding and non-coding RNAs showed the trend to exhibit highly correlated ontogenic expression patterns. Gene ontology (GO) analysis revealed that some lncRNAs enriched at neonatal ages have their neighbor protein coding genes also enriched at neonatal ages and associated with cell proliferation, immune activation related processes, tissue organization pathways, and hematopoiesis; other lncRNAs enriched at adolescent ages have their neighbor protein coding genes associated with different metabolic processes. These data reveal significant functional transition during postnatal liver development and imply the potential importance of lncRNAs in liver maturation.

  14. Non-coding RNAs and heme oxygenase-1 in vaccinia virus infection

    SciTech Connect

    Meseda, Clement A.; Srinivasan, Kumar; Wise, Jasen; Catalano, Jennifer; Yamada, Kenneth M.; Dhawan, Subhash

    2014-11-07

    Highlights: • Heme oxygenase-1 (HO-1) induction inhibited vaccinia virus infection of macrophages. • Reduced infectivity inversely correlated with increased expression of non-coding RNAs. • The regulation of HO-1 and ncRNAs suggests a novel host defense response against vaccinia virus infection. - Abstract: Small nuclear RNAs (snRNAs) are <200 nucleotide non-coding uridylate-rich RNAs. Although the functions of many snRNAs remain undetermined, a population of snRNAs is produced during the early phase of infection of cells by vaccinia virus. In the present study, we demonstrate a direct correlation between expression of the cytoprotective enzyme heme oxygenase-1 (HO-1), suppression of selective snRNA expression, and inhibition of vaccinia virus infection of macrophages. Hemin induced HO-1 expression, completely reversed virus-induced host snRNA expression, and suppressed vaccinia virus infection. This involvement of specific virus-induced snRNAs and associated gene clusters suggests a novel HO-1-dependent host-defense pathway in poxvirus infection.

  15. Non-Coding RNAs: The “Dark Matter” of Cardiovascular Pathophysiology

    PubMed Central

    Iaconetti, Claudio; Gareri, Clarice; Polimeni, Alberto; Indolfi, Ciro

    2013-01-01

    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. PMID:24113581

  16. Role of non-coding RNAs in pancreatic cancer: the bane of the microworld.

    PubMed

    Tang, Yi-Ting; Xu, Xiao-Hui; Yang, Xiao-Dong; Hao, Jun; Cao, Han; Zhu, Wei; Zhang, Shu-Yu; Cao, Jian-Ping

    2014-07-28

    Our understanding of the mechanisms underlying the development of pancreatic cancer has been greatly advanced. However, the molecular events involved in the initiation and development of pancreatic cancer remain inscrutable. None of the present medical technologies have been proven to be effective in significantly improving early detection or reducing the mortality/morbidity of this disease. Thus, a better understanding of the molecular basis of pancreatic cancer is required for the identification of more effective diagnostic markers and therapeutic targets. Non-coding RNAs (ncRNAs), generally including microRNAs and long non-coding RNAs, have recently been found to be deregulated in many human cancers, which provides new opportunities for identifying both functional drivers and specific biomarkers of pancreatic cancer. In this article, we review the existing literature in the field documenting the significance of aberrantly expressed and functional ncRNAs in human pancreatic cancer, and discuss how oncogenic ncRNAs may be involved in the genetic and epigenetic networks regulating functional pathways that are deregulated in this malignancy, particularly of the ncRNAs' role in drug resistance and epithelial-mesenchymal transition biological phenotype, with the aim of analyzing the feasibility of clinical application of ncRNAs in the diagnosis and treatment of pancreatic cancer.

  17. Whole transcriptome microarrays identify long non-coding RNAs associated with cardiac hypertrophy

    PubMed Central

    Zhang, Lu; Hamad, Eman A.; Vausort, Mélanie; Funakoshi, Hajime; Nicot, Nathalie; Nazarov, Petr V.; Vallar, Laurent; Feldman, Arthur M.; Wagner, Daniel R.; Devaux, Yvan

    2015-01-01

    Long non-coding RNAs (lncRNAs) have recently emerged as a novel group of non-coding RNAs able to regulate gene expression. While their role in cardiac disease is only starting to be understood, their involvement in cardiac hypertrophy is poorly known. We studied the association between lncRNAs and left ventricular hypertrophy using whole transcriptome microarrays. Wild-type mice and mice overexpressing the adenosine A2A receptor were subjected to transverse aortic constriction (TAC) to induce left ventricular hypertrophy. Expression profiles of lncRNAs in the heart were characterized using genome-wide microarrays. An analytical pipeline was specifically developed to extract lncRNA data from microarrays. We identified 2 lncRNAs up-regulated and 3 lncRNAs down-regulated in the hearts of A2A-receptor overexpressing-mice subjected to TAC compared to wild-type mice. Differential expression of these 2 lncRNAs was validated by quantitative PCR. Complete microarray dataset is available at Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE45423. Here, we describe in details the experimental design, microarray performance and analysis. PMID:26484228

  18. Long non-coding RNAs as novel therapeutic targets in cancer.

    PubMed

    Lavorgna, Giovanni; Vago, Riccardo; Sarmini, Mohamad; Montorsi, Francesco; Salonia, Andrea; Bellone, Matteo

    2016-08-01

    Thanks to impressive technology advancements, pervasive expression of non-coding RNAs (ncRNAs) has been recently identified in the genome of numerous cancers. Long ncRNAs (lncRNAs) belong to a new class of ncRNAs including tens of thousands different species. A fraction of these molecules shows a striking cancer-enriched expression pattern, suggesting an essential role in tumor cells and, possibly, a utility in therapeutic terms. This review aims at summarizing current knowledge for the identification and validation of lncRNAs as therapeutics targets in tumors. Both in-silico and wet-biology resources are presented in relation to the many challenges that the scientific community still needs to address in terms of lncRNA identification, stratification, patient personalization, drug delivery and toxicity.

  19. The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease

    PubMed Central

    Roberts, Thomas C.; Morris, Kevin V.; Wood, Matthew J. A.

    2014-01-01

    Long non-coding RNAs (lncRNAs) are transcripts with low protein-coding potential that represent a large proportion of the transcriptional output of the cell. Many lncRNAs exhibit features indicative of functionality including tissue-restricted expression, localization to distinct subcellular structures, regulated expression and evolutionary conservation. Some lncRNAs have been shown to associate with chromatin-modifying activities and transcription factors, suggesting that a common mode of action may be to guide protein complexes to target genomic loci. However, the functions (if any) of the vast majority of lncRNA transcripts are currently unknown, and the subject of investigation. Here, we consider the putative role(s) of lncRNAs in neurodevelopment and brain function with an emphasis on the epigenetic regulation of gene expression. Associations of lncRNAs with neurodevelopmental/neuropsychiatric disorders, neurodegeneration and brain cancers are also discussed. PMID:25135968

  20. The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease.

    PubMed

    Roberts, Thomas C; Morris, Kevin V; Wood, Matthew J A

    2014-09-26

    Long non-coding RNAs (lncRNAs) are transcripts with low protein-coding potential that represent a large proportion of the transcriptional output of the cell. Many lncRNAs exhibit features indicative of functionality including tissue-restricted expression, localization to distinct subcellular structures, regulated expression and evolutionary conservation. Some lncRNAs have been shown to associate with chromatin-modifying activities and transcription factors, suggesting that a common mode of action may be to guide protein complexes to target genomic loci. However, the functions (if any) of the vast majority of lncRNA transcripts are currently unknown, and the subject of investigation. Here, we consider the putative role(s) of lncRNAs in neurodevelopment and brain function with an emphasis on the epigenetic regulation of gene expression. Associations of lncRNAs with neurodevelopmental/neuropsychiatric disorders, neurodegeneration and brain cancers are also discussed.

  1. MetastamiRs: Non-Coding MicroRNAs Driving Cancer Invasion and Metastasis

    PubMed Central

    Lopez-Camarillo, Cesar; Marchat, Laurence A.; Arechaga-Ocampo, Elena; Perez-Plasencia, Carlos; del Moral-Hernandez, Oscar; Castaneda-Ortiz, Elizabeth J.; Rodriguez-Cuevas, Sergio

    2012-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides that function as negative regulators of gene expression by either inhibiting translation or inducing deadenylation-dependent degradation of target transcripts. Notably, deregulation of miRNAs expression is associated with the initiation and progression of human cancers where they act as oncogenes or tumor suppressors contributing to tumorigenesis. Abnormal miRNA expression may provide potential diagnostic and prognostic tumor biomarkers and new therapeutic targets in cancer. Recently, several miRNAs have been shown to initiate invasion and metastasis by targeting multiple proteins that are major players in these cellular events, thus they have been denominated as metastamiRs. Here, we present a review of the current knowledge of miRNAs in cancer with a special focus on metastamiRs. In addition we discuss their potential use as novel specific markers for cancer progression. PMID:22408395

  2. New Neurons in Aging Brains: Molecular Control by Small Non-Coding RNAs

    PubMed Central

    Schouten, Marijn; Buijink, M. Renate; Lucassen, Paul J.; Fitzsimons, Carlos P.

    2012-01-01

    Adult neurogenesis generates functional neurons from neural stem cells present in specific brain regions. It is largely confined to two main regions: the subventricular zone of the lateral ventricle, and the subgranular zone of the dentate gyrus (DG), in the hippocampus. With age, the function of the hippocampus and particularly the DG is impaired. For instance, adult neurogenesis is decreased with aging, in both proliferating and differentiation of newborn cells, while in parallel an age-associated decline in cognitive performance is often seen. Surprisingly, the synaptogenic potential of adult-born neurons is only marginally influenced by aging. Therefore, although proliferation, differentiation, and synaptogenesis of adult-born new neurons in the DG are closely related to each other, they are differentially affected by aging. In this review we discuss the crucial roles of a novel class of recently discovered modulators of gene expression, the small non-coding RNAs, in the regulation of adult neurogenesis. Multiple small non-coding RNAs are differentially expressed in the hippocampus. In particular a subgroup of the small non-coding RNAs, the microRNAs, fine-tune the progression of adult neurogenesis. This makes small non-coding RNAs appealing candidates to orchestrate the functional alterations in adult neurogenesis and cognition associated with aging. Finally, we summarize observations that link changes in circulating levels of steroid hormones with alterations in adult neurogenesis, cognitive decline, and vulnerability to psychopathology in advanced age, and discuss a potential interplay between steroid hormone receptors and microRNAs in cognitive decline in aging individuals. PMID:22363255

  3. Non-coding RNAs and Hypertension–Unveiling Unexpected Mechanisms of Hypertension by the Dark Matter of the Genome

    PubMed Central

    Murakami, Kazuo

    2015-01-01

    Hypertension is a major risk factor of cardiovascular diseases and a most important health problem in developed countries. Investigations on pathophysiology of hypertension have been based on gene products from coding region that occupies only about 1% of total genome region. On the other hand, non-coding region that occupies almost 99% of human genome has been regarded as “junk” for a long time and went unnoticed until these days. But recently, it turned out that non-coding region is extensively transcribed to non-coding RNAs and has various functions. This review highlights recent updates on the significance of non-coding RNAs such as micro RNAs and long non-coding RNAs (lncRNAs) on the pathogenesis of hypertension, also providing an introduction to basic biology of non-coding RNAs. For example, microRNAs are associated with hypertension via neuro-fumoral factor, sympathetic nerve activity, ion transporters in kidneys, endothelial function, vascular smooth muscle phenotype transformation, or communication between cells. Although reports of lncRNAs on pathogenesis of hypertension are scarce at the moment, new lncRNAs in relation to hypertension are being discovered at a rapid pace owing to novel techniques such as microarray or next-generation sequencing. In the clinical settings, clinical use of non-coding RNAs in identifying cardiovascular risks or developing novel tools for treating hypertension such as molecular decoy or mimicks is promising, although improvement in chemical modification or drug delivery system is necessary. PMID:25828869

  4. Identification and Role of Regulatory Non-Coding RNAs in Listeria monocytogenes

    PubMed Central

    Izar, Benjamin; Mraheil, Mobarak Abu; Hain, Torsten

    2011-01-01

    Bacterial regulatory non-coding RNAs control numerous mRNA targets that direct a plethora of biological processes, such as the adaption to environmental changes, growth and virulence. Recently developed high-throughput techniques, such as genomic tiling arrays and RNA-Seq have allowed investigating prokaryotic cis- and trans-acting regulatory RNAs, including sRNAs, asRNAs, untranslated regions (UTR) and riboswitches. As a result, we obtained a more comprehensive view on the complexity and plasticity of the prokaryotic genome biology. Listeria monocytogenes was utilized as a model system for intracellular pathogenic bacteria in several studies, which revealed the presence of about 180 regulatory RNAs in the listerial genome. A regulatory role of non-coding RNAs in survival, virulence and adaptation mechanisms of L. monocytogenes was confirmed in subsequent experiments, thus, providing insight into a multifaceted modulatory function of RNA/mRNA interference. In this review, we discuss the identification of regulatory RNAs by high-throughput techniques and in their functional role in L. monocytogenes. PMID:21954346

  5. Non-Coding RNAs are Differentially Expressed by Nocardia brasiliensis in Vitro and in Experimental Actinomycetoma.

    PubMed

    Cruz-Rabadán, Josué S; Miranda-Ríos, Juan; Espín-Ocampo, Guadalupe; Méndez-Tovar, Luis J; Maya-Pineda, Héctor Rubén; Hernández-Hernández, Francisca

    2017-01-01

    Nocardia spp. are common soil-inhabiting bacteria that frequently infect humans through traumatic injuries or inhalation routes and cause infections, such as actinomycetoma and nocardiosis, respectively. Nocardia brasiliensis is the main aetiological agent of actinomycetoma in various countries. Many bacterial non-coding RNAs are regulators of genes associated with virulence factors. The aim of this work was to identify non-coding RNAs (ncRNAs) expressed during infection conditions and in free-living form (in vitro) in Nocardia brasiliensis. The N. brasiliensis transcriptome (predominately < 200 nucleotides) was determined by RNA next-generation sequencing in both conditions. A total of seventy ncRNAs were identified in both conditions. Among these ncRNAs, 18 were differentially expressed, 12 were located within intergenic regions, and 2 were encoded as antisense of 2 different genes. Finally, 10 of these ncRNAs were studied by rapid amplification of cDNA ends and/or quantitative reverse transcription polymerase chain reaction. Interestingly, 3 transcripts corresponded to tRNA-derived fragments (tRNAs(Cys, Met, Thr)), and one transcript was overlapped between an intergenic region and the 5´end of the 23S rRNA. Expression of these last four transcripts was increased during N. brasiliensis infection compared with the in vitro conditions. The results of this work suggest a possible role for these transcripts in the regulation of virulence genes in actinomycetoma pathogenesis.

  6. LncRNAWiki: harnessing community knowledge in collaborative curation of human long non-coding RNAs.

    PubMed

    Ma, Lina; Li, Ang; Zou, Dong; Xu, Xingjian; Xia, Lin; Yu, Jun; Bajic, Vladimir B; Zhang, Zhang

    2015-01-01

    Long non-coding RNAs (lncRNAs) perform a diversity of functions in numerous important biological processes and are implicated in many human diseases. In this report we present lncRNAWiki (http://lncrna.big.ac.cn), a wiki-based platform that is open-content and publicly editable and aimed at community-based curation and collection of information on human lncRNAs. Current related databases are dependent primarily on curation by experts, making it laborious to annotate the exponentially accumulated information on lncRNAs, which inevitably requires collective efforts in community-based curation of lncRNAs. Unlike existing databases, lncRNAWiki features comprehensive integration of information on human lncRNAs obtained from multiple different resources and allows not only existing lncRNAs to be edited, updated and curated by different users but also the addition of newly identified lncRNAs by any user. It harnesses community collective knowledge in collecting, editing and annotating human lncRNAs and rewards community-curated efforts by providing explicit authorship based on quantified contributions. LncRNAWiki relies on the underling knowledge of scientific community for collective and collaborative curation of human lncRNAs and thus has the potential to serve as an up-to-date and comprehensive knowledgebase for human lncRNAs. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. Functional annotation of the vlinc class of non-coding RNAs using systems biology approach

    PubMed Central

    Laurent, Georges St.; Vyatkin, Yuri; Antonets, Denis; Ri, Maxim; Qi, Yao; Saik, Olga; Shtokalo, Dmitry; de Hoon, Michiel J.L.; Kawaji, Hideya; Itoh, Masayoshi; Lassmann, Timo; Arner, Erik; Forrest, Alistair R.R.; Nicolas, Estelle; McCaffrey, Timothy A.; Carninci, Piero; Hayashizaki, Yoshihide; Wahlestedt, Claes; Kapranov, Philipp

    2016-01-01

    Functionality of the non-coding transcripts encoded by the human genome is the coveted goal of the modern genomics research. While commonly relied on the classical methods of forward genetics, integration of different genomics datasets in a global Systems Biology fashion presents a more productive avenue of achieving this very complex aim. Here we report application of a Systems Biology-based approach to dissect functionality of a newly identified vast class of very long intergenic non-coding (vlinc) RNAs. Using highly quantitative FANTOM5 CAGE dataset, we show that these RNAs could be grouped into 1542 novel human genes based on analysis of insulators that we show here indeed function as genomic barrier elements. We show that vlincRNAs genes likely function in cis to activate nearby genes. This effect while most pronounced in closely spaced vlincRNA–gene pairs can be detected over relatively large genomic distances. Furthermore, we identified 101 vlincRNA genes likely involved in early embryogenesis based on patterns of their expression and regulation. We also found another 109 such genes potentially involved in cellular functions also happening at early stages of development such as proliferation, migration and apoptosis. Overall, we show that Systems Biology-based methods have great promise for functional annotation of non-coding RNAs. PMID:27001520

  8. Long non-coding RNAs in anti-cancer drug resistance

    PubMed Central

    Chen, Qin-nan; Wei, Chen-chen; Wang, Zhao-xia; Sun, Ming

    2017-01-01

    Chemotherapy is one of the basic treatments for cancers; however, drug resistance is mainly responsible for the failure of clinical treatment. The mechanism of drug resistance is complicated because of interaction among various factors including drug efflux, DNA damage repair, apoptosis and targets mutation. Long non-coding RNAs (lncRNAs) have been a focus of research in the field of bioscience, and the latest studies have revealed that lncRNAs play essential roles in drug resistance in breast cancer, gastric cancer and lung cancer, et al. Dysregulation of multiple targets and pathways by lncRNAs results in the occurrence of chemoresistance. In this review, we will discuss the mechanisms underlying lncRNA-mediated resistance to chemotherapy and the therapeutic potential of lncRNAs in future cancer treatment. PMID:27713133

  9. Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression.

    PubMed

    Engreitz, Jesse M; Ollikainen, Noah; Guttman, Mitchell

    2016-12-01

    Over the past decade, it has become clear that mammalian genomes encode thousands of long non-coding RNAs (lncRNAs), many of which are now implicated in diverse biological processes. Recent work studying the molecular mechanisms of several key examples - including Xist, which orchestrates X chromosome inactivation - has provided new insights into how lncRNAs can control cellular functions by acting in the nucleus. Here we discuss emerging mechanistic insights into how lncRNAs can regulate gene expression by coordinating regulatory proteins, localizing to target loci and shaping three-dimensional (3D) nuclear organization. We explore these principles to highlight biological challenges in gene regulation, in which lncRNAs are well-suited to perform roles that cannot be carried out by DNA elements or protein regulators alone, such as acting as spatial amplifiers of regulatory signals in the nucleus.

  10. A Long Journey Ahead: Long Non-coding RNAs in Bacterial Infections

    PubMed Central

    zur Bruegge, Jennifer; Einspanier, Ralf; Sharbati, Soroush

    2017-01-01

    Bacterial pathogens have coevolved with their hosts and acquired strategies to circumvent defense mechanisms of host cells. It was shown that bacteria interfere with the expression of mammalian microRNAs to modify immune signaling, autophagy, or the apoptotic machinery. Recently, a new class of regulatory RNAs, long non-coding RNAs (lncRNAs), was reported to have a pivotal role in the regulation of eukaryotic gene expression. A growing body of literature reports on specific involvement of lncRNAs in the host cell response toward bacterial infections. This mini review summarizes recent data that focuses on lncRNA function in host cells during bacterial infection and provides a perspective where future research in this regard may be going. PMID:28401065

  11. Long Non-coding RNAs in Urologic Malignancies: Functional Roles and Clinical Translation

    PubMed Central

    Chen, Jiajia; Miao, Zhijun; Xue, Boxin; Shan, Yuxi; Weng, Guobin; Shen, Bairong

    2016-01-01

    Early diagnosis and surveillance for metastasis and recurrences are critical issues of urologic cancer. Deregulation of long non-coding RNAs (lncRNAs) has been implicated in urologic malignancies and represents potential markers or therapeutic targets. However, the utility of lncRNA as biomarkers appears to be overstated due to heterogeneous or irreproducible results from different studies. Thus, a critical and cautious review on the biomarker potential of lncRNAs is needed. This review provides an update on new findings of lncRNA-based markers for urologic cancer. The diverse mechanisms and associated examples of lncRNAs involved during the carcinogenesis of prostate cancer, bladder cancer and renal cancer were discussed in a more balanced and critical manner, as were the suitability of lncRNAs as diagnostic or prognostics markers. PMID:27698924

  12. [Research advances in diagnostic and therapeutic application of long-chain non-coding RNAs in hepatocellular carcinoma].

    PubMed

    Li, W X; Li, Q; Lin, Y; Huang, Y X; Chen, L

    2016-08-20

    In recent years, hepatocellular carcinoma (HCC) has become one of the serious health-threatening malignancies worldwide, and its incidence and mortality rates continue to rise. Hepatitis B (HBV) is moderately endemic in China, with enormous numbers of HBV-related HCC cases. Although serum alpha-fetoprotein (AFP) and ultrasound are the major diagnostic methods for HCC, they have limited application for screening out early or small HCC. The current management of HCC is based on tumor size and location, not on suppressing tumorigenesis, and therefore patients are often faced with low 5-year survival and high relapse rates. Recent studies have shown that long-chain non-coding RNAs (lncRNAs) are closely associated with HCC tumorigenesis, which may have considerable utility as new diagnostic marker and treatment target for HCC. Here, we review the application of lncRNAs in the diagnosis, metastasis, treatment, recurrence, and prognosis of HCC.

  13. Comparison of non-coding RNAs in human and canine cancer

    PubMed Central

    Wagner, Siegfried; Willenbrock, Saskia; Nolte, Ingo; Escobar, Hugo Murua

    2012-01-01

    The discovery of the post-transcriptional gene silencing (PTGS) by small non-protein-coding RNAs is considered as a major breakthrough in biology. In the last decade we just started to realize the biologic function and complexity of gene regulation by small non-coding RNAs. PTGS is a conserved phenomenon which was observed in various species such as fungi, worms, plants, and mammals. Micro RNAs (miRNA) and small interfering RNAs (siRNAs) are two gene silencing mediators constituting an evolutionary conserved class of non-coding RNAs regulating many biological processes in eukaryotes. As this small RNAs appear to regulate gene expression at translational and transcriptional level it is not surprising that during the last decade many human diseases among them Alzheimer's disease, cardiovascular diseases, and various cancer types were associated with deregulated miRNA expression. Consequently small RNAs are considered to hold big promises as therapeutic agents. However, despite of the enormous therapeutic potential many questions remain unanswered. A major critical point, when evaluating novel therapeutic approaches, is the transfer of in vitro settings to an in vivo model. Classical animal models rely on the laboratory kept animals under artificial conditions and often missing an intact immune system. Model organisms with spontaneously occurring tumors as e.g., dogs provide the possibility to evaluate therapeutic agents under the surveillance of an in intact immune system and thereby providing an authentic tumor reacting scenario. Considering the genomic similarity between canines and humans and the advantages of the dog as cancer model system for human neoplasias the analyses of the complex role of small RNAs in canine tumor development could be of major value for both species. Herein we discuss comparatively the role of miRNAs in human and canine cancer development and highlight the potential and advantages of the model organism dog for tumor research. PMID

  14. Identification of Long Non-Coding RNAs Deregulated in Multiple Myeloma Cells Resistant to Proteasome Inhibitors

    PubMed Central

    Malek, Ehsan; Kim, Byung-Gyu; Driscoll, James J.

    2016-01-01

    While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib, carfilzomib, or ixazomib. Genome-wide profiling identified lncRNAs that were significantly deregulated in all three PI-resistant cell lines relative to the drug-sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI-resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM. PMID:27782060

  15. Non-coding RNAs in crop genetic modification: considerations and predictable environmental risk assessments (ERA).

    PubMed

    Ramesh, S V

    2013-09-01

    Of late non-coding RNAs (ncRNAs)-mediated gene silencing is an influential tool deliberately deployed to negatively regulate the expression of targeted genes. In addition to the widely employed small interfering RNA (siRNA)-mediated gene silencing approach, other variants like artificial miRNA (amiRNA), miRNA mimics, and artificial transacting siRNAs (tasiRNAs) are being explored and successfully deployed in developing non-coding RNA-based genetically modified plants. The ncRNA-based gene manipulations are typified with mobile nature of silencing signals, interference from viral genome-derived suppressor proteins, and an obligation for meticulous computational analysis to prevaricate any inadvertent effects. In a broad sense, risk assessment inquiries for genetically modified plants based on the expression of ncRNAs are competently addressed by the environmental risk assessment (ERA) models, currently in vogue, designed for the first generation transgenic plants which are based on the expression of heterologous proteins. Nevertheless, transgenic plants functioning on the foundation of ncRNAs warrant due attention with respect to their unique attributes like off-target or non-target gene silencing effects, small RNAs (sRNAs) persistence, food and feed safety assessments, problems in detection and tracking of sRNAs in food, impact of ncRNAs in plant protection measures, effect of mutations etc. The role of recent developments in sequencing techniques like next generation sequencing (NGS) and the ERA paradigm of the different countries in vogue are also discussed in the context of ncRNA-based gene manipulations.

  16. Acute liver failure is associated with altered cerebral expression profiles of long non-coding RNAs.

    PubMed

    Silva, Vinícius R; Secolin, Rodrigo; Vemuganti, Raghu; Lopes-Cendes, Iscia; Hazell, Alan S

    2017-08-24

    Hepatic encephalopathy (HE) represents a serious complication of acute liver failure (ALF) in which cerebral edema leading to brainstem herniation as a result of increased intracranial hypertension is a major consequence. Long non-coding RNAs (lncRNAs) play a significant role in coordinating gene expression, with recent studies indicating an influence in the pathogenesis of several diseases. To investigate their involvement in the cerebral pathophysiology of ALF, we profiled the expression of lncRNAs in the frontal cortex of mice at coma stage following treatment with the hepatotoxin azoxymethane. Of the 35,923 lncRNAs profiled using microarrays, 868 transcripts were found to be differentially expressed in the ALF-treated group compared to the sham control group. Of these, 382 lncRNAs were upregulated and 486 lncRNAs downregulated. Pathway analysis revealed these lncRNAs target a number of biological and molecular pathways that include cytokine-cytokine receptor interaction, the mitogen activated protein kinase signaling pathway, the insulin signaling pathway, and the nuclear factor-κB signaling pathway. False discovery rate adjustment identified 9 upregulated lncRNAs, 2 of which are associated with neuroepithelial transforming gene 1 (NET1) and the monocarboxylate transporter 2 (Slc16a7), potential contributors to astrocyte cytoskeletal disruption/swelling and lactate production, respectively. Our findings suggest an important role for lncRNAs in the brain in ALF in relation to inflammation, neuropathology, and in terms of the functional basis of HE. Further work on these non-coding RNAs may lead to new therapeutic approaches for the treatment and management of cerebral dysfunction resulting from this potentially life-threatening disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Transcriptomic profiling of long non-coding RNAs in dermatomyositis by microarray analysis

    PubMed Central

    Peng, Qing-Lin; Zhang, Ya-Mei; Yang, Han-Bo; Shu, Xiao-Ming; Lu, Xin; Wang, Guo-Chun

    2016-01-01

    Long non-coding RNAs (lncRNAs) are prevalently transcribed in the genome and have been found to be of functional importance. However, the potential roles of lncRNAs in dermatomyositis (DM) remain unknown. In this study, a lncRNA + mRNA microarray analysis was performed to profile lncRNAs and mRNAs from 15 treatment-naive DM patients and 5 healthy controls. We revealed a total of 1198 lncRNAs (322 up-regulated and 876 down-regulated) and 1213 mRNAs (665 up-regulated and 548 down-regulated) were significantly differentially expressed in DM patients compared with the healthy controls (fold change>2, P < 0.05). Subgrouping DM patients according to the presence of interstitial lung disease and anti-Jo-1 antibody revealed different expression patterns of the lncRNAs. Pathway and gene ontology analysis for the differentially expressed mRNAs confirmed that type 1 interferon signaling was the most significantly dysregulated pathway in all DM subgroups. In addition, distinct pathways that uniquely associated with DM subgroup were also identified. Bioinformatics prediction suggested that linc-DGCR6-1 may be a lncRNA that regulates type 1 interferon-inducible gene USP18, which was found highly expressed in the perifascicular areas of the muscle fibers of DM patients. Our findings provide an overview of aberrantly expressed lncRNAs in DM muscle and further broaden the understanding of DM pathogenesis. PMID:27605457

  18. Transcriptomic profiling of long non-coding RNAs in dermatomyositis by microarray analysis.

    PubMed

    Peng, Qing-Lin; Zhang, Ya-Mei; Yang, Han-Bo; Shu, Xiao-Ming; Lu, Xin; Wang, Guo-Chun

    2016-09-08

    Long non-coding RNAs (lncRNAs) are prevalently transcribed in the genome and have been found to be of functional importance. However, the potential roles of lncRNAs in dermatomyositis (DM) remain unknown. In this study, a lncRNA + mRNA microarray analysis was performed to profile lncRNAs and mRNAs from 15 treatment-naive DM patients and 5 healthy controls. We revealed a total of 1198 lncRNAs (322 up-regulated and 876 down-regulated) and 1213 mRNAs (665 up-regulated and 548 down-regulated) were significantly differentially expressed in DM patients compared with the healthy controls (fold change>2, P < 0.05). Subgrouping DM patients according to the presence of interstitial lung disease and anti-Jo-1 antibody revealed different expression patterns of the lncRNAs. Pathway and gene ontology analysis for the differentially expressed mRNAs confirmed that type 1 interferon signaling was the most significantly dysregulated pathway in all DM subgroups. In addition, distinct pathways that uniquely associated with DM subgroup were also identified. Bioinformatics prediction suggested that linc-DGCR6-1 may be a lncRNA that regulates type 1 interferon-inducible gene USP18, which was found highly expressed in the perifascicular areas of the muscle fibers of DM patients. Our findings provide an overview of aberrantly expressed lncRNAs in DM muscle and further broaden the understanding of DM pathogenesis.

  19. Identification of novel long non-coding RNAs in triple-negative breast cancer

    PubMed Central

    Yu, Wenjie; Wang, Wenmin; Xu, Dong; Yan, Xinqiang; Chen, Beibei; Yu, Longyao; Li, Jicheng; Chen, Xiaobing; Ding, Kan; Cao, Feilin

    2015-01-01

    Triple-negative breast carcinomas (TNBC) are characterized by particularly poor outcomes, and there are no established markers significantly associated with prognosis. Long non-coding RNAs (lncRNAs) are subclass of noncoding RNAs that have been recently shown to play critical roles in cancer biology. However, little is known about their mechanistic role in TNBC pathogenesis. In this report, we investigated the expression patterns of lncRNAs from TNBC tissues and matched normal tissues with Agilent Human lncRNA array. We identified 1,758 lncRNAs and 1,254 mRNAs that were differentially expressed (≥ 2-fold change), indicating that many lncRNAs are significantly upregulated or downregulated in TNBC. Among these, XR_250621.1 and NONHSAT125629 were the most upregulated and downregulated lncRNAs respectively. qRT-PCR was employed to validate the microarray analysis findings, and results were consistent with the data from the microarrays. GO and KEGG pathway analysis were applied to explore the potential lncRNAs functions, some pathways including microtubule motor activity and DNA replication were identified in TNBC pathogenesis. Our study revealed that a set of lncRNAs were differentially expressed in TNBC tissues, suggesting that they may play role in TNBC. These results shed light on lncRNAs’ biological functions and provide useful information for exploring potential therapeutic targets for breast cancer. PMID:26078338

  20. An atlas of human long non-coding RNAs with accurate 5' ends.

    PubMed

    Hon, Chung-Chau; Ramilowski, Jordan A; Harshbarger, Jayson; Bertin, Nicolas; Rackham, Owen J L; Gough, Julian; Denisenko, Elena; Schmeier, Sebastian; Poulsen, Thomas M; Severin, Jessica; Lizio, Marina; Kawaji, Hideya; Kasukawa, Takeya; Itoh, Masayoshi; Burroughs, A Maxwell; Noma, Shohei; Djebali, Sarah; Alam, Tanvir; Medvedeva, Yulia A; Testa, Alison C; Lipovich, Leonard; Yip, Chi-Wai; Abugessaisa, Imad; Mendez, Mickaël; Hasegawa, Akira; Tang, Dave; Lassmann, Timo; Heutink, Peter; Babina, Magda; Wells, Christine A; Kojima, Soichi; Nakamura, Yukio; Suzuki, Harukazu; Daub, Carsten O; de Hoon, Michiel J L; Arner, Erik; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R R

    2017-03-09

    Long non-coding RNAs (lncRNAs) are largely heterogeneous and functionally uncharacterized. Here, using FANTOM5 cap analysis of gene expression (CAGE) data, we integrate multiple transcript collections to generate a comprehensive atlas of 27,919 human lncRNA genes with high-confidence 5' ends and expression profiles across 1,829 samples from the major human primary cell types and tissues. Genomic and epigenomic classification of these lncRNAs reveals that most intergenic lncRNAs originate from enhancers rather than from promoters. Incorporating genetic and expression data, we show that lncRNAs overlapping trait-associated single nucleotide polymorphisms are specifically expressed in cell types relevant to the traits, implicating these lncRNAs in multiple diseases. We further demonstrate that lncRNAs overlapping expression quantitative trait loci (eQTL)-associated single nucleotide polymorphisms of messenger RNAs are co-expressed with the corresponding messenger RNAs, suggesting their potential roles in transcriptional regulation. Combining these findings with conservation data, we identify 19,175 potentially functional lncRNAs in the human genome.

  1. NRDTD: a database for clinically or experimentally supported non-coding RNAs and drug targets associations

    PubMed Central

    Sun, Ya-Zhou; Zhang, De-Hong; Yan, Gui-Ying; An, Ji-Yong; You, Zhu-Hong

    2017-01-01

    Abstract In recent years, more and more non-coding RNAs (ncRNAs) have been identified and increasing evidences have shown that ncRNAs may affect gene expression and disease progression, making them a new class of targets for drug discovery. It thus becomes important to understand the relationship between ncRNAs and drug targets. For this purpose, an ncRNAs and drug targets association database would be extremely beneficial. Here, we developed ncRNA Drug Targets Database (NRDTD) that collected 165 entries of clinically or experimentally supported ncRNAs as drug targets, including 97 ncRNAs and 96 drugs. Moreover, we annotated ncRNA-drug target associations with drug information from KEGG, PubChem, DrugBank, CTD or Wikipedia, GenBank sequence links, OMIM disease ID, pathway and function annotation for ncRNAs, detailed description of associations between ncRNAs and diseases from HMDD or LncRNADisease and the publication PubMed ID. Additionally, we provided users a link to submit novel disease-ncRNA-drug associations and corresponding supporting evidences into the database. We hope NRDTD will be a useful resource for investigating the roles of ncRNAs in drug target identification, drug discovery and disease treatment. Database URL: http://chengroup.cumt.edu.cn/NRDTD

  2. Transcriptional Dynamics Reveal Critical Roles for Non-coding RNAs in the Immediate-Early Response

    PubMed Central

    Aitken, Stuart; Magi, Shigeyuki; Alhendi, Ahmad M. N.; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Daub, Carsten O.; Arner, Erik; Carninci, Piero; Forrest, Alistair R. R.; Hayashizaki, Yoshihide; Khachigian, Levon M.; Okada-Hatakeyama, Mariko; Semple, Colin A.

    2015-01-01

    The immediate-early response mediates cell fate in response to a variety of extracellular stimuli and is dysregulated in many cancers. However, the specificity of the response across stimuli and cell types, and the roles of non-coding RNAs are not well understood. Using a large collection of densely-sampled time series expression data we have examined the induction of the immediate-early response in unparalleled detail, across cell types and stimuli. We exploit cap analysis of gene expression (CAGE) time series datasets to directly measure promoter activities over time. Using a novel analysis method for time series data we identify transcripts with expression patterns that closely resemble the dynamics of known immediate-early genes (IEGs) and this enables a comprehensive comparative study of these genes and their chromatin state. Surprisingly, these data suggest that the earliest transcriptional responses often involve promoters generating non-coding RNAs, many of which are produced in advance of canonical protein-coding IEGs. IEGs are known to be capable of induction without de novo protein synthesis. Consistent with this, we find that the response of both protein-coding and non-coding RNA IEGs can be explained by their transcriptionally poised, permissive chromatin state prior to stimulation. We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line. Our computational statistical method is well suited to meta-analyses as there is no requirement for transcripts to pass thresholds for significant differential expression between time points, and it is agnostic to the number of time points per dataset. PMID:25885578

  3. Transcriptional dynamics reveal critical roles for non-coding RNAs in the immediate-early response.

    PubMed

    Aitken, Stuart; Magi, Shigeyuki; Alhendi, Ahmad M N; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Daub, Carsten O; Arner, Erik; Carninci, Piero; Forrest, Alistair R R; Hayashizaki, Yoshihide; Khachigian, Levon M; Okada-Hatakeyama, Mariko; Semple, Colin A

    2015-04-01

    The immediate-early response mediates cell fate in response to a variety of extracellular stimuli and is dysregulated in many cancers. However, the specificity of the response across stimuli and cell types, and the roles of non-coding RNAs are not well understood. Using a large collection of densely-sampled time series expression data we have examined the induction of the immediate-early response in unparalleled detail, across cell types and stimuli. We exploit cap analysis of gene expression (CAGE) time series datasets to directly measure promoter activities over time. Using a novel analysis method for time series data we identify transcripts with expression patterns that closely resemble the dynamics of known immediate-early genes (IEGs) and this enables a comprehensive comparative study of these genes and their chromatin state. Surprisingly, these data suggest that the earliest transcriptional responses often involve promoters generating non-coding RNAs, many of which are produced in advance of canonical protein-coding IEGs. IEGs are known to be capable of induction without de novo protein synthesis. Consistent with this, we find that the response of both protein-coding and non-coding RNA IEGs can be explained by their transcriptionally poised, permissive chromatin state prior to stimulation. We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line. Our computational statistical method is well suited to meta-analyses as there is no requirement for transcripts to pass thresholds for significant differential expression between time points, and it is agnostic to the number of time points per dataset.

  4. Intronic RNAs constitute the major fraction of the non-coding RNA in mammalian cells

    PubMed Central

    2012-01-01

    Background The function of RNA from the non-coding (the so called “dark matter”) regions of the genome has been a subject of considerable recent debate. Perhaps the most controversy is regarding the function of RNAs found in introns of annotated transcripts, where most of the reads that map outside of exons are usually found. However, it has been reported that the levels of RNA in introns are minor relative to those of the corresponding exons, and that changes in the levels of intronic RNAs correlate tightly with that of adjacent exons. This would suggest that RNAs produced from the vast expanse of intronic space are just pieces of pre-mRNAs or excised introns en route to degradation. Results We present data that challenges the notion that intronic RNAs are mere by-standers in the cell. By performing a highly quantitative RNAseq analysis of transcriptome changes during an inflammation time course, we show that intronic RNAs have a number of features that would be expected from functional, standalone RNA species. We show that there are thousands of introns in the mouse genome that generate RNAs whose overall abundance, which changes throughout the inflammation timecourse, and other properties suggest that they function in yet unknown ways. Conclusions So far, the focus of non-coding RNA discovery has shied away from intronic regions as those were believed to simply encode parts of pre-mRNAs. Results presented here suggest a very different situation – the sequences encoded in the introns appear to harbor a yet unexplored reservoir of novel, functional RNAs. As such, they should not be ignored in surveys of functional transcripts or other genomic studies. PMID:23006825

  5. Genome-wide identification and characterization of long intergenic non-coding RNAs in Ganoderma lucidum.

    PubMed

    Li, Jianqin; Wu, Bin; Xu, Jiang; Liu, Chang

    2014-01-01

    Ganoderma lucidum is a white-rot fungus best-known for its medicinal activities. We have previously sequenced its genome and annotated the protein coding genes. However, long non-coding RNAs in G. lucidum genome have not been analyzed. In this study, we have identified and characterized long intergenic non-coding RNAs (lincRNA) in G. lucidum systematically. We developed a computational pipeline, which was used to analyze RNA-Seq data derived from G. lucidum samples collected from three developmental stages. A total of 402 lincRNA candidates were identified, with an average length of 609 bp. Analysis of their adjacent protein-coding genes (apcGenes) revealed that 46 apcGenes belong to the pathways of triterpenoid biosynthesis and lignin degradation, or families of cytochrome P450, mating type B genes, and carbohydrate-active enzymes. To determine if lincRNAs and these apcGenes have any interactions, the corresponding pairs of lincRNAs and apcGenes were analyzed in detail. We developed a modified 3' RACE method to analyze the transcriptional direction of a transcript. Among the 46 lincRNAs, 37 were found unidirectionally transcribed, and 9 were found bidirectionally transcribed. The expression profiles of 16 of these 37 lincRNAs were found to be highly correlated with those of the apcGenes across the three developmental stages. Among them, 11 are positively correlated (r>0.8) and 5 are negatively correlated (r<-0.8). The co-localization and co-expression of lincRNAs and those apcGenes playing important functions is consistent with the notion that lincRNAs might be important regulators for cellular processes. In summary, this represents the very first study to identify and characterize lincRNAs in the genomes of basidiomycetes. The results obtained here have laid the foundation for study of potential lincRNA-mediated expression regulation of genes in G. lucidum.

  6. Regulation of Non-coding RNAs in Heat Stress Responses of Plants

    PubMed Central

    Zhao, Jianguo; He, Qingsong; Chen, Gang; Wang, Li; Jin, Biao

    2016-01-01

    Heat stress is an important factor limiting plant growth, development, and productivity; thus, plants have evolved special adaptive mechanisms to cope with high-temperature stress. Non-coding RNAs (ncRNAs) are a class of regulatory RNAs that play an important role in many biological processes. Recently developed advanced technologies, such as genome-wide transcriptomic analysis, have revealed that abundant ncRNAs are expressed under heat stress. Although this area of research is still in its infancy, an increasing number of several classes of regulatory ncRNA (i.e., miRNA, siRNA, and lncRNA) related to heat stress responses have been reported. In this mini-review, we discuss our current understanding of the role of ncRNAs in heat stress responses in plants, especially miRNAs, siRNAs, and their targets. For example, the miR398-CSD/CCS-HSF, miR396-WRKY6, miR159-GAMYB, and TAS1-HTT-HSF pathways regulate plant heat tolerance. We highlight the hormone/development-related miRNAs involved in heat stress, and discuss the regulatory networks of miRNA-targets. We also note that DNA methylation and alternative splicing could affect miRNA expression under heat stress, and some lncRNAs could respond to heat stress. Finally, we briefly discuss future prospects concerning the ncRNA-related mechanisms of heat stress responses in plants. PMID:27588021

  7. Retinal expression of small non-coding RNAs in a murine model of proliferative retinopathy

    PubMed Central

    Liu, Chi-Hsiu; Wang, Zhongxiao; Sun, Ye; SanGiovanni, John Paul; Chen, Jing

    2016-01-01

    Ocular neovascularization is a leading cause of blindness in proliferative retinopathy. Small non-coding RNAs (sncRNAs) play critical roles in both vascular and neuronal development of the retina through post-transcriptional regulation of target gene expression. To identify the function and therapeutic potential of sncRNAs in retinopathy, we assessed the expression profile of retinal sncRNAs in a mouse model of oxygen-induced retinopathy (OIR) with pathologic proliferation of neovessels. Approximately 2% of all analyzed sncRNAs were significantly altered in OIR retinas compared with normoxic controls. Twenty three microRNAs with substantial up- or down-regulation were identified, including miR-351, -762, -210, 145, -155, -129-5p, -150, -203, and -375, which were further analyzed for their potential target genes in angiogenic, hypoxic, and immune response-related pathways. In addition, nineteen small nucleolar RNAs also revealed differential expression in OIR retinas compared with control retinas. A decrease of overall microRNA expression in OIR retinas was consistent with reduced microRNA processing enzyme Dicer, and increased expression of Alu element in OIR. Together, our findings elucidated a group of differentially expressed sncRNAs in a murine model of proliferative retinopathy. These sncRNAs may exert critical post-transcriptional regulatory roles in regulating pathological neovascularization in eye diseases. PMID:27653551

  8. Decoding the usefulness of non-coding RNAs as breast cancer markers.

    PubMed

    Amorim, Maria; Salta, Sofia; Henrique, Rui; Jerónimo, Carmen

    2016-09-15

    Although important advances in the management of breast cancer (BC) have been recently accomplished, it still constitutes the leading cause of cancer death in women worldwide. BC is a heterogeneous and complex disease, making clinical prediction of outcome a very challenging task. In recent years, gene expression profiling emerged as a tool to assist in clinical decision, enabling the identification of genetic signatures that better predict prognosis and response to therapy. Nevertheless, translation to routine practice has been limited by economical and technical reasons and, thus, novel biomarkers, especially those requiring non-invasive or minimally invasive collection procedures, while retaining high sensitivity and specificity might represent a significant development in this field. An increasing amount of evidence demonstrates that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are aberrantly expressed in several cancers, including BC. miRNAs are of particular interest as new, easily accessible, cost-effective and non-invasive tools for precise management of BC patients because they circulate in bodily fluids (e.g., serum and plasma) in a very stable manner, enabling BC assessment and monitoring through liquid biopsies. This review focus on how ncRNAs have the potential to answer present clinical needs in the personalized management of patients with BC and comprehensively describes the state of the art on the role of ncRNAs in the diagnosis, prognosis and prediction of response to therapy in BC.

  9. Correia Repeat Enclosed Elements and Non-Coding RNAs in the Neisseria Species

    PubMed Central

    Roberts, Sabrina B.; Spencer-Smith, Russell; Shah, Mahwish; Nebel, Jean-Christophe; Cook, Richard T.; Snyder, Lori A. S.

    2016-01-01

    Neisseria gonorrhoeae is capable of causing gonorrhoea and more complex diseases in the human host. Neisseria meningitidis is a closely related pathogen that shares many of the same genomic features and virulence factors, but causes the life threatening diseases meningococcal meningitis and septicaemia. The importance of non-coding RNAs in gene regulation has become increasingly evident having been demonstrated to be involved in regulons responsible for iron acquisition, antigenic variation, and virulence. Neisseria spp. contain an IS-like element, the Correia Repeat Enclosed Element, which has been predicted to be mobile within the genomes or to have been in the past. This repeat, present in over 100 copies in the genome, has the ability to alter gene expression and regulation in several ways. We reveal here that Correia Repeat Enclosed Elements tend to be near non-coding RNAs in the Neisseria spp., especially N. gonorrhoeae. These results suggest that Correia Repeat Enclosed Elements may have disrupted ancestral regulatory networks not just through their influence on regulatory proteins but also for non-coding RNAs. PMID:27681925

  10. Non-coding RNAs as clinical biomarkers for cancer diagnosis and prognosis.

    PubMed

    Mishra, Prasun J

    2014-11-01

    Developing more precise diagnostics approaches to predict cancer progression and prognosis is the key to precision medicine. Overwhelming evidence now suggests that small non-coding RNAs such as miRNAs can be useful tools as biomarkers for molecular diagnostics. miRNAs can serve as biomarkers in a variety of diseases, such as neurological disorders, cardiovascular disease, Type II diabetes, cancer and so on. miRNAs can not only be utilized for monitoring treatment but also for patient stratification and hence are promising predictive biomarkers in cancer progression and prognosis, as well as in predicting drug response. This article focuses on some of the recent findings in the field of miRNA biomarkers and discusses its implications for cancer diagnostics and precision medicine.

  11. Current Insights into Long Non-Coding RNAs in Renal Cell Carcinoma

    PubMed Central

    Seles, Maximilian; Hutterer, Georg C.; Kiesslich, Tobias; Pummer, Karl; Berindan-Neagoe, Ioana; Perakis, Samantha; Schwarzenbacher, Daniela; Stotz, Michael; Gerger, Armin; Pichler, Martin

    2016-01-01

    Renal cell carcinoma (RCC) represents a deadly disease with rising mortality despite intensive therapeutic efforts. It comprises several subtypes in terms of distinct histopathological features and different clinical presentations. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts in the genome which vary in expression levels and length and perform diverse functions. They are involved in the inititation, evolution and progression of primary cancer, as well as in the development and spread of metastases. Recently, several lncRNAs were described in RCC. This review emphasises the rising importance of lncRNAs in RCC. Moreover, it provides an outlook on their therapeutic potential in the future. PMID:27092491

  12. Integrative Analysis of Normal Long Intergenic Non-Coding RNAs in Prostate Cancer

    PubMed Central

    Bawa, Pushpinder; Zackaria, Sajna; Verma, Mohit; Gupta, Saurabh; Srivatsan, R; Chaudhary, Bibha; Srinivasan, Subhashini

    2015-01-01

    Recently, large numbers of normal human tissues have been profiled for non-coding RNAs and more than fourteen thousand long intergenic non-coding RNAs (lincRNAs) are found expressed in normal human tissues. The functional roles of these normal lincRNAs (nlincRNAs) in the regulation of protein coding genes in normal and disease biology are yet to be established. Here, we have profiled two RNA-seq datasets including cancer and matched non-neoplastic tissues from 12 individuals from diverse demography for both coding genes and nlincRNAs. We find 130 nlincRNAs significantly regulated in cancer, with 127 regulated in the same direction in the two datasets. Interestingly, according to Illumina Body Map, significant numbers of these nlincRNAs display baseline null expression in normal prostate tissues but are specific to other tissues such as thyroid, kidney, liver and testis. A number of the regulated nlincRNAs share loci with coding genes, which are either co-regulated or oppositely regulated in all cancer samples studied here. For example, in all cancer samples i) the nlincRNA, TCONS_00029157, and a neighboring tumor suppressor factor, SIK1, are both down regulated; ii) several thyroid-specific nlincRNAs in the neighborhood of the thyroid-specific gene TPO, are both up-regulated; and iii) the TCONS_00010581, an isoform of HEIH, is down-regulated while the neighboring EZH2 gene is up-regulated in cancer. Several nlincRNAs from a prostate cancer associated chromosomal locus, 8q24, are up-regulated in cancer along with other known prostate cancer associated genes including PCAT-1, PVT1, and PCAT-92. We observe that there is significant bias towards up-regulation of nlincRNAs with as high as 118 out of 127 up-regulated in cancer, even though regulation of coding genes is skewed towards down-regulation. Considering that all reported cancer associated lincRNAs (clincRNAs) are biased towards up-regulation, we conclude that this bias may be functionally relevant. PMID:25933431

  13. An Interactive network of long non-coding RNAs facilitates the Drosophila sex determination decision

    PubMed Central

    Mulvey, Brett B.; Olcese, Ursula; Cabrera, Janel R.; Horabin, Jamila I.

    2014-01-01

    Genome analysis in several eukaryotes shows a surprising number of transcripts which do not encode conventional messenger RNAs. Once considered noise, these non-coding RNAs (ncRNAs) appear capable of controlling gene expression by various means. We find Drosophila sex determination, specifically the master-switch gene Sex-lethal (Sxl), is regulated by long ncRNAs (>200 nt). The lncRNAs influence the dose sensitive establishment promoter of Sxl, SxlPe, which must be activated to specify female sex. They are primarily from two regions, R1 and R2, upstream of SxlPeand show a dynamic developmental profile. Of the four lncRNA strands only one, R2 antisense, has its peak coincident with SxlPe transcription, suggesting it may promote activation. Indeed, its expression is regulated by the X chromosome counting genes, whose dose determines whether SxlPe is transcribed. Transgenic lines which ectopically express each of the lncRNAs show they can act in trans, impacting the process of sex determination but also altering the levels of the other lncRNAs. Generally, expression of R1 is negative whereas R2 is positive to females. This ectopic expression also results in a change in the local chromatin marks, affecting the timing and strength of SxlPe transcription. The chromatin marks are those deposited by the Polycomb and Trithorax groups of chromatin modifying proteins, which we find bind to the lncRNAs. We suggest the increasing numbers of non-coding transcripts being identified are a harbinger of interacting networks similar to the one we describe. PMID:24954180

  14. Expression profile of long non-coding RNAs in colorectal cancer: A microarray analysis.

    PubMed

    Luo, Jia; Xu, Luning; Jiang, Yigui; Zhuo, Dexiang; Zhang, Shengjun; Wu, Lianhui; Xu, Huadong; Huang, Yue

    2016-04-01

    Colorectal cancer (CRC) is one of the most prevalent malignant tumors and the second cause of cancer-related mortality worldwide. Due to increased morbidity and mortality rates, there is an urgent need to understand the pathogenesis of CRC, discover strategies that can improve diagnosis, and ultimately identify therapies targeting this disease. Over the past several years, research into tumor progression mechanisms has been devoted to identifying and understanding various coding and non-coding regions of the genome and how these genetic variants may affect tumorigenesis and progression. Recently, long non-coding RNAs (lncRNAs), which are non‑protein coding transcripts longer than 200 nucleotides, have emerged as a key aspect in tumor pathogenesis. In the present study, we examined the lncRNA and mRNA expression profiles in 4 patients with colon adenocarcinoma, with paired adjacent normal tissues as controls. Microarray data showed that a total of 3,523 lncRNAs and 2,515 mRNAs were consistently differentially expressed in the CRC tissues compared to adjacent normal tissues. Upon comparison of the differentially expressed transcripts between the groups, we identified 22 pathways which were related to the upregulated transcripts and 24 pathways that corresponded to the downregulated transcripts. Gene ontology analysis revealed that the upregulated transcripts were predominantly enriched in DNA metabolic processes, and the downregulated transcripts were predominantly enriched in organic hydroxyl compound metabolic processes. Coding-non-coding gene co-expression analysis showed that these differentially expressed lncRNAs were closely correlated with 'Wnt signaling pathway' components, whose aberrant activation plays a central role in CRC, indicating that a functional correlation exists between them. In conclusion, the results of the microarray and informatic analysis strongly suggest that lncRNA dysregulation is involved in the complicated process of CRC development

  15. Non-coding sRNAs regulate virulence in the bacterial pathogen Vibrio cholerae

    PubMed Central

    Bardill, J. Patrick; Hammer, Brian

    2012-01-01

    Vibrio cholerae is the waterborne bacterium responsible for worldwide outbreaks of the acute, potentially fatal cholera diarrhea. The primary factors this human pathogen uses to cause the disease are controlled by a complex regulatory program linking extracellular signaling inputs to changes in expression of several critical virulence genes. Recently it has been uncovered that many non-coding regulatory sRNAs are important components of the V. cholerae virulence regulon. Most of these sRNAs appear to require the RNA-binding protein, Hfq, to interact with and alter the expression of target genes, while a few sRNAs appear to function by an Hfq-independent mechanism. Direct base-pairing between the sRNAs and putative target mRNAs has been shown in a few cases but the extent of each sRNAs regulon is not fully known. Genetic and biochemical methods, coupled with computational and genomics approaches, are being used to validate known sRNAs and also to identify many additional putative sRNAs that may play a role in the pathogenic lifestyle of V. cholerae. PMID:22546941

  16. Noncoder: a web interface for exon array-based detection of long non-coding RNAs

    PubMed Central

    Gellert, Pascal; Ponomareva, Yuliya; Braun, Thomas; Uchida, Shizuka

    2013-01-01

    Due to recent technical developments, a high number of long non-coding RNAs (lncRNAs) have been discovered in mammals. Although it has been shown that lncRNAs are regulated differently among tissues and disease statuses, functions of these transcripts are still unknown in most cases. GeneChip Exon 1.0 ST Arrays (exon arrays) from Affymetrix, Inc. have been used widely to profile genome-wide expression changes and alternative splicing of protein-coding genes. Here, we demonstrate that re-annotation of exon array probes can be used to profile expressions of tens of thousands of lncRNAs. With this annotation, a detailed inspection of lncRNAs and their isoforms is possible. To allow for a general usage to the research community, we developed a user-friendly web interface called ‘noncoder’. By uploading CEL files from exon arrays and with a few mouse clicks and parameter settings, exon array data will be normalized and analysed to identify differentially expressed lncRNAs. Noncoder provides the detailed annotation information of lncRNAs and is equipped with unique features to allow for an efficient search for interesting lncRNAs to be studied further. The web interface is available at http://noncoder.mpi-bn.mpg.de. PMID:23012263

  17. The ways of action of long non-coding RNAs in cytoplasm and nucleus.

    PubMed

    Zhang, Kun; Shi, Zhe-Min; Chang, Ya-Nan; Hu, Zhi-Mei; Qi, Hai-Xia; Hong, Wei

    2014-08-15

    Over the past fifteen years, small regulatory RNAs, such as siRNA and miRNA, have been extensively investigated and the underlying molecular mechanisms have been well documented, suggesting that ncRNAs play a major function in many cellular processes. An expanding body of evidence reveals that long non-coding RNAs (lncRNAs), once described as dark matter, are involved in diverse cellular progresses, including regulation of gene expression, dosage compensation, genomic imprinting, nuclear organization and nuclear-cytoplasm trafficking via a number of complex mechanisms. The emerging links between lncRNAs and diseases as well as their tissue-specific expression patterns also indicate that lncRNAs comprise a core transcriptional regulatory circuitry. The function of lncRNAs is based on their sequence and structure; and they can combine with DNA, RNA, and proteins both in the nucleus and the cytoplasm. However, detailed insights into their biological and mechanistic functions are only beginning to emerge. In this review, we will mainly talk about diverse ways of action of lncRNAs in different sub-cellular locations and provide clues for following studies. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Form and Function of Exosome-Associated Long Non-coding RNAs in Cancer.

    PubMed

    Hewson, Chris; Morris, Kevin V

    2016-01-01

    The recent discovery that long non-coding RNAs (lncRNAs) are functional and are not merely "transcriptional noise" has spawned an entirely new arena of investigation. LncRNAs have been found to be functional in the regulation of a wide variety of genes, including those involved in cancer. Studies have identified that lncRNAs play a role in the development and regulation of cancer and can also act as prognostic markers. Meanwhile, exosomes , which are extracellular particles generated endogenously by cells, have been observed to act as transport vesicles for a variety of biological components, particularly proteins and RNAs. This transportation of biological components has been shown to impact a variety of biological processes including the development of cancer. Collectively, these observations, along with those of several recent studies, suggest that lncRNAs and exosomes may function together to disseminate cell signals that alter and/or control local cellular microenvironments. This review will identify the various roles that lncRNAs and exosomes play in cancer development, as well as the possibility that exosomes may transfer functional lncRNAs between cells as a means of cell-to-cell communication.

  19. Evolutionarily conserved long intergenic non-coding RNAs in the eye

    PubMed Central

    Mustafi, Debarshi; Kevany, Brian M.; Bai, Xiaodong; Maeda, Tadao; Sears, Jonathan E.; Khalil, Ahmad M.; Palczewski, Krzysztof

    2013-01-01

    The discovery that the mammalian transcriptome encodes thousands of long intergenic non-coding (linc) RNA transcripts, together with recent evidence that lincRNAs can regulate protein-coding genes, has added a new level of complexity to cellular transcriptional/translational regulation. Indeed several reports now link mutations in lincRNAs to heritable human disorders. Here, we identified a subset of lincRNAs in terminally differentiated adult human retinal neurons based on their sequence conservation across species. RNA sequencing of eye tissue from several mammalian species with varied rod/cone photoreceptor content identified 18 lincRNAs that were highly conserved across these species. Sixteen of the 18 were conserved in human retinal tissue with 14 of these also conserved in the macular region. A subset of lincRNAs exhibited restricted tissue expression profiles in mice, with preferential expression in the retina. Mouse models with different populations of retinal cells as well as in situ hybridization provided evidence that these lincRNAs localized to specific retinal compartments, most notably to the photoreceptor neuronal layer. Computational genomic loci and promoter region analyses provided a basis for regulated expression of these conserved lincRNAs in retinal post-mitotic neurons. This combined approach identified several lincRNAs that could be critical for retinal and visual maintenance in adults. PMID:23562822

  20. Annotating long intergenic non-coding RNAs under artificial selection during chicken domestication.

    PubMed

    Wang, Yun-Mei; Xu, Hai-Bo; Wang, Ming-Shan; Otecko, Newton Otieno; Ye, Ling-Qun; Wu, Dong-Dong; Zhang, Ya-Ping

    2017-08-15

    Numerous biological functions of long intergenic non-coding RNAs (lincRNAs) have been identified. However, the contribution of lincRNAs to the domestication process has remained elusive. Following domestication from their wild ancestors, animals display substantial changes in many phenotypic traits. Therefore, it is possible that diverse molecular drivers play important roles in this process. We analyzed 821 transcriptomes in this study and annotated 4754 lincRNA genes in the chicken genome. Our population genomic analysis indicates that 419 lincRNAs potentially evolved during artificial selection related to the domestication of chicken, while a comparative transcriptomic analysis identified 68 lincRNAs that were differentially expressed under different conditions. We also found 47 lincRNAs linked to special phenotypes. Our study provides a comprehensive view of the genome-wide landscape of lincRNAs in chicken. This will promote a better understanding of the roles of lincRNAs in domestication, and the genetic mechanisms associated with the artificial selection of domestic animals.

  1. Systematically profiling and annotating long intergenic non-coding RNAs in human embryonic stem cell

    PubMed Central

    2013-01-01

    Background While more and more long intergenic non-coding RNAs (lincRNAs) were identified to take important roles in both maintaining pluripotency and regulating differentiation, how these lincRNAs may define and drive cell fate decisions on a global scale are still mostly elusive. Systematical profiling and comprehensive annotation of embryonic stem cells lincRNAs may not only bring a clearer big picture of these novel regulators but also shed light on their functionalities. Results Based on multiple RNA-Seq datasets, we systematically identified 300 human embryonic stem cell lincRNAs (hES lincRNAs). Of which, one forth (78 out of 300) hES lincRNAs were further identified to be biasedly expressed in human ES cells. Functional analysis showed that they were preferentially involved in several early-development related biological processes. Comparative genomics analysis further suggested that around half of the identified hES lincRNAs were conserved in mouse. To facilitate further investigation of these hES lincRNAs, we constructed an online portal for biologists to access all their sequences and annotations interactively. In addition to navigation through a genome browse interface, users can also locate lincRNAs through an advanced query interface based on both keywords and expression profiles, and analyze results through multiple tools. Conclusions By integrating multiple RNA-Seq datasets, we systematically characterized and annotated 300 hES lincRNAs. A full functional web portal is available freely at http://scbrowse.cbi.pku.edu.cn. As the first global profiling and annotating of human embryonic stem cell lincRNAs, this work aims to provide a valuable resource for both experimental biologists and bioinformaticians. PMID:24564552

  2. miRNAs and other non-coding RNAs in posttraumatic stress disorder: A systematic review of clinical and animal studies.

    PubMed

    Schmidt, Ulrike; Keck, Martin E; Buell, Dominik R

    2015-06-01

    In the last couple of years, non-coding (nc) RNAs like micro-RNAs (miRNAs), small interference RNAs (siRNAs) and long ncRNAs (lncRNAs) have emerged as promising candidates for biomarkers and drug-targets in a variety of psychiatric disorders. In contrast to reports on ncRNAs in affective disorders, schizophrenia and anxiety disorders, manuscripts on ncRNAs in posttraumatic stress disorder (PTSD) and associated animal models are scarce. Aiming to stimulate ncRNA research in PTSD and to identify the hitherto most promising ncRNA candidates and associated pathways for psychotrauma research, we conducted the first review on ncRNAs in PTSD. We aimed to identify studies reporting on the expression, function and regulation of ncRNAs in PTSD patients and in animals exhibiting a PTSD-like syndrome. Following the PRISMA guidelines for systematic reviews, we systematically screened the PubMed database for clinical and animal studies on ncRNAs in PTSD, animal models for PTSD and animal models employing a classical fear conditioning paradigm. Using 112 different combinations of search terms, we retrieved 523 articles of which we finally included and evaluated three clinical and 12 animal studies. In addition, using the web-based tool DIANA miRPath v2.0, we searched for molecular pathways shared by the predicted targets of the here-evaluated miRNA candidates. Our findings suggest that mir-132, which has been found to be regulated in three of the here included studies, as well as miRNAs with an already established role in Alzheimer's disease (AD) seem to be particularly promising candidates for future miRNA studies in PTSD. These results are limited by the low number of human trials and by the heterogeneity of included animal studies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Circulating long non-coding RNAs NRON and MHRT as novel predictive biomarkers of heart failure.

    PubMed

    Xuan, Lina; Sun, Lihua; Zhang, Ying; Huang, Yuechao; Hou, Yan; Li, Qingqi; Guo, Ying; Feng, Bingbing; Cui, Lina; Wang, Xiaoxue; Wang, Zhiguo; Tian, Ye; Yu, Bo; Wang, Shu; Xu, Chaoqian; Zhang, Mingyu; Du, Zhimin; Lu, Yanjie; Yang, Bao Feng

    2017-03-14

    This study sought to evaluate the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers for heart failure (HF). We measured the circulating levels of 13 individual lncRNAs which are known to be relevant to cardiovascular disease in the plasma samples from 72 HF patients and 60 non-HF control participants using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) methods. We found that out of the 13 lncRNAs tested, non-coding repressor of NFAT (NRON) and myosin heavy-chain-associated RNA transcripts (MHRT) had significantly higher plasma levels in HF than in non-HF subjects: 3.17 ± 0.30 versus 1.0 ± 0.07 for NRON (P < 0.0001) and 1.66 ± 0.14 versus 1.0 ± 0.12 for MHRT (P < 0.0001). The area under the ROC curve was 0.865 for NRON and 0.702 for MHRT. Univariate and multivariate analyses identified NRON and MHRT as independent predictors for HF. Spearman's rank correlation analysis showed that NRON was negatively correlated with HDL and positively correlated with LDH, whereas MHRT was positively correlated with AST and LDH. Hence, elevation of circulating NRON and MHRT predicts HF and may be considered as novel biomarkers of HF.

  4. Non-coding RNAs and hypertension-unveiling unexpected mechanisms of hypertension by the dark matter of the genome.

    PubMed

    Murakami, Kazuo

    2015-01-01

    Hypertension is a major risk factor of cardiovascular diseases and a most important health problem in developed countries. Investigations on pathophysiology of hypertension have been based on gene products from coding region that occupies only about 1% of total genome region. On the other hand, non-coding region that occupies almost 99% of human genome has been regarded as "junk" for a long time and went unnoticed until these days. But recently, it turned out that noncoding region is extensively transcribed to non-coding RNAs and has various functions. This review highlights recent updates on the significance of non-coding RNAs such as micro RNAs and long non-coding RNAs (lncRNAs) on the pathogenesis of hypertension, also providing an introduction to basic biology of noncoding RNAs. For example, microRNAs are associated with hypertension via neuro-fumoral factor, sympathetic nerve activity, ion transporters in kidneys, endothelial function, vascular smooth muscle phenotype transformation, or communication between cells. Although reports of lncRNAs on pathogenesis of hypertension are scarce at the moment, new lncRNAs in relation to hypertension are being discovered at a rapid pace owing to novel techniques such as microarray or next-generation sequencing. In the clinical settings, clinical use of non-coding RNAs in identifying cardiovascular risks or developing novel tools for treating hypertension such as molecular decoy or mimicks is promising, although improvement in chemical modification or drug delivery system is necessary.

  5. Synthetic long non-coding RNAs [SINEUPs] rescue defective gene expression in vivo

    PubMed Central

    Indrieri, Alessia; Grimaldi, Claudia; Zucchelli, Silvia; Tammaro, Roberta; Gustincich, Stefano; Franco, Brunella

    2016-01-01

    Non-coding RNAs provide additional regulatory layers to gene expression as well as the potential to being exploited as therapeutic tools. Non-coding RNA-based therapeutic approaches have been attempted in dominant diseases, however their use for treatment of genetic diseases caused by insufficient gene dosage is currently more challenging. SINEUPs are long antisense non-coding RNAs that up-regulate translation in mammalian cells in a gene-specific manner, although, so far evidence of SINEUP efficacy has only been demonstrated in in vitro systems. We now show that synthetic SINEUPs effectively and specifically increase protein levels of a gene of interest in vivo. We demonstrated that SINEUPs rescue haploinsufficient gene dosage in a medakafish model of a human disorder leading to amelioration of the disease phenotype. Our results demonstrate that SINEUPs act through mechanisms conserved among vertebrates and that SINEUP technology can be successfully applied in vivo as a new research and therapeutic tool for gene-specific up-regulation of endogenous functional proteins. PMID:27265476

  6. The 5' and 3' ends of alphavirus RNAs--Non-coding is not non-functional.

    PubMed

    Hyde, Jennifer L; Chen, Rubing; Trobaugh, Derek W; Diamond, Michael S; Weaver, Scott C; Klimstra, William B; Wilusz, Jeffrey

    2015-08-03

    The non-coding regions found at the 5' and 3' ends of alphavirus genomes regulate viral gene expression, replication, translation and virus-host interactions, which have significant implications for viral evolution, host range, and pathogenesis. The functions of these non-coding regions are mediated by a combination of linear sequence and structural elements. The capped 5' untranslated region (UTR) contains promoter elements, translational regulatory sequences that modulate dependence on cellular translation factors, and structures that help to avoid innate immune defenses. The polyadenylated 3' UTR contains highly conserved sequence elements for viral replication, binding sites for cellular miRNAs that determine cell tropism, host range, and pathogenesis, and conserved binding regions for a cellular protein that influences viral RNA stability. Nonetheless, there are additional conserved elements in non-coding regions of the virus (e.g., the repeated sequence elements in the 3' UTR) whose function remains obscure. Thus, key questions remain as to the function of these short yet influential untranslated segments of alphavirus RNAs.

  7. Long non-coding RNAs as regulators of the endocrine system.

    PubMed

    Knoll, Marko; Lodish, Harvey F; Sun, Lei

    2015-03-01

    Long non-coding RNAs (lncRNAs) are a large and diverse group of RNAs that are often lineage-specific and that regulate multiple biological functions. Many are nuclear and are essential parts of ribonucleoprotein complexes that modify chromatin segments and establish active or repressive chromatin states; others are cytosolic and regulate the stability of mRNA or act as microRNA sponges. This Review summarizes the current knowledge of lncRNAs as regulators of the endocrine system, with a focus on the identification and mode of action of several endocrine-important lncRNAs. We highlight lncRNAs that have a role in the development and function of pancreatic β cells, white and brown adipose tissue, and other endocrine organs, and discuss the involvement of these molecules in endocrine dysfunction (for example, diabetes mellitus). We also address the associations of lncRNAs with nuclear receptors involved in major hormonal signalling pathways, such as estrogen and androgen receptors, and the relevance of these associations in certain endocrine cancers.

  8. Exploration of small non coding RNAs in wheat (Triticum aestivum L.).

    PubMed

    Yao, Yingyin; Sun, Qixin

    2012-09-01

    Large numbers of noncoding RNA transcripts (ncRNAs) are being revealed in animals and plants, which can function at the transcriptional or posttranscriptional level to negatively regulate or control genes, repetitive sequences, viruses, and mobile elements. With the identification of microRNA and siRNAs in diverse organisms, increasing evidences indicate that these short npcRNAs play important roles in development, stress response and diseases by cleavage of target mRNA or interfere with translation of target genes. To explore the small RNA transcriptome in wheat (Triticum aestivum L.), a couple of small RNA libraries were constructed and sequenced by high throughput sequencing method. In this review, we focused on the discovery of wheat small RNAs including miRNA and some other non coding small RNAs, then have a view of miRNAs conservations and differences among wheat and other plant species. We also summarized the developmental and stress responsive expression of wheat miRNAs and these observations could serve as a foundation for future functional studies.

  9. Long non-coding RNAs as regulators of the endocrine system

    PubMed Central

    Knoll, Marko; Lodish, Harvey F.; Sun, Lei

    2015-01-01

    Long non-coding RNAs (lncRNAs) are a large and diverse group of RNAs that are often lineage-specific and that regulate multiple biological functions. Many are nuclear and are essential parts of ribonucleoprotein complexes that modify chromatin segments and establish active or repressive chromatin states; others are cytosolic and regulate the stability of mRNA or act as microRNA sponges. This Review summarizes the current knowledge of lncRNAs as regulators of the endocrine system, with a focus on the identification and mode of action of several endocrine-important lncRNAs. We highlight lncRNAs that have a role in the development and function of pancreatic β cells, white and brown adipose tissue, and other endocrine organs, and discuss the involvement of these molecules in endocrine dysfunction (for example, diabetes mellitus). We also address the associations of lncRNAs with nuclear receptors involved in major hormonal signalling pathways, such as estrogen and androgen receptors, and the relevance of these associations in certain endocrine cancers. PMID:25560704

  10. Identification of Non-Coding RNAs in the Candida parapsilosis Species Group

    PubMed Central

    Donovan, Paul D.; Schröder, Markus S.; Higgins, Desmond G.

    2016-01-01

    The Candida CTG clade is a monophyletic group of fungal species that translates CTG as serine, and includes the pathogens Candida albicans and Candida parapsilosis. Research has typically focused on identifying protein-coding genes in these species. Here, we use bioinformatic and experimental approaches to annotate known classes of non-coding RNAs in three CTG-clade species, Candida parapsilosis, Candida orthopsilosis and Lodderomyces elongisporus. We also update the annotation of ncRNAs in the C. albicans genome. The majority of ncRNAs identified were snoRNAs. Approximately 50% of snoRNAs (including most of the C/D box class) are encoded in introns. Most are within mono- and polycistronic transcripts with no protein coding potential. Five polycistronic clusters of snoRNAs are highly conserved in fungi. In polycistronic regions, splicing occurs via the classical pathway, as well as by nested and recursive splicing. We identified spliceosomal small nuclear RNAs, the telomerase RNA component, signal recognition particle, RNase P RNA component and the related RNase MRP RNA component in all three genomes. Stem loop IV of the U2 spliceosomal RNA and the associated binding proteins were lost from the ancestor of C. parapsilosis and C. orthopsilosis, following the divergence from L. elongisporus. The RNA component of the MRP is longer in C. parapsilosis, C. orthopsilosis and L. elongisporus than in S. cerevisiae, but is substantially shorter than in C. albicans. PMID:27658249

  11. Discovery of putative small non-coding RNAs from the obligate intracellular bacterium Wolbachia pipientis.

    PubMed

    Woolfit, Megan; Algama, Manjula; Keith, Jonathan M; McGraw, Elizabeth A; Popovici, Jean

    2015-01-01

    Wolbachia pipientis is an endosymbiotic bacterium that induces a wide range of effects in its insect hosts, including manipulation of reproduction and protection against pathogens. Little is known of the molecular mechanisms underlying the insect-Wolbachia interaction, though it is likely to be mediated via the secretion of proteins or other factors. There is an increasing amount of evidence that bacteria regulate many cellular processes, including secretion of virulence factors, using small non-coding RNAs (sRNAs), but sRNAs have not previously been described from Wolbachia. We have used two independent approaches, one based on comparative genomics and the other using RNA-Seq data generated for gene expression studies, to identify candidate sRNAs in Wolbachia. We experimentally characterized the expression of one of these candidates in four Wolbachia strains, and showed that it is differentially regulated in different host tissues and sexes. Given the roles played by sRNAs in other host-associated bacteria, the conservation of the candidate sRNAs between different Wolbachia strains, and the sex- and tissue-specific differential regulation we have identified, we hypothesise that sRNAs may play a significant role in the biology of Wolbachia, and in particular in its interactions with its host.

  12. Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease.

    PubMed

    Maiese, Kenneth

    2017-01-01

    Noncommunicable diseases (NCDs) contribute to a significant amount of disability and death in the world. Of these disorders, vascular disease is ranked high, falls within the five leading causes of death, and impacts multiple other disease entities such as those of the cardiac system, nervous system, and metabolic disease. Targeting the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) pathway and the modulation of micro ribonucleic acids (miRNAs) may hold great promise for the development of novel strategies for the treatment of vascular disease since each of these pathways are highly relevant to cardiac and nervous system disorders as well as to metabolic dysfunction. SIRT1 is vital in determining the course of stem cell development and the survival, metabolism, and life span of differentiated cells that are overseen by both autophagy and apoptosis. SIRT1 interfaces with a number of pathways that involve forkhead transcription factors, mechanistic of rapamycin (mTOR), AMP activated protein kinase (AMPK) and Wnt1 inducible signaling pathway protein 1 (WISP1) such that the level of activity of SIRT1 can become a critical determinant for biological and clinical outcomes. The essential fine control of SIRT1 is directly tied to the world of non-coding RNAs that ultimately oversee SIRT1 activity to either extend or end cellular survival. Future studies that can further elucidate the crosstalk between SIRT1 and non-coding RNAs should serve well our ability to harness the power of SIRT1 and non-coding RNAs for the treatment of vascular disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease

    PubMed Central

    Maiese, Kenneth

    2016-01-01

    Noncommunicable diseases (NCDs) contribute to a significant amount of disability and death in the world. Of these disorders, vascular disease is ranked high, falls within the five leading causes of death, and impacts multiple other disease entities such as those of the cardiac system, nervous system, and metabolic disease. Targeting the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) pathway and the modulation of micro ribonucleic acids (miRNAs) may hold great promise for the development of novel strategies for the treatment of vascular disease since each of these pathways are highly relevant to cardiac and nervous system disorders as well as to metabolic dysfunction. SIRT1 is vital in determining the course of stem cell development and the survival, metabolism, and life span of differentiated cells that are overseen by both autophagy and apoptosis. SIRT1 interfaces with a number of pathways that involve forkhead transcription factors, mechanistic of rapamycin (mTOR), AMP activated protein kinase (AMPK) and Wnt1 inducible signaling pathway protein 1 (WISP1) such that the level of activity of SIRT1 can become a critical determinant for biological and clinical outcomes. The essential fine control of SIRT1 is directly tied to the world of non-coding RNAs that ultimately oversee SIRT1 activity to either extend or end cellular survival. Future studies that can further elucidate the crosstalk between SIRT1 and non-coding RNAs should serve well our ability to harness the power of SIRT1 and non-coding RNAs for the treatment of vascular disorders. PMID:27897112

  14. Systematic identification and characterization of long non-coding RNAs in mouse mature sperm

    PubMed Central

    Zhang, Xiaoning; Gao, Fengxin; Fu, Jianbo; Zhang, Peng; Wang, Yuqing; Zeng, Xuhui

    2017-01-01

    Increasing studies have shown that mature spermatozoa contain many transcripts including mRNAs and miRNAs. However, the expression profile of long non-coding RNAs (lncRNAs) in mammalian sperm has not been systematically investigated. Here, we used highly purified RNA to investigate lncRNA expression profiles in mouse mature sperm by stranded-specific RNA-seq. We identified 20,907 known and 4,088 novel lncRNAs transcripts, and the existence of intact lncRNAs was confirmed by RT-PCR and fluorescence in situ hybridization on two representative lncRNAs. Compared to round spermatids, 1,794 upregulated and 165 downregulated lncRNAs and 4,435 upregulated and 3,920 downregulated mRNAs were identified in sperm. Based on the “Cis and Trans” RNA-RNA interaction principle, we found 14,259 targeted coding genes of differently expressed lncRNAs. In terms of Gene ontology (GO) analysis, differentially expressed lncRNAs targeted genes mainly related to nucleic acid metabolic, protein modification, chromatin and histone modification, heterocycle compound metabolic, sperm function, spermatogenesis and other processes. In contrast, differentially expressed transcripts of mRNAs were highly enriched for protein metabolic process and RNA metabolic, spermatogenesis, sperm motility, cell cycle, chromatin organization, heterocycle and aromatic compound metabolic processes. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that the differentially expressed lncRNAs were involved in RNA transport, mRNA surveillance pathway, PI3K-Akt signaling pathway, AMPK signaling pathway, protein processing in endoplasmic reticulum. Metabolic pathways, mRNA surveillance pathway, AMPK signaling pathway, cell cycle, RNA transport splicesome and endocytosis incorporated with the differentially expressed mRNA. Furthermore, many lncRNAs were specifically expressed in testis/sperm, and 880 lncRNAs were conserved between human and mouse. In summary, this study provides a preliminary

  15. Hominoid-Specific De Novo Protein-Coding Genes Originating from Long Non-Coding RNAs

    PubMed Central

    Liu, Chu-Jun; Zhou, Wei-Zhen; Li, Ying; Zhang, Mao; Zhang, Rongli; Wei, Liping; Li, Chuan-Yun

    2012-01-01

    Tinkering with pre-existing genes has long been known as a major way to create new genes. Recently, however, motherless protein-coding genes have been found to have emerged de novo from ancestral non-coding DNAs. How these genes originated is not well addressed to date. Here we identified 24 hominoid-specific de novo protein-coding genes with precise origination timing in vertebrate phylogeny. Strand-specific RNA–Seq analyses were performed in five rhesus macaque tissues (liver, prefrontal cortex, skeletal muscle, adipose, and testis), which were then integrated with public transcriptome data from human, chimpanzee, and rhesus macaque. On the basis of comparing the RNA expression profiles in the three species, we found that most of the hominoid-specific de novo protein-coding genes encoded polyadenylated non-coding RNAs in rhesus macaque or chimpanzee with a similar transcript structure and correlated tissue expression profile. According to the rule of parsimony, the majority of these hominoid-specific de novo protein-coding genes appear to have acquired a regulated transcript structure and expression profile before acquiring coding potential. Interestingly, although the expression profile was largely correlated, the coding genes in human often showed higher transcriptional abundance than their non-coding counterparts in rhesus macaque. The major findings we report in this manuscript are robust and insensitive to the parameters used in the identification and analysis of de novo genes. Our results suggest that at least a portion of long non-coding RNAs, especially those with active and regulated transcription, may serve as a birth pool for protein-coding genes, which are then further optimized at the transcriptional level. PMID:23028352

  16. Mining Mammalian Transcript Data for Functional Long Non-Coding RNAs

    PubMed Central

    Khachane, Amit N.; Harrison, Paul M.

    2010-01-01

    Background The role of long non-coding RNAs (lncRNAs) in controlling gene expression has garnered increased interest in recent years. Sequencing projects, such as Fantom3 for mouse and H-InvDB for human, have generated abundant data on transcribed components of mammalian cells, the majority of which appear not to be protein-coding. However, much of the non-protein-coding transcriptome could merely be a consequence of ‘transcription noise’. It is therefore essential to use bioinformatic approaches to identify the likely functional candidates in a high throughput manner. Principal Findings We derived a scheme for classifying and annotating likely functional lncRNAs in mammals. Using the available experimental full-length cDNA data sets for human and mouse, we identified 78 lncRNAs that are either syntenically conserved between human and mouse, or that originate from the same protein-coding genes. Of these, 11 have significant sequence homology. We found that these lncRNAs exhibit: (i) patterns of codon substitution typical of non-coding transcripts; (ii) preservation of sequences in distant mammals such as dog and cow, (iii) significant sequence conservation relative to their corresponding flanking regions (in 50% cases, flanking regions do not have homology at all; and in the remaining, the degree of conservation is significantly less); (iv) existence mostly as single-exon forms (8/11); and, (v) presence of conserved and stable secondary structure motifs within them. We further identified orthologous protein-coding genes that are contributing to the pool of lncRNAs; of which, genes implicated in carcinogenesis are significantly over-represented. Conclusion Our comparative mammalian genomics approach coupled with evolutionary analysis identified a small population of conserved long non-protein-coding RNAs (lncRNAs) that are potentially functional across Mammalia. Additionally, our analysis indicates that amongst the orthologous protein-coding genes that produce

  17. Cis-encoded non-coding antisense RNAs in streptococci and other low GC Gram (+) bacterial pathogens

    PubMed Central

    Cho, Kyu Hong; Kim, Jeong-Ho

    2015-01-01

    Due to recent advances of bioinformatics and high throughput sequencing technology, discovery of regulatory non-coding RNAs in bacteria has been increased to a great extent. Based on this bandwagon, many studies searching for trans-acting small non-coding RNAs in streptococci have been performed intensively, especially in the important human pathogen, group A and B streptococci. However, studies for cis-encoded non-coding antisense RNAs in streptococci have been scarce. A recent study shows antisense RNAs are involved in virulence gene regulation in group B streptococcus, S. agalactiae. This suggests antisense RNAs could have important roles in the pathogenesis of streptococcal pathogens. In this review, we describe recent discoveries of chromosomal cis-encoded antisense RNAs in streptococcal pathogens and other low GC Gram (+) bacteria to provide a guide for future studies. PMID:25859258

  18. Conservation and Losses of Non-Coding RNAs in Avian Genomes

    PubMed Central

    Gardner, Paul P.; Fasold, Mario; Burge, Sarah W.; Ninova, Maria; Hertel, Jana; Kehr, Stephanie; Steeves, Tammy E.; Griffiths-Jones, Sam; Stadler, Peter F.

    2015-01-01

    Here we present the results of a large-scale bioinformatics annotation of non-coding RNA loci in 48 avian genomes. Our approach uses probabilistic models of hand-curated families from the Rfam database to infer conserved RNA families within each avian genome. We supplement these annotations with predictions from the tRNA annotation tool, tRNAscan-SE and microRNAs from miRBase. We identify 34 lncRNA-associated loci that are conserved between birds and mammals and validate 12 of these in chicken. We report several intriguing cases where a reported mammalian lncRNA, but not its function, is conserved. We also demonstrate extensive conservation of classical ncRNAs (e.g., tRNAs) and more recently discovered ncRNAs (e.g., snoRNAs and miRNAs) in birds. Furthermore, we describe numerous “losses” of several RNA families, and attribute these to either genuine loss, divergence or missing data. In particular, we show that many of these losses are due to the challenges associated with assembling avian microchromosomes. These combined results illustrate the utility of applying homology-based methods for annotating novel vertebrate genomes. PMID:25822729

  19. Experimental identification and analysis of macronuclear non-coding RNAs from the ciliate Tetrahymena thermophila

    PubMed Central

    Andersen, Kasper L.; Nielsen, Henrik

    2012-01-01

    The ciliate Tetrahymena thermophila is an important eukaryotic model organism that has been used in pioneering studies of general phenomena, such as ribozymes, telomeres, chromatin structure and genome reorganization. Recent work has shown that Tetrahymena has many classes of small RNA molecules expressed during vegetative growth or sexual reorganization. In order to get an overview of medium-sized (40–500 nt) RNAs expressed from the Tetrahymena genome, we created a size-fractionated cDNA library from macronuclear RNA and analyzed 80 RNAs, most of which were previously unknown. The most abundant class was small nucleolar RNAs (snoRNAs), many of which are formed by an unusual maturation pathway. The modifications guided by the snoRNAs were analyzed bioinformatically and experimentally and many Tetrahymena-specific modifications were found, including several in an essential, but not conserved domain of ribosomal RNA. Of particular interest, we detected two methylations in the 5′-end of U6 small nuclear RNA (snRNA) that has an unusual structure in Tetrahymena. Further, we found a candidate for the first U8 outside metazoans, and an unusual U14 candidate. In addition, a number of candidates for new non-coding RNAs were characterized by expression analysis at different growth conditions. PMID:21967850

  20. Non-coding RNAs in the plant response to abiotic stress.

    PubMed

    Contreras-Cubas, Cecilia; Palomar, Miguel; Arteaga-Vázquez, Mario; Reyes, José Luis; Covarrubias, Alejandra A

    2012-10-01

    As sessile organisms, plants have to cope with the ever-changing environment as well as with numerous forms of stress. To react to these external cues, plants have evolved a suite of response mechanisms operating at many different levels, ranging from physiological to molecular processes that provide the organism with a wide phenotypic plasticity, allowing for fine tuning of the reactions to these adverse circumstances. During the past decade, non-coding RNAs (ncRNAs) have emerged as key regulatory molecules, which contribute to a significant portion of the transcriptome in eukaryotes and are involved in the control of transcriptional and post-transcriptional gene regulatory pathways. Although accumulated evidence supports an important role for ncRNAs in plant response and adaptation to abiotic stress, their mechanism(s) of action still remains obscure and a functional characterization of the ncRNA repertoire in plants is still needed. Moreover, common features in the biogenesis of different small ncRNAs, and in some cases, cross talk between different gene regulatory pathways may add to the complexity of these pathways and could play important roles in modulating stress responses. Here we review the various ncRNAs that have been reported to participate in the response to abiotic stress in plants, focusing on their importance in plant adaptation and evolution. Understanding how ncRNAs work may reveal novel mechanisms involved in the plant responses to the environment.

  1. Retroposition as a source of antisense long non-coding RNAs with possible regulatory functions.

    PubMed

    Bryzghalov, Oleksii; Szcześniak, Michał Wojciech; Makałowska, Izabela

    2016-01-01

    Long non-coding RNAs (lncRNAs) are a class of intensely studied, yet enigmatic molecules that make up a substantial portion of the human transcriptome. In this work, we link the origins and functions of some lncRNAs to retroposition, a process resulting in the creation of intronless copies (retrocopies) of the so-called parental genes. We found 35 human retrocopies transcribed in antisense and giving rise to 58 lncRNA transcripts. These lncRNAs share sequence similarity with the corresponding parental genes but in the sense/antisense orientation, meaning they have the potential to interact with each other and to form RNA:RNA duplexes. We took a closer look at these duplexes and found that 10 of the lncRNAs might regulate parental gene expression and processing at the pre-mRNA and mRNA levels. Further analysis of the co-expression and expression correlation provided support for the existence of functional coupling between lncRNAs and their mate parental gene transcripts.

  2. Development of cytotoxicity-sensitive human cells using overexpression of long non-coding RNAs.

    PubMed

    Tani, Hidenori; Torimura, Masaki

    2015-05-01

    Biosensors using live cells are analytical devices that have the advantage of being highly sensitive for their targets. Although attention has primarily focused on reporter gene assays using functional promoters, cell viability assays are still efficient. We focus on long non-coding RNAs (lncRNAs) that are involved in the molecular mechanisms associated with responses to cellular stresses as a new biological material. Here we have developed human live cells transfected with lncRNAs that can be used as an intelligent sensor of cytotoxicity for a broad range of environmental stresses. We identified three lncRNAs (GAS5, IDI2-AS1, and SNHG15) that responded to cycloheximide in HEK293 cells. Overexpression of these lncRNAs sensitized human cells to cell death in response to various stresses (cycloheximide, ultraviolet irradiation, mercury II chloride, or hydrogen peroxide). In particular, dual lncRNA (GAS5 plus IDI2-AS1, or GAS5 plus SNHG15) overexpression sensitized cells to cell death by more cellular stresses. We propose a method for highly sensitive biosensors using overexpression of lncRNAs that can potentially measure the cytotoxicity signals of various environmental stresses.

  3. Small Non-coding RNAs Associated with Viral Infectious Diseases of Veterinary Importance: Potential Clinical Applications

    PubMed Central

    Samir, Mohamed; Pessler, Frank

    2016-01-01

    MicroRNAs (miRNAs) represent a class of small non-coding RNA (sncRNA) molecules that can regulate mRNAs by inducing their degradation or by blocking translation. Considering that miRNAs are ubiquitous, stable, and conserved across animal species, it seems feasible to exploit them for clinical applications. Unlike in human viral diseases, where some miRNA-based molecules have progressed to clinical application, in veterinary medicine, this concept is just starting to come into view. Clinically, miRNAs could represent powerful diagnostic tools to pinpoint animal viral diseases and/or prognostic tools to follow up disease progression or remission. Additionally, the possible consequences of miRNA dysregulation make them potential therapeutic targets and open the possibilities to use them as tools to generate viral disease-resistant livestock. This review presents an update of preclinical studies on using sncRNAs to combat viral diseases that affect pet and farm animals. Moreover, we discuss the possibilities and challenges of bringing these bench-based discoveries to the veterinary clinic. PMID:27092305

  4. Non-coding RNAs in Prostate Cancer: From Discovery to Clinical Applications.

    PubMed

    Ceder, Yvonne

    2016-01-01

    Prostate cancer is a heterogeneous disease for which the molecular mechanisms are still not fully elucidated. Prostate cancer research has traditionally focused on genomic and epigenetic alterations affecting the proteome, but over the last decade non-coding RNAs, especially microRNAs, have been recognized to play a key role in prostate cancer progression. A considerable number of individual microRNAs have been found to be deregulated in prostate cancer and their biological significance elucidated in functional studies. This review will delineate the current advances regarding the involvement of microRNAs and their targets in prostate cancer biology as well as their potential usage in the clinical management of the disease. The main focus will be on microRNAs contributing to initiation and progression of prostate cancer, including androgen signalling, cellular plasticity, stem cells biology and metastatic processes. To conclude, implications on potential future microRNA-based therapeutics based on the recent advances regarding the interplay between microRNAs and their targets are discussed.

  5. Regulation of influenza virus infection by long non-coding RNAs.

    PubMed

    Landeras-Bueno, Sara; Ortín, Juan

    2016-01-02

    Influenza A viruses generate annual epidemics and occasional pandemics of respiratory disease with important consequences for human health and economy. To establish a productive infection, influenza viruses interact with cellular factors to favour their own replication and to suppress antiviral cell responses. Although most virus-host interaction studies have been centred on cell protein factors, most of the human transcriptome comprises non-coding RNAs, as miRNAs and lncRNAs. The latter are key cellular regulators in many cellular processes, including transcriptional and post-transcriptional regulation. Influenza virus infection induces the differential expression of hundreds of potential lncRNAs, some of which are related to the antiviral pathways activated by the cell while others may be deregulated by the infection to allow efficient virus multiplication. Although our knowledge on the role of cellular lncRNAs for influenza virus replication and pathogenesis is still at its infancy, several lncRNAs have been described to influence the cell innate response to the virus by altering the histone modification at specific sites, by interaction with specific transcription factors or directly stimulating in cis the expression of specific IFN-induced genes. In addition, at least one lncRNA appears to be required for virus multiplication in an IFN-independent way. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. microRNAs: short non-coding bullets of gain of function mutant p53 proteins

    PubMed Central

    Donzelli, Sara; Strano, Sabrina; Blandino, Giovanni

    2014-01-01

    TP53 gene mutations are present in more than half of all human cancers. The resulting proteins are mostly full-length with a single aminoacid change and are abundantly present in cancer cells. Some of mutant p53 proteins gain oncogenic activities through which actively contribute to the aberrant cell proliferation, increased resistance to apoptotic stimuli and ability to metastatize of cancer cells. Gain of function mutant p53 proteins can transcriptionally regulate the expression of a large plethora of target genes. This mainly occurs through the formation of oncogenic transcriptional competent complexes that include mutant p53 protein, known transcription factors, posttranslational modifiers and scaffold proteins. Mutant p53 protein can also transcriptionally regulate the expression of microRNAs, small non-coding RNAs that regulate gene expression at the posttranscriptional level. Each microRNA can putatively target the expression of hundred mRNAs and consequently impact on many cellular functions. Thus, gain of function mutant p53 proteins can exert their oncogenic activities through the modulation of both non-coding and coding regions of human genome. PMID:25594041

  7. Genome-wide discovery of long non-coding RNAs in Rainbow Trout and their potential roles in muscle growth and quality

    USDA-ARS?s Scientific Manuscript database

    The ENCODE project revealed that ~70% of the human genome is transcribed. While only 1-2% of the RNAs encode for proteins, the rest are non-coding RNAs. LncRNAs form a diverse class of non-coding RNAs that are longer than 200nt. Evidences are emerging that lncRNAs play critical roles in various cel...

  8. Long Intergenic Non-Coding RNAs: Novel Drivers of Human Lymphocyte Differentiation

    PubMed Central

    Panzeri, Ilaria; Rossetti, Grazisa; Abrignani, Sergio; Pagani, Massimiliano

    2015-01-01

    Upon recognition of a foreign antigen, CD4+ naïve T lymphocytes proliferate and differentiate into subsets with distinct functions. This process is fundamental for the effective immune system function, as CD4+ T cells orchestrate both the innate and adaptive immune response. Traditionally, this differentiation event has been regarded as the acquisition of an irreversible cell fate so that memory and effector CD4+ T subsets were considered terminally differentiated cells or lineages. Consequently, these lineages are conventionally defined thanks to their prototypical set of cytokines and transcription factors. However, recent findings suggest that CD4+ T lymphocytes possess a remarkable phenotypic plasticity, as they can often re-direct their functional program depending on the milieu they encounter. Therefore, new questions are now compelling such as which are the molecular determinants underlying plasticity and stability and how the balance between these two opposite forces drives the cell fate. As already mentioned, in some cases, the mere expression of cytokines and master regulators could not fully explain lymphocytes plasticity. We should consider other layers of regulation, including epigenetic factors such as the modulation of chromatin state or the transcription of non-coding RNAs, whose high cell-specificity give a hint on their involvement in cell fate determination. In this review, we will focus on the recent advances in understanding CD4+ T lymphocytes subsets specification from an epigenetic point of view. In particular, we will emphasize the emerging importance of non-coding RNAs as key players in these differentiation events. We will also present here new data from our laboratory highlighting the contribution of long non-coding RNAs in driving human CD4+ T lymphocytes differentiation. PMID:25926836

  9. Identification of Aedes aegypti Long Intergenic Non-coding RNAs and Their Association with Wolbachia and Dengue Virus Infection

    PubMed Central

    Etebari, Kayvan; Asad, Sultan; Zhang, Guangmei; Asgari, Sassan

    2016-01-01

    Long intergenic non-coding RNAs (lincRNAs) are appearing as an important class of regulatory RNAs with a variety of biological functions. The aim of this study was to identify the lincRNA profile in the dengue vector Aedes aegypti and evaluate their potential role in host-pathogen interaction. The majority of previous RNA-Seq transcriptome studies in Ae. aegypti have focused on the expression pattern of annotated protein coding genes under different biological conditions. Here, we used 35 publically available RNA-Seq datasets with relatively high depth to screen the Ae. aegypti genome for lincRNA discovery. This led to the identification of 3,482 putative lincRNAs. These lincRNA genes displayed a slightly lower GC content and shorter transcript lengths compared to protein-encoding genes. Ae. aegypti lincRNAs also demonstrate low evolutionary sequence conservation even among closely related species such as Culex quinquefasciatus and Anopheles gambiae. We examined their expression in dengue virus serotype 2 (DENV-2) and Wolbachia infected and non-infected adult mosquitoes and Aa20 cells. The results revealed that DENV-2 infection increased the abundance of a number of host lincRNAs, from which some suppress viral replication in mosquito cells. RNAi-mediated silencing of lincRNA_1317 led to enhancement in viral replication, which possibly indicates its potential involvement in the host anti-viral defense. A number of lincRNAs were also differentially expressed in Wolbachia-infected mosquitoes. The results will facilitate future studies to unravel the function of lncRNAs in insects and may prove to be beneficial in developing new ways to control vectors or inhibit replication of viruses in them. PMID:27760142

  10. Role of microRNAs and long-non-coding RNAs in CD4(+) T-cell differentiation.

    PubMed

    Pagani, Massimiliano; Rossetti, Grazisa; Panzeri, Ilaria; de Candia, Paola; Bonnal, Raoul J P; Rossi, Riccardo L; Geginat, Jens; Abrignani, Sergio

    2013-05-01

    CD4(+) T lymphocytes orchestrate adaptive immune responses by differentiating into various subsets of effector T cells such as T-helper 1 (Th1), Th2, Th17, and regulatory T cells. These subsets have been generally described by master transcription factors that dictate the expression of cytokines and receptors, which ultimately define lymphocyte effector functions. However, the view of T-lymphocyte subsets as stable and terminally differentiated lineages has been challenged by increasing evidence of functional plasticity within CD4(+) T-cell subsets, which implies flexible programming of effector functions depending on time and space of T-cell activation. An outstanding question with broad basic and traslational implications relates to the mechanisms, besides transcriptional regulation, which define the plasticity of effector functions. In this study, we discuss the emerging role of regulatory non-coding RNAs in T-cell differentiation and plasticity. Not only microRNAs have been proven to be important for CD4(+) T-cell differentiation, but it is also likely that the overall T-cell functioning is the result of a multilayered network composed by coding RNAs as well as by short and long non-coding RNAs. The integrated study of all the nodes of this network will provide a comprehensive view of the molecular mechanisms underlying T-cell functions in health and disease.

  11. Genome-Wide Identification and Characterization of Long Intergenic Non-Coding RNAs in Ganoderma lucidum

    PubMed Central

    Xu, Jiang; Liu, Chang

    2014-01-01

    Ganoderma lucidum is a white-rot fungus best-known for its medicinal activities. We have previously sequenced its genome and annotated the protein coding genes. However, long non-coding RNAs in G. lucidum genome have not been analyzed. In this study, we have identified and characterized long intergenic non-coding RNAs (lincRNA) in G. lucidum systematically. We developed a computational pipeline, which was used to analyze RNA-Seq data derived from G. lucidum samples collected from three developmental stages. A total of 402 lincRNA candidates were identified, with an average length of 609 bp. Analysis of their adjacent protein-coding genes (apcGenes) revealed that 46 apcGenes belong to the pathways of triterpenoid biosynthesis and lignin degradation, or families of cytochrome P450, mating type B genes, and carbohydrate-active enzymes. To determine if lincRNAs and these apcGenes have any interactions, the corresponding pairs of lincRNAs and apcGenes were analyzed in detail. We developed a modified 3′ RACE method to analyze the transcriptional direction of a transcript. Among the 46 lincRNAs, 37 were found unidirectionally transcribed, and 9 were found bidirectionally transcribed. The expression profiles of 16 of these 37 lincRNAs were found to be highly correlated with those of the apcGenes across the three developmental stages. Among them, 11 are positively correlated (r>0.8) and 5 are negatively correlated (r<−0.8). The co-localization and co-expression of lincRNAs and those apcGenes playing important functions is consistent with the notion that lincRNAs might be important regulators for cellular processes. In summary, this represents the very first study to identify and characterize lincRNAs in the genomes of basidiomycetes. The results obtained here have laid the foundation for study of potential lincRNA-mediated expression regulation of genes in G. lucidum. PMID:24932683

  12. Control of competence by related non-coding csRNAs in Streptococcus pneumoniae R6

    PubMed Central

    Laux, Anke; Sexauer, Anne; Sivaselvarajah, Dineshan; Kaysen, Anne; Brückner, Reinhold

    2015-01-01

    The two-component regulatory system CiaRH of Streptococcus pneumoniae is involved in β-lactam resistance, maintenance of cell integrity, bacteriocin production, host colonization, virulence, and competence. The response regulator CiaR controls, among other genes, expression of five highly similar small non-coding RNAs, designated csRNAs. These csRNAs control competence development by targeting comC, encoding the precursor of the competence stimulating peptide, which is essential to initiate the regulatory cascade leading to competence. In addition, another gene product of the CiaR regulon, the serine protease HtrA, is also involved in competence control. In the absence of HtrA, five csRNAs could suppress competence, but one csRNA alone was not effective. To determine if all csRNAs are needed, reporter gene fusions to competence genes were used to monitor competence gene expression in the presence of different csRNAs. These experiments showed that two csRNAs were not enough to prevent competence, but combinations of three csRNAs, csRNA1,2,3, or csRNA1,2,4 were sufficient. In S. pneumoniae strains expressing only csRNA5, a surprising positive effect was detected on the level of early competence gene expression. Hence, the role of the csRNAs in competence regulation is more complex than anticipated. Mutations in comC (comC8) partially disrupting predicted complementarity to the csRNAs led to competence even in the presence of all csRNAs. Reconstitution of csRNA complementarity to comC8 restored competence suppression. Again, more than one csRNA was needed. In this case, even two mutated csRNAs complementary to comC8, csRNA1–8 and csRNA2–8, were suppressive. In conclusion, competence in S. pneumoniae is additively controlled by the csRNAs via post-transcriptional regulation of comC. PMID:26257773

  13. Genome-wide analysis of long intergenic non-coding RNAs in chickpea and their potential role in flower development

    PubMed Central

    Khemka, Niraj; Singh, Vikash Kumar; Garg, Rohini; Jain, Mukesh

    2016-01-01

    Non-coding RNAs constitute a major portion of the transcriptome in most of eukaryotes. Long non-coding transcripts originating from the DNA segment present between the protein coding genes are termed as long intergenic non-coding RNAs (lincRNAs). Several evidences suggest the role of lincRNAs in regulation of various biological processes. In this study, we identified a total of 2248 lincRNAs in chickpea using RNA-seq data from eight successive stages of flower development and three vegetative tissues via an optimized pipeline. Different characteristic features of lincRNAs were studied and compared with those of predicted mRNAs in chickpea. Further, we utilized a method using network propagation algorithm to reveal the putative function of lincRNAs in plants. In total, at least 79% of the identified chickpea lincRNAs were assigned with a putative function. A comprehensive expression profiling revealed differential expression patterns and tissue specificity of lincRNAs in different stages of flower development in chickpea. In addition, potential lincRNAs-miRNA interactions were explored for the predicted lincRNAs in chickpea. These findings will pave the way for understanding the role of lincRNAs in the regulatory mechanism underlying flower development in chickpea and other legumes. PMID:27628568

  14. Expression Analysis of Long Non-coding RNAs in the Blood of Multiple Sclerosis Patients.

    PubMed

    Eftekharian, Mohammad Mahdi; Ghafouri-Fard, Soudeh; Soudyab, Mohammad; Omrani, Mir Davood; Rahimi, Mahnoosh; Sayad, Arezou; Komaki, Alireza; Mazdeh, Mehrdokht; Taheri, Mohammad

    2017-10-01

    Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) with multiple genetic and environmental risk factors. Long non-coding RNAs (lncRNAs) have been recently reported to participate in the regulation of immune responses. Consequently, aberrant expression of lncRNAs has been suggested as an underlying cause of MS. In the present study, we evaluated the expression of three lncRNAs with putative roles in the regulation of immune response, namely TNF-α and heterogeneous nuclear ribonucleoprotein L (THRIL), Fas cell surface death receptor- antisense 1 (FAS-AS1), and plasmacytoma variant translocation 1 (PVT1) in circulating blood cells of 50 Iranian relapsing-remitting multiple sclerosis (RRMS) patients compared with healthy subjects by means of quantitative real-time polymerase chain reaction (PCR). We detected a significant downregulation of PVT1 and FAS-AS1 expressions in RRMS patients while a significant upregulation of THRIL in patients compared with controls (P < 0.001). Correlation analyses between lncRNA expression levels and clinical data of MS patients revealed no significant correlation between lncRNAs expression levels and Expanded Disability Status Scale (EDSS), a moderate correlation between PVT1 expression levels and duration of the disorder and no significant correlation between lncRNAs expression levels and age at onset. In addition, we demonstrated correlations between the expression levels of PVT1 and THRIL as well as expression levels of THRIL and FAS-AS1 in RRMS patients. In brief, we have demonstrated dysregulation of three lncRNAs in MS patients. Further studies are needed to explore the exact mechanisms by which these lncRNAs participate in regulation of immune responses.

  15. Systematically characterizing dysfunctional long intergenic non-coding RNAs in multiple brain regions of major psychosis

    PubMed Central

    Zhao, Hongying; Li, Feng; Deng, Yulan; Liu, Ling; Lan, Yujia; Zhang, Xinxin; Zhao, Tingting; Xu, Chaohan; Xu, Chun; Xiao, Yun; Li, Xia

    2016-01-01

    Schizophrenia (SZ) and bipolar disorder (BD) are severe neuropsychiatric disorders with serious impact on patients, together termed “major psychosis”. Recently, long intergenic non-coding RNAs (lincRNAs) were reported to play important roles in mental diseases. However, little was known about their molecular mechanism in pathogenesis of SZ and BD. Here, we performed RNA sequencing on 82 post-mortem brain tissues from three brain regions (orbitofrontal cortex (BA11), anterior cingulate cortex (BA24) and dorsolateral prefrontal cortex (BA9)) of patients with SZ and BD and control subjects, generating over one billion reads. We characterized lincRNA transcriptome in the three brain regions and identified 20 differentially expressed lincRNAs (DELincRNAs) in BA11 for BD, 34 and 1 in BA24 and BA9 for SZ, respectively. Our results showed that these DELincRNAs exhibited brain region-specific patterns. Applying weighted gene co-expression network analysis, we revealed that DELincRNAs together with other genes can function as modules to perform different functions in different brain regions, such as immune system development in BA24 and oligodendrocyte differentiation in BA9. Additionally, we found that DNA methylation alteration could partly explain the dysregulation of lincRNAs, some of which could function as enhancers in the pathogenesis of major psychosis. Together, we performed systematical characterization of dysfunctional lincRNAs in multiple brain regions of major psychosis, which provided a valuable resource to understand their roles in SZ and BD pathology and helped to discover novel biomarkers. PMID:27661005

  16. Insights into the Regulatory Role of Non-coding RNAs in Cancer Metabolism

    PubMed Central

    Beltrán-Anaya, Fredy O.; Cedro-Tanda, Alberto; Hidalgo-Miranda, Alfredo; Romero-Cordoba, Sandra L.

    2016-01-01

    Cancer represents a complex disease originated from alterations in several genes leading to disturbances in important signaling pathways in tumor biology, favoring heterogeneity that promotes adaptability and pharmacological resistance of tumor cells. Metabolic reprogramming has emerged as an important hallmark of cancer characterized by the presence of aerobic glycolysis, increased glutaminolysis and fatty acid biosynthesis, as well as an altered mitochondrial energy production. The metabolic switches that support energetic requirements of cancer cells are closely related to either activation of oncogenes or down-modulation of tumor-suppressor genes, finally leading to dysregulation of cell proliferation, metastasis and drug resistance signals. Non-coding RNAs (ncRNAs) have emerged as one important kind of molecules that can regulate altered genes contributing, to the establishment of metabolic reprogramming. Moreover, diverse metabolic signals can regulate ncRNA expression and activity at genetic, transcriptional, or epigenetic levels. The regulatory landscape of ncRNAs may provide a new approach for understanding and treatment of different types of malignancies. In this review we discuss the regulatory role exerted by ncRNAs on metabolic enzymes and pathways involved in glucose, lipid, and amino acid metabolism. We also review how metabolic stress conditions and tumoral microenvironment influence ncRNA expression and activity. Furthermore, we comment on the therapeutic potential of metabolism-related ncRNAs in cancer. PMID:27551267

  17. Expression of macro non-coding RNAs Meg8 and Irm in mouse embryonic development.

    PubMed

    Gu, Tiantian; He, Hongjuan; Han, Zhengbin; Zeng, Tiebo; Huang, Zhijun; Liu, Qi; Gu, Ning; Chen, Yan; Sugimoto, Kenkichi; Jiang, Huijie; Wu, Qiong

    2012-07-01

    Non-coding RNAs (ncRNAs) Meg8 and Irm were previously identified as alternatively splicing isoforms of Rian gene. Ascertaining ncRNAs spatiotemporal expression patterns is crucial for understanding the physiological roles of ncRNAs during tissue and organ development. In this study in mouse embryos, we focused on the developmental regulation expression of imprinted macro ncRNAs, Meg8 and Irm by using in situ hybridization and quantitative real-time RT-PCR (QRT-PCR). The in situ hybridization results showed that Meg8 and Irm were expressed in the developing brain at embryonic day 10.5 (E10.5) and E11.5, while Irm expression signals were strikingly detected in the somite, where Meg8 expression signals were undetectable. By E15.5, they were expressed in brain, tongue, liver, lung and neuroendocrine tissues, while Irm displayed more restricted expression in tongue and skeletal muscle than Meg8. Furthermore, quantitative analysis confirmed that they were highly expressed in tongue and brain at E12.5, E15.5 and E18.5. These results indicated that Meg8 and Irm might be coordinately expressed and functionally correlated in diverse of organs. Notably, Irm was more closely associated with morphogenesis of skeletal muscle in contrast to Meg8 during embryonic development.

  18. The Role of Long Non-Coding RNAs in Ovarian Cancer

    PubMed Central

    Nikpayam, Elahe; Tasharrofi, Behnoosh; Sarrafzadeh, Shaghayegh; Ghafouri-Fard, Soudeh

    2017-01-01

    Ovarian cancer is the most fatal tumor of female’s reproductive system, and several genetics and environmental factors are involved in its development. Various studies have already identified some suitable biomarkers to facilitate the early detection, the prognosis evaluation, and the assessment of treatment response. However, the aim of this review is to investigate the role of long non-coding RNAs (lncRNAs) in tumorigenesis process of ovarian cancer and their potential applications as ovarian cancer biomarkers. We performed an online literature search of the MEDLINE/PubMed databases using the keywords, including ovarian cancer, lncRNA, and biomarker. We found that several lncRNAs have been shown to be deregulated in ovarian cancer and the specific mechanism of their enrollment in ovarian cancer has been defined for a few of them. In addition, expression profiling has revealed an association between lncRNAs and patients’ survival, metastasis potential, as well as treatment response. Expression profiling and methylation analysis of lncRNAs in ovarian cancer may lead to the identification of novel biomarkers that can help in the classification of patients based on prognosis and treatment response. PMID:27664137

  19. Profiling analysis of long non-coding RNAs in early postnatal mouse hearts

    PubMed Central

    Sun, Xiongshan; Han, Qi; Luo, Hongqin; Pan, Xiaodong; Ji, Yan; Yang, Yao; Chen, Hanying; Wang, Fangjie; Lai, Wenjing; Guan, Xiao; Zhang, Qi; Tang, Yuan; Chu, Jianhong; Yu, Jianhua; Shou, Weinian; Deng, Youcai; Li, Xiaohui

    2017-01-01

    Mammalian cardiomyocytes undergo a critical hyperplastic-to-hypertrophic growth transition at early postnatal age, which is important in establishing normal physiological function of postnatal hearts. In the current study, we intended to explore the role of long non-coding (lnc) RNAs in this transitional stage. We analyzed lncRNA expression profiles in mouse hearts at postnatal day (P) 1, P7 and P28 via microarray. We identified 1,146 differentially expressed lncRNAs with more than 2.0-fold change when compared the expression profiles of P1 to P7, P1 to P28, and P7 to P28. The neighboring genes of these differentially expressed lncRNAs were mainly involved in DNA replication-associated biological processes. We were particularly interested in one novel cardiac-enriched lncRNA, ENSMUST00000117266, whose expression was dramatically down-regulated from P1 to P28 and was also sensitive to hypoxia, paraquat, and myocardial infarction. Knockdown ENSMUST00000117266 led to a significant increase of neonatal mouse cardiomyocytes in G0/G1 phase and reduction in G2/M phase, suggesting that ENSMUST00000117266 is involved in regulating cardiomyocyte proliferative activity and is likely associated with hyperplastic-to-hypertrophic growth transition. In conclusion, our data have identified a large group of lncRNAs presented in the early postnatal mouse heart. Some of these lncRNAs may have important functions in cardiac hyperplastic-to-hypertrophic growth transition. PMID:28266538

  20. Regulation of spermatogenesis by small non-coding RNAs: role of the germ granule.

    PubMed

    de Mateo, Sara; Sassone-Corsi, Paolo

    2014-05-01

    The spermatogenic process relays in highly regulated gene expression mechanisms at the transcriptional and post-transcriptional levels to generate the male gamete that is needed for the perpetuation of the species. Small non-coding RNA pathways have been determined to participate in the post-transcriptional regulatory processes of germ cells. The most important sncRNA molecules that are critically involved in spermatogenesis belong to the miRNA and piRNAs pathways as illustrated by animal models where ablation of specific protein components displays male infertility. Several elements of these regulatory pathways have been found in the nuage or germ granule, a non-membranous cytoplasmatic structure that can be seen in spermatocytes and spermatids. This notion suggests that germ granules may act as organizer centers for silencing pathways in the germline. In general, miRNAs regulate spermatogenesis through targeting and down-regulation of specific transcripts to eventually promote sperm development. However, piRNAs are powerful repressors of transposon elements expression in the spermatogenic process. Here we describe the suggested functions that miRNA and piRNAs pathways execute in the regulation of spermatogenesis and include some recent studies in the field. Despite major strides on the detailed molecular mechanisms of sncRNAs in relation to spermatogenesis, there is plenty to discover on this fascinating regulatory program.

  1. Effective knockdown of Drosophila long non-coding RNAs by CRISPR interference

    PubMed Central

    Ghosh, Sanjay; Tibbit, Charlotte; Liu, Ji-Long

    2016-01-01

    Long non-coding RNAs (lncRNAs) have emerged as regulators of gene expression across metazoa. Interestingly, some lncRNAs function independently of their transcripts – the transcription of the lncRNA locus itself affects target genes. However, current methods of loss-of-function analysis are insufficient to address the role of lncRNA transcription from the transcript which has impeded analysis of their function. Using the minimal CRISPR interference (CRISPRi) system, we show that coexpression of the catalytically inactive Cas9 (dCas9) and guide RNAs targeting the endogenous roX locus in the Drosophila cells results in a robust and specific knockdown of roX1 and roX2 RNAs, thus eliminating the need for recruiting chromatin modifying proteins for effective gene silencing. Additionally, we find that the human and Drosophila codon optimized dCas9 genes are functional and show similar transcription repressive activity. Finally, we demonstrate that the minimal CRISPRi system suppresses roX transcription efficiently in vivo resulting in loss-of-function phenotype, thus validating the method for the first time in a multicelluar organism. Our analysis expands the genetic toolkit available for interrogating lncRNA function in situ and is adaptable for targeting multiple genes across model organisms. PMID:26850642

  2. Non-Coding RNAs in Lung Cancer: Contribution of Bioinformatics Analysis to the Development of Non-Invasive Diagnostic Tools.

    PubMed

    Kunz, Meik; Wolf, Beat; Schulze, Harald; Atlan, David; Walles, Thorsten; Walles, Heike; Dandekar, Thomas

    2016-12-26

    Lung cancer is currently the leading cause of cancer related mortality due to late diagnosis and limited treatment intervention. Non-coding RNAs are not translated into proteins and have emerged as fundamental regulators of gene expression. Recent studies reported that microRNAs and long non-coding RNAs are involved in lung cancer development and progression. Moreover, they appear as new promising non-invasive biomarkers for early lung cancer diagnosis. Here, we highlight their potential as biomarker in lung cancer and present how bioinformatics can contribute to the development of non-invasive diagnostic tools. For this, we discuss several bioinformatics algorithms and software tools for a comprehensive understanding and functional characterization of microRNAs and long non-coding RNAs.

  3. Non-Coding RNAs in Lung Cancer: Contribution of Bioinformatics Analysis to the Development of Non-Invasive Diagnostic Tools

    PubMed Central

    Kunz, Meik; Wolf, Beat; Schulze, Harald; Atlan, David; Walles, Thorsten; Walles, Heike; Dandekar, Thomas

    2016-01-01

    Lung cancer is currently the leading cause of cancer related mortality due to late diagnosis and limited treatment intervention. Non-coding RNAs are not translated into proteins and have emerged as fundamental regulators of gene expression. Recent studies reported that microRNAs and long non-coding RNAs are involved in lung cancer development and progression. Moreover, they appear as new promising non-invasive biomarkers for early lung cancer diagnosis. Here, we highlight their potential as biomarker in lung cancer and present how bioinformatics can contribute to the development of non-invasive diagnostic tools. For this, we discuss several bioinformatics algorithms and software tools for a comprehensive understanding and functional characterization of microRNAs and long non-coding RNAs. PMID:28035947

  4. The role of non-coding RNAs in male sex determination and differentiation.

    PubMed

    Rastetter, Raphael H; Smith, Craig A; Wilhelm, Dagmar

    2015-09-01

    A complex network of gene regulation and interaction drives male sex determination and differentiation. While many important protein-coding genes that are necessary for proper male development have been identified, many disorders in human sex development are still unexplained at the molecular level. This suggests that key factors and regulatory mechanisms are still unknown. In recent years, extensive data have shown that different classes of non-coding RNAs (ncRNAs) play a role in almost all developmental and physiological pathways. Here we review what is known about their role in male sex determination and differentiation not only in mammals, but also other species. While for some processes a key role for ncRNA has been identified, we are still far from having a complete picture.

  5. A-to-I editing of coding and non-coding RNAs by ADARs

    PubMed Central

    Nishikura, Kazuko

    2016-01-01

    Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference. PMID:26648264

  6. The Underexploited Role of Non-Coding RNAs in Lysosomal Storage Diseases.

    PubMed

    Queiroz, Matheus Trovão; Pereira, Vanessa Gonçalves; do Nascimento, Cinthia Castro; D'Almeida, Vânia

    2016-01-01

    Non-coding RNAs (ncRNAs) are a functional class of RNA involved in the regulation of several cellular processes which may modulate disease onset, progression, and prognosis. Lysosomal storage diseases (LSD) are a group of rare disorders caused by mutations of genes encoding specific hydrolases or non-enzymatic proteins, characterized by a wide spectrum of manifestations. The alteration of ncRNA levels is well established in several human diseases such as cancer and auto-immune disorders; however, there is a lack of information focused on the role of ncRNA in rare diseases. Recent reports related to changes in ncRNA expression and its consequences on LSD physiopathology show us the importance to keep advancing in this field. This article will summarize recent findings and provide key points for further studies on LSD and ncRNA association.

  7. The Underexploited Role of Non-Coding RNAs in Lysosomal Storage Diseases

    PubMed Central

    de Queiroz, Matheus Trovão; Pereira, Vanessa Gonçalves; do Nascimento, Cinthia Castro; D’Almeida, Vânia

    2016-01-01

    Non-coding RNAs (ncRNAs) are a functional class of RNA involved in the regulation of several cellular processes which may modulate disease onset, progression, and prognosis. Lysosomal storage diseases (LSD) are a group of rare disorders caused by mutations of genes encoding specific hydrolases or non-enzymatic proteins, characterized by a wide spectrum of manifestations. The alteration of ncRNA levels is well established in several human diseases such as cancer and auto-immune disorders; however, there is a lack of information focused on the role of ncRNA in rare diseases. Recent reports related to changes in ncRNA expression and its consequences on LSD physiopathology show us the importance to keep advancing in this field. This article will summarize recent findings and provide key points for further studies on LSD and ncRNA association. PMID:27708618

  8. Differential expression of small non-coding RNAs in serum from cattle challenged with viruses causing bovine respiratory disease

    USDA-ARS?s Scientific Manuscript database

    MicroRNAs and tRNA-derived RNA fragments (tRFs) are the two most abundant groups of small non-coding RNAs. The potential for microRNAs and tRFs to be used as pathogen exposure indicators is yet to be fully explored. Our objective was to identify microRNAs and tRFs in cattle challenged with a non-cy...

  9. Differential expression of small non-coding RNAs in serum from cattle challenged with viruses causing bovine respiratory disease

    USDA-ARS?s Scientific Manuscript database

    MicroRNAs and tRNA-derived RNA fragments (tRFs) are the two most abundant groups of small non-coding RNAs. The potential for microRNAs and tRFs to be used as pathogen exposure indicators is yet to be fully explored. Our objective was to identify microRNAs and tRFs in cattle challenged with a non-cy...

  10. The Role of Ctk1 Kinase in Termination of Small Non-Coding RNAs

    PubMed Central

    Lenstra, Tineke L.; Tudek, Agnieszka; Clauder, Sandra; Xu, Zhenyu; Pachis, Spyridon T.; van Leenen, Dik; Kemmeren, Patrick; Steinmetz, Lars M.; Libri, Domenico; Holstege, Frank C. P.

    2013-01-01

    Transcription termination in Saccharomyces cerevisiae can be performed by at least two distinct pathways and is influenced by the phosphorylation status of the carboxy-terminal domain (CTD) of RNA polymerase II (Pol II). Late termination of mRNAs is performed by the CPF/CF complex, the recruitment of which is dependent on CTD-Ser2 phosphorylation (Ser2P). Early termination of shorter cryptic unstable transcripts (CUTs) and small nucleolar/nuclear RNAs (sno/snRNAs) is performed by the Nrd1-Nab3-Sen1 (NNS) complex that binds phosphorylated CTD-Ser5 (Ser5P) via the CTD-interacting domain (CID) of Nrd1p. In this study, mutants of the different termination pathways were compared by genome-wide expression analysis. Surprisingly, the expression changes observed upon loss of the CTD-Ser2 kinase Ctk1p are more similar to those derived from alterations in the Ser5P-dependent NNS pathway, than from loss of CTD-Ser2P binding factors. Tiling array analysis of ctk1Δ cells reveals readthrough at snoRNAs, at many cryptic unstable transcripts (CUTs) and stable uncharacterized transcripts (SUTs), but only at some mRNAs. Despite the suggested predominant role in termination of mRNAs, we observed that a CTK1 deletion or a Pol II CTD mutant lacking all Ser2 positions does not result in a global mRNA termination defect. Rather, termination defects in these strains are widely observed at NNS-dependent genes. These results indicate that Ctk1p and Ser2 CTD phosphorylation have a wide impact in termination of small non-coding RNAs but only affect a subset of mRNA coding genes. PMID:24324601

  11. Functional elucidation of the non-coding RNAs of Kluyveromyces marxianus in the exponential growth phase.

    PubMed

    Cho, Yoo-Bok; Lee, Eun Ju; Cho, Suhyung; Kim, Tae Yong; Park, Jin Hwan; Cho, Byung-Kwan

    2016-02-29

    Non-coding RNAs (ncRNAs), which perform diverse regulatory roles, have been found in organisms from all superkingdoms of life. However, there have been limited numbers of studies on the functions of ncRNAs, especially in nonmodel organisms such as Kluyveromyces marxianus that is widely used in the field of industrial biotechnology. In this study, we measured changes in transcriptome at three time points during the exponential growth phase of K. marxianus by using strand-specific RNA-seq. We found that approximately 60% of the transcriptome consists of ncRNAs transcribed from antisense and intergenic regions of the genome that were transcribed at lower levels than mRNA. In the transcriptome, a substantial number of long antisense ncRNAs (lancRNAs) are differentially expressed and enriched in carbohydrate and energy metabolism pathways. Furthermore, this enrichment is evolutionarily conserved, at least in yeast. Particularly, the mode of regulation of mRNA/lancRNA pairs is associated with mRNA transcription levels; the correlation between the pairs is positive at high mRNA transcriptional levels and negative at low levels. In addition, significant induction of mRNA and coverage of more than half of the mRNA sequence by a lancRNA strengthens the positive correlation between mRNA/lancRNA pairs. Transcriptome sequencing of K. marxianus in the exponential growth phase reveals pervasive transcription of ncRNAs with evolutionarily conserved functions. Studies of the mode of regulation of mRNA/lancRNA pairs suggest that induction of lancRNA may be associated with switch-like behavior of mRNA/lancRNA pairs and efficient regulation of the carbohydrate and energy metabolism pathways in the exponential growth phase of K. marxianus being used in industrial applications.

  12. Non-Coding RNAs in Saliva: Emerging Biomarkers for Molecular Diagnostics

    PubMed Central

    Majem, Blanca; Rigau, Marina; Reventós, Jaume; Wong, David T.

    2015-01-01

    Saliva is a complex body fluid that comprises secretions from the major and minor salivary glands, which are extensively supplied by blood. Therefore, molecules such as proteins, DNA, RNA, etc., present in plasma could be also present in saliva. Many studies have reported that saliva body fluid can be useful for discriminating several oral diseases, but also systemic diseases including cancer. Most of these studies revealed messenger RNA (mRNA) and proteomic biomarker signatures rather than specific non-coding RNA (ncRNA) profiles. NcRNAs are emerging as new regulators of diverse biological functions, playing an important role in oncogenesis and tumor progression. Indeed, the small size of these molecules makes them very stable in different body fluids and not as susceptible as mRNAs to degradation by ribonucleases (RNases). Therefore, the development of a non-invasive salivary test, based on ncRNAs profiles, could have a significant applicability to clinical practice, not only by reducing the cost of the health system, but also by benefitting the patient. Here, we summarize the current status and clinical implications of the ncRNAs present in human saliva as a source of biological information. PMID:25898412

  13. Functions of long non-coding RNAs in human disease and their conservation in Drosophila development.

    PubMed

    Rogoyski, Oliver M; Pueyo, Jose Ignacio; Couso, Juan Pablo; Newbury, Sarah F

    2017-08-15

    Genomic analysis has found that the transcriptome in both humans and Drosophila melanogaster features large numbers of long non-coding RNA transcripts (lncRNAs). This recently discovered class of RNAs regulates gene expression in diverse ways and has been involved in a large variety of important biological functions. Importantly, an increasing number of lncRNAs have also been associated with a range of human diseases, including cancer. Comparative analyses of their functions among these organisms suggest that some of their modes of action appear to be conserved. This highlights the importance of model organisms such as Drosophila, which shares many gene regulatory networks with humans, in understanding lncRNA function and its possible impact in human health. This review discusses some known functions and mechanisms of action of lncRNAs and their implication in human diseases, together with their functional conservation and relevance in Drosophila development. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  14. Transcription of Satellite III non-coding RNAs is a general stress response in human cells.

    PubMed

    Valgardsdottir, Rut; Chiodi, Ilaria; Giordano, Manuela; Rossi, Antonio; Bazzini, Silvia; Ghigna, Claudia; Riva, Silvano; Biamonti, Giuseppe

    2008-02-01

    In heat-shocked human cells, heat shock factor 1 activates transcription of tandem arrays of repetitive Satellite III (SatIII) DNA in pericentromeric heterochromatin. Satellite III RNAs remain associated with sites of transcription in nuclear stress bodies (nSBs). Here we use real-time RT-PCR to study the expression of these genomic regions. Transcription is highly asymmetrical and most of the transcripts contain the G-rich strand of the repeat. A low level of G-rich RNAs is detectable in unstressed cells and a 10(4)-fold induction occurs after heat shock. G-rich RNAs are induced by a wide range of stress treatments including heavy metals, UV-C, oxidative and hyper-osmotic stress. Differences exist among stressing agents both for the kinetics and the extent of induction (>100- to 80.000-fold). In all cases, G-rich transcripts are associated with nSBs. On the contrary, C-rich transcripts are almost undetectable in unstressed cells and modestly increase after stress. Production of SatIII RNAs after hyper-osmotic stress depends on the Tonicity Element Binding Protein indicating that activation of the arrays is triggered by different transcription factors. This is the first example of a non-coding RNA whose transcription is controlled by different transcription factors under different growth conditions.

  15. Satellite non-coding RNAs: the emerging players in cells, cellular pathways and cancer.

    PubMed

    Ferreira, Daniela; Meles, Susana; Escudeiro, Ana; Mendes-da-Silva, Ana; Adega, Filomena; Chaves, Raquel

    2015-09-01

    For several decades, transcriptional inactivity was considered as one of the particular features of constitutive heterochromatin and, therefore, of its major component, satellite DNA sequences. However, more recently, succeeding evidences have demonstrated that these sequences can indeed be transcribed, yielding satellite non-coding RNAs with important roles in the organization and regulation of genomes. Since then, several studies have been conducted, trying to understand the function(s) of these sequences not only in the normal but also in cancer genomes. It is thought that the association between cancer and satncRNAs is mostly due to the influence of these transcripts in the genome instability, a hallmark of cancer. The few reports on satellite DNA transcription in cancer contexts point to its overexpression; however, this scenario may be far more complex, variable, and influenced by a number of factors and the exact role of satncRNAs in the oncogenic process remains poorly understood. The greater is the knowledge on the association of satncRNAs with cancer, the greater would be the opportunity to assist cancer treatment, either by the design of effective therapies targeting these molecules or by using them as biomarkers in cancer diagnosis, prognosis, and with predictive value.

  16. Quantitative Profiling of Peptides from RNAs classified as non-coding

    PubMed Central

    Prabakaran, Sudhakaran; Hemberg, Martin; Chauhan, Ruchi; Winter, Dominic; Tweedie-Cullen, Ry Y.; Dittrich, Christian; Hong, Elizabeth; Gunawardena, Jeremy; Steen, Hanno; Kreiman, Gabriel; Steen, Judith A.

    2014-01-01

    Only a small fraction of the mammalian genome codes for messenger RNAs destined to be translated into proteins, and it is generally assumed that a large portion of transcribed sequences - including introns and several classes of non-coding RNAs (ncRNAs) do not give rise to peptide products. A systematic examination of translation and physiological regulation of ncRNAs has not been conducted. Here, we use computational methods to identify the products of non-canonical translation in mouse neurons by analyzing unannotated transcripts in combination with proteomic data. This study supports the existence of non-canonical translation products from both intragenic and extragenic genomic regions, including peptides derived from anti-sense transcripts and introns. Moreover, the studied novel translation products exhibit temporal regulation similar to that of proteins known to be involved in neuronal activity processes. These observations highlight a potentially large and complex set of biologically regulated translational events from transcripts formerly thought to lack coding potential. PMID:25403355

  17. Transcription of Satellite III non-coding RNAs is a general stress response in human cells

    PubMed Central

    Valgardsdottir, Rut; Chiodi, Ilaria; Giordano, Manuela; Rossi, Antonio; Bazzini, Silvia; Ghigna, Claudia; Riva, Silvano; Biamonti, Giuseppe

    2008-01-01

    In heat-shocked human cells, heat shock factor 1 activates transcription of tandem arrays of repetitive Satellite III (SatIII) DNA in pericentromeric heterochromatin. Satellite III RNAs remain associated with sites of transcription in nuclear stress bodies (nSBs). Here we use real-time RT-PCR to study the expression of these genomic regions. Transcription is highly asymmetrical and most of the transcripts contain the G-rich strand of the repeat. A low level of G-rich RNAs is detectable in unstressed cells and a 104-fold induction occurs after heat shock. G-rich RNAs are induced by a wide range of stress treatments including heavy metals, UV-C, oxidative and hyper-osmotic stress. Differences exist among stressing agents both for the kinetics and the extent of induction (>100- to 80.000-fold). In all cases, G-rich transcripts are associated with nSBs. On the contrary, C-rich transcripts are almost undetectable in unstressed cells and modestly increase after stress. Production of SatIII RNAs after hyper-osmotic stress depends on the Tonicity Element Binding Protein indicating that activation of the arrays is triggered by different transcription factors. This is the first example of a non-coding RNA whose transcription is controlled by different transcription factors under different growth conditions. PMID:18039709

  18. Mechanisms of Long Non-coding RNAs in Mammalian Nervous System Development, Plasticity, Disease, and Evolution.

    PubMed

    Briggs, James A; Wolvetang, Ernst J; Mattick, John S; Rinn, John L; Barry, Guy

    2015-12-02

    Only relatively recently has it become clear that mammalian genomes encode tens of thousands of long non-coding RNAs (lncRNAs). A striking 40% of these are expressed specifically in the brain, where they show precisely regulated temporal and spatial expression patterns. This begs the question, what is the functional role of these many lncRNA transcripts in the brain? Here we canvass a growing number of mechanistic studies that have elucidated central roles for lncRNAs in the regulation of nervous system development and function. We also survey studies indicating that neurological and psychiatric disorders may ensue when these mechanisms break down. Finally, we synthesize these insights with evidence from comparative genomics to argue that lncRNAs may have played important roles in brain evolution, by virtue of their abundant sequence innovation in mammals and plausible mechanistic connections to the adaptive processes that occurred recently in the primate and human lineages. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Current Status of Long Non-Coding RNAs in Human Cancer with Specific Focus on Colorectal Cancer

    PubMed Central

    Smolle, Maria; Uranitsch, Stefan; Gerger, Armin; Pichler, Martin; Haybaeck, Johannes

    2014-01-01

    The latest investigations of long non-coding RNAs (lncRNAs) have revealed their important role in human cancers. LncRNAs are larger than 200 nucleotides in length and fulfill their cellular purpose without being translated into proteins. Though the molecular functions of some lncRNAs have been elucidated, there is still a high number of lncRNAs with unknown or controversial functions. In this review, we provide an overview of different lncRNAs and their role in human cancers. In particular, we emphasize their importance in tumorigenesis of colorectal cancer, the third most common cancer worldwide. PMID:25119862

  20. Small Open Reading Frames, Non-Coding RNAs and Repetitive Elements in Bradyrhizobium japonicum USDA 110

    PubMed Central

    Hahn, Julia; Tsoy, Olga V.; Thalmann, Sebastian; Čuklina, Jelena; Gelfand, Mikhail S.

    2016-01-01

    Small open reading frames (sORFs) and genes for non-coding RNAs are poorly investigated components of most genomes. Our analysis of 1391 ORFs recently annotated in the soybean symbiont Bradyrhizobium japonicum USDA 110 revealed that 78% of them contain less than 80 codons. Twenty-one of these sORFs are conserved in or outside Alphaproteobacteria and most of them are similar to genes found in transposable elements, in line with their broad distribution. Stabilizing selection was demonstrated for sORFs with proteomic evidence and bll1319_ISGA which is conserved at the nucleotide level in 16 alphaproteobacterial species, 79 species from other taxa and 49 other Proteobacteria. Further we used Northern blot hybridization to validate ten small RNAs (BjsR1 to BjsR10) belonging to new RNA families. We found that BjsR1 and BjsR3 have homologs outside the genus Bradyrhizobium, and BjsR5, BjsR6, BjsR7, and BjsR10 have up to four imperfect copies in Bradyrhizobium genomes. BjsR8, BjsR9, and BjsR10 are present exclusively in nodules, while the other sRNAs are also expressed in liquid cultures. We also found that the level of BjsR4 decreases after exposure to tellurite and iron, and this down-regulation contributes to survival under high iron conditions. Analysis of additional small RNAs overlapping with 3’-UTRs revealed two new repetitive elements named Br-REP1 and Br-REP2. These REP elements may play roles in the genomic plasticity and gene regulation and could be useful for strain identification by PCR-fingerprinting. Furthermore, we studied two potential toxin genes in the symbiotic island and confirmed toxicity of the yhaV homolog bll1687 but not of the newly annotated higB homolog blr0229_ISGA in E. coli. Finally, we revealed transcription interference resulting in an antisense RNA complementary to blr1853, a gene induced in symbiosis. The presented results expand our knowledge on sORFs, non-coding RNAs and repetitive elements in B. japonicum and related bacteria. PMID

  1. Spatial-temporal transcriptional dynamics of long non-coding RNAs in human brain.

    PubMed

    Zhang, Xiao-Qin; Wang, Ze-Lin; Poon, Ming-Wai; Yang, Jian-Hua

    2017-08-15

    The functional architecture of the human brain is greatly determined by the temporal and spatial regulation of the transcription process. However, the spatial and temporal transcriptional landscape of long non-coding RNAs (lncRNAs) during human brain development remains poorly understood. Here, we report the genome-wide lncRNA transcriptional analysis in an extensive series of 1340 post-mortem human brain specimens collected from 16 regions spanning the period from early embryo development to late adulthood. We discovered that lncRNA transcriptome dramatically changed during fetal development, while transited to a surprisingly relatively stable state after birth till the late adulthood. We also discovered that the transcription map of lncRNAs was spatially different, and that this spatial difference was developmentally regulated. Of the 16 brain regions explored (cerebellar cortex, thalamus, striatum, amygdala, hippocampus and 11 neocortex areas), cerebellar cortex showed the most distinct lncRNA expression features from all remaining brain regions throughout the whole developmental period, reflecting its unique developmental and functional features. Furthermore, by characterizing the functional modules and cellular processes of the spatial-temporal dynamic lncRNAs, we found that they were significantly associated with the RNA processing, neuron differentiation and synaptic signal transportation processes. Furthermore, we found that many lncRNAs associated with the neurodegenerative Alzheimer and Parkinson diseases were co-expressed in the fetal development of the human brain, and affected the convergent biological processes. In summary, our study provides a comprehensive map for lncRNA transcription dynamics in human brain development, which might shed light on the understanding of the molecular underpinnings of human brain function and disease. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. The Sm Complex Is Required for the Processing of Non-Coding RNAs by the Exosome

    PubMed Central

    Coy, Sarah; Volanakis, Adam; Shah, Sneha; Vasiljeva, Lidia

    2013-01-01

    A key question in the field of RNA regulation is how some exosome substrates, such as spliceosomal snRNAs and telomerase RNA, evade degradation and are processed into stable, functional RNA molecules. Typical feature of these non-coding RNAs is presence of the Sm complex at the 3′end of the mature RNA molecule. Here, we report that in Saccharomyces cerevisiae presence of intact Sm binding site is required for the exosome-mediated processing of telomerase RNA from a polyadenylated precursor into its mature form and is essential for its function in elongating telomeres. Additionally, we demonstrate that the same pathway is involved in the maturation of snRNAs. Furthermore, the insertion of an Sm binding site into an unstable RNA that is normally completely destroyed by the exosome, leads to its partial stabilization. We also show that telomerase RNA accumulates in Schizosaccharomyces pombe exosome mutants, suggesting a conserved role for the exosome in processing and degradation of telomerase RNA. In summary, our data provide important mechanistic insight into the regulation of exosome dependent RNA processing as well as telomerase RNA biogenesis. PMID:23755256

  3. Prediction and Characterization of Small Non-Coding RNAs Related to Secondary Metabolites in Saccharopolyspora erythraea

    PubMed Central

    Liu, Wei-Bing; Shi, Yang; Yao, Li-Li; Zhou, Ying; Ye, Bang-Ce

    2013-01-01

    Saccharopolyspora erythraea produces a large number of secondary metabolites with biological activities, including erythromycin. Elucidation of the mechanisms through which the production of these secondary metabolites is regulated may help to identify new strategies for improved biosynthesis of erythromycin. In this paper, we describe the systematic prediction and analysis of small non-coding RNAs (sRNAs) in S. erythraea, with the aim to elucidate sRNA-mediated regulation of secondary metabolite biosynthesis. In silico and deep-sequencing technologies were applied to predict sRNAs in S. erythraea. Six hundred and forty-seven potential sRNA loci were identified, of which 382 cis-encoded antisense RNA are complementary to protein-coding regions and 265 predicted transcripts are located in intergenic regions. Six candidate sRNAs (sernc292, sernc293, sernc350, sernc351, sernc361, and sernc389) belong to four gene clusters (tpc3, pke, pks6, and nrps5) that are involved in secondary metabolite biosynthesis. Deep-sequencing data showed that the expression of all sRNAs in the strain HL3168 E3 (E3) was higher than that in NRRL23338 (M), except for sernc292 and sernc361 expression. The relative expression of six sRNAs in strain M and E3 were validated by qRT-PCR at three different time points (24, 48, and 72 h). The results showed that, at each time point, the transcription levels of sernc293, sernc350, sernc351, and sernc389 were higher in E3 than in M, with the largest difference observed at 72 h, whereas no signals for sernc292 and sernc361 were detected. sernc293, sernc350, sernc351, and sernc389 probably regulate iron transport, terpene metabolism, geosmin synthesis, and polyketide biosynthesis, respectively. The major significance of this study is the successful prediction and identification of sRNAs in genomic regions close to the secondary metabolism-related genes in S. erythraea. A better understanding of the sRNA-target interaction would help to elucidate the

  4. The Long Non-Coding RNAs: A New (P)layer in the “Dark Matter”

    PubMed Central

    Derrien, Thomas; Guigó, Roderic; Johnson, Rory

    2012-01-01

    The transcriptome of a cell is represented by a myriad of different RNA molecules with and without protein-coding capacities. In recent years, advances in sequencing technologies have allowed researchers to more fully appreciate the complexity of whole transcriptomes, showing that the vast majority of the genome is transcribed, producing a diverse population of non-protein coding RNAs (ncRNAs). Thus, the biological significance of non-coding RNAs (ncRNAs) have been largely underestimated. Amongst these multiple classes of ncRNAs, the long non-coding RNAs (lncRNAs) are apparently the most numerous and functionally diverse. A small but growing number of lncRNAs have been experimentally studied, and a view is emerging that these are key regulators of epigenetic gene regulation in mammalian cells. LncRNAs have already been implicated in human diseases such as cancer and neurodegeneration, highlighting the importance of this emergent field. In this article, we review the catalogs of annotated lncRNAs and the latest advances in our understanding of lncRNAs. PMID:22303401

  5. The pivotal role of small non-coding RNAs in the regulation of seed development.

    PubMed

    Rodrigues, Andreia S; Miguel, Célia M

    2017-03-13

    Seeds represent a crucial stage of the seed plants life cycle. It is during seed development that the foundations of the future plant body, and the ability to give rise to a new plant capable of growing under sometimes adverse environmental conditions, are established. Small non-coding RNAs are major regulators of gene expression both at the post-transcriptional and transcriptional levels and, not surprisingly, these elements play major roles in seed development and germination. We review here the current knowledge about small RNA expression and functions in seed development, going from the morphogenesis phase comprehending embryo development and patterning, to the several steps of the maturation phase, ending in the transition to the germination. A special focus is given to the small RNAs for which functional studies have been conducted and their participation in regulatory networks operating in seeds. Many challenges remain ahead for dissecting the complex small RNA landscape in seeds, but this is a highly relevant issue in plant biology and advances in this area will most certainly impact plant breeding.

  6. Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs

    PubMed Central

    Ranoa, Diana Rose E.; Parekh, Akash D.; Pitroda, Sean P.; Huang, Xiaona; Darga, Thomas; Wong, Anthony C.; Huang, Lei; Andrade, Jorge; Staley, Jonathan P.; Satoh, Takashi; Akira, Shizuo

    2016-01-01

    Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism. PMID:27034163

  7. Identification of long non-coding RNAs biomarkers for early diagnosis of myocardial infarction from the dysregulated coding-non-coding co-expression network

    PubMed Central

    Sun, Chaoyu; Jiang, Hao; Sun, Zhiguo; Gui, Yifang; Xia, Hongyuan

    2016-01-01

    Long non-coding RNAs (lncRNAs) have recently been shown as novel promising diagnostic or prognostic biomarkers for various cancers. However, lncRNA expression patterns and their predictive value in early diagnosis of myocardial infarction (MI) have not been systematically investigated. In our study, we performed a comprehensive analysis of lncRNA expression profiles in MI and found altered lncRNA expression pattern in MI compared to healthy samples. We then constructed a lncRNA-mRNA dysregulation network (DLMCEN) by integrating aberrant lncRNAs, mRNAs and their co-dysregulation relationships, and found that some of mRNAs were previously reported to be involved in cardiovascular disease, suggesting the functional roles of dysregulated lncRNAs in the pathogenesis of MI. Therefore, using support vector machine (SVM) and leave one out cross-validation (LOOCV), we developed a 9-lncRNA signature (termed 9LncSigAMI) from the discovery cohort which could distinguish MI patients from healthy samples with accuracy of 95.96%, sensitivity of 93.88% and specificity of 98%, and validated its predictive power in early diagnosis of MI in another completely independent cohort. Functional analysis demonstrated that these nine lncRNA biomarkers in the 9LncSigAMI may be involved in myocardial innate immune and inflammatory response, and their deregulation may lead to the dysfunction of the inflammatory and immune system contributing to MI recurrence. With prospective validation, the 9LncSigAMI identified by our work will provide additional diagnostic information beyond other known clinical parameters, and increase the understanding of the molecular mechanism underlying the pathogenesis of MI. PMID:27634901

  8. Targeting Non-Coding RNAs in Plants with the CRISPR-Cas Technology is a Challenge yet Worth Accepting.

    PubMed

    Basak, Jolly; Nithin, Chandran

    2015-01-01

    Non-coding RNAs (ncRNAs) have emerged as versatile master regulator of biological functions in recent years. MicroRNAs (miRNAs) are small endogenous ncRNAs of 18-24 nucleotides in length that originates from long self-complementary precursors. Besides their direct involvement in developmental processes, plant miRNAs play key roles in gene regulatory networks and varied biological processes. Alternatively, long ncRNAs (lncRNAs) are a large and diverse class of transcribed ncRNAs whose length exceed that of 200 nucleotides. Plant lncRNAs are transcribed by different RNA polymerases, showing diverse structural features. Plant lncRNAs also are important regulators of gene expression in diverse biological processes. There has been a breakthrough in the technology of genome editing, the CRISPR-Cas9 (clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9) technology, in the last decade. CRISPR loci are transcribed into ncRNA and eventually form a functional complex with Cas9 and further guide the complex to cleave complementary invading DNA. The CRISPR-Cas technology has been successfully applied in model plants such as Arabidopsis and tobacco and important crops like wheat, maize, and rice. However, all these studies are focused on protein coding genes. Information about targeting non-coding genes is scarce. Hitherto, the CRISPR-Cas technology has been exclusively used in vertebrate systems to engineer miRNA/lncRNAs, but it is still relatively unexplored in plants. While briefing miRNAs, lncRNAs and applications of the CRISPR-Cas technology in human and animals, this review essentially elaborates several strategies to overcome the challenges of applying the CRISPR-Cas technology in editing ncRNAs in plants and the future perspective of this field.

  9. Targeting Non-Coding RNAs in Plants with the CRISPR-Cas Technology is a Challenge yet Worth Accepting

    PubMed Central

    Basak, Jolly; Nithin, Chandran

    2015-01-01

    Non-coding RNAs (ncRNAs) have emerged as versatile master regulator of biological functions in recent years. MicroRNAs (miRNAs) are small endogenous ncRNAs of 18–24 nucleotides in length that originates from long self-complementary precursors. Besides their direct involvement in developmental processes, plant miRNAs play key roles in gene regulatory networks and varied biological processes. Alternatively, long ncRNAs (lncRNAs) are a large and diverse class of transcribed ncRNAs whose length exceed that of 200 nucleotides. Plant lncRNAs are transcribed by different RNA polymerases, showing diverse structural features. Plant lncRNAs also are important regulators of gene expression in diverse biological processes. There has been a breakthrough in the technology of genome editing, the CRISPR-Cas9 (clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9) technology, in the last decade. CRISPR loci are transcribed into ncRNA and eventually form a functional complex with Cas9 and further guide the complex to cleave complementary invading DNA. The CRISPR-Cas technology has been successfully applied in model plants such as Arabidopsis and tobacco and important crops like wheat, maize, and rice. However, all these studies are focused on protein coding genes. Information about targeting non-coding genes is scarce. Hitherto, the CRISPR-Cas technology has been exclusively used in vertebrate systems to engineer miRNA/lncRNAs, but it is still relatively unexplored in plants. While briefing miRNAs, lncRNAs and applications of the CRISPR-Cas technology in human and animals, this review essentially elaborates several strategies to overcome the challenges of applying the CRISPR-Cas technology in editing ncRNAs in plants and the future perspective of this field. PMID:26635829

  10. Exploration of small RNA-seq data for small non-coding RNAs in Human Colorectal Cancer.

    PubMed

    Koduru, Srinivas V; Tiwari, Amit K; Hazard, Sprague W; Mahajan, Milind; Ravnic, Dino J

    2017-01-01

    Background: Improved healthcare and recent breakthroughs in technology have substantially reduced cancer mortality rates worldwide. Recent advancements in next-generation sequencing (NGS) have allowed genomic analysis of the human transcriptome. Now, using NGS we can further look into small non-coding regions of RNAs (sncRNAs) such as microRNAs (miRNAs), Piwi-interacting-RNAs (piRNAs), long non-coding RNAs (lncRNAs), and small nuclear/nucleolar RNAs (sn/snoRNAs) among others. Recent studies looking at sncRNAs indicate their role in important biological processes such as cancer progression and predict their role as biomarkers for disease diagnosis, prognosis, and therapy. Results: In the present study, we data mined publically available small RNA sequencing data from colorectal tissue samples of eight matched patients (benign, tumor, and metastasis) and remapped the data for various small RNA annotations. We identified aberrant expression of 13 miRNAs in tumor and metastasis specimens [tumor vs benign group (19 miRNAs) and metastasis vs benign group (38 miRNAs)] of which five were upregulated, and eight were downregulated, during disease progression. Pathway analysis of aberrantly expressed miRNAs showed that the majority of miRNAs involved in colon cancer were also involved in other cancers. Analysis of piRNAs revealed six to be over-expressed in the tumor vs benign cohort and 24 in the metastasis vs benign group. Only two piRNAs were shared between the two cohorts. Examining other types of small RNAs [sn/snoRNAs, mt_rRNA, miscRNA, nonsense mediated decay (NMD), and rRNAs] identified 15 sncRNAs in the tumor vs benign group and 104 in the metastasis vs benign group, with only four others being commonly expressed. Conclusion: In summary, our comprehensive analysis on publicly available small RNA-seq data identified multiple differentially expressed sncRNAs during colorectal cancer progression at different stages compared to normal colon tissue. We speculate that

  11. Exploration of small RNA-seq data for small non-coding RNAs in Human Colorectal Cancer

    PubMed Central

    Koduru, Srinivas V; Tiwari, Amit K; Hazard, Sprague W; Mahajan, Milind; Ravnic, Dino J

    2017-01-01

    Background: Improved healthcare and recent breakthroughs in technology have substantially reduced cancer mortality rates worldwide. Recent advancements in next-generation sequencing (NGS) have allowed genomic analysis of the human transcriptome. Now, using NGS we can further look into small non-coding regions of RNAs (sncRNAs) such as microRNAs (miRNAs), Piwi-interacting-RNAs (piRNAs), long non-coding RNAs (lncRNAs), and small nuclear/nucleolar RNAs (sn/snoRNAs) among others. Recent studies looking at sncRNAs indicate their role in important biological processes such as cancer progression and predict their role as biomarkers for disease diagnosis, prognosis, and therapy. Results: In the present study, we data mined publically available small RNA sequencing data from colorectal tissue samples of eight matched patients (benign, tumor, and metastasis) and remapped the data for various small RNA annotations. We identified aberrant expression of 13 miRNAs in tumor and metastasis specimens [tumor vs benign group (19 miRNAs) and metastasis vs benign group (38 miRNAs)] of which five were upregulated, and eight were downregulated, during disease progression. Pathway analysis of aberrantly expressed miRNAs showed that the majority of miRNAs involved in colon cancer were also involved in other cancers. Analysis of piRNAs revealed six to be over-expressed in the tumor vs benign cohort and 24 in the metastasis vs benign group. Only two piRNAs were shared between the two cohorts. Examining other types of small RNAs [sn/snoRNAs, mt_rRNA, miscRNA, nonsense mediated decay (NMD), and rRNAs] identified 15 sncRNAs in the tumor vs benign group and 104 in the metastasis vs benign group, with only four others being commonly expressed. Conclusion: In summary, our comprehensive analysis on publicly available small RNA-seq data identified multiple differentially expressed sncRNAs during colorectal cancer progression at different stages compared to normal colon tissue. We speculate that

  12. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism

    PubMed Central

    Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

    2015-01-01

    Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed. PMID:26690121

  13. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

    PubMed

    Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

    2015-12-04

    Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

  14. Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers

    PubMed Central

    2012-01-01

    Background Molecular characterization of tumors has been critical for identifying important genes in cancer biology and for improving tumor classification and diagnosis. Long non-coding RNAs, as a new, relatively unstudied class of transcripts, provide a rich opportunity to identify both functional drivers and cancer-type-specific biomarkers. However, despite the potential importance of long non-coding RNAs to the cancer field, no comprehensive survey of long non-coding RNA expression across various cancers has been reported. Results We performed a sequencing-based transcriptional survey of both known long non-coding RNAs and novel intergenic transcripts across a panel of 64 archival tumor samples comprising 17 diagnostic subtypes of adenocarcinomas, squamous cell carcinomas and sarcomas. We identified hundreds of transcripts from among the known 1,065 long non-coding RNAs surveyed that showed variability in transcript levels between the tumor types and are therefore potential biomarker candidates. We discovered 1,071 novel intergenic transcribed regions and demonstrate that these show similar patterns of variability between tumor types. We found that many of these differentially expressed cancer transcripts are also expressed in normal tissues. One such novel transcript specifically expressed in breast tissue was further evaluated using RNA in situ hybridization on a panel of breast tumors. It was shown to correlate with low tumor grade and estrogen receptor expression, thereby representing a potentially important new breast cancer biomarker. Conclusions This study provides the first large survey of long non-coding RNA expression within a panel of solid cancers and also identifies a number of novel transcribed regions differentially expressed across distinct cancer types that represent candidate biomarkers for future research. PMID:22929540

  15. Deregulation of small non-coding RNAs at the DLK1-DIO3 imprinted locus predicts lung cancer patient outcome

    PubMed Central

    Enfield, Katey S.S.; Martinez, Victor D.; Marshall, Erin A.; Stewart, Greg L.; Kung, Sonia H.Y.; Enterina, Jhon R.; Lam, Wan L.

    2016-01-01

    Deregulation of the imprinted DLK1-DIO3 locus at chromosome 14q32.1-14q32.31 has been associated with developmental and respiratory disorders, including cancer. In lung cancer, deregulation of imprinting at DLK1-DIO3 was recently described in smokers. Deregulated expression of a microRNA (miRNA) cluster mapping to this locus was also associated with patient outcome, suggesting the importance of this locus to lung cancer disease phenotypes. The DLK1-DIO3 locus is complex, and encodes several protein-coding genes, in addition to long and short non-coding RNAs. While the role of miRNAs is established, the biological importance of another relevant class of small RNAs, PIWI-interacting RNAs (piRNAs), has not been investigated. When somatically expressed, piRNAs regulate gene transcription through DNA methylation. Interestingly, their expression patterns have been observed to be altered in cancer and correlated with patient outcome. Here, we characterize the somatic expression of piRNAs encoded at DLK1-DIO3 in two independent cohorts of lung adenocarcinoma and lung squamous cell carcinoma and investigate their associations with patient outcome. We find that the expression of piRNAs encoded at DLK1-DIO3 enhances the prognostic potential of small non-coding RNAs specific to this locus in predicting patient outcome, further emphasizing the importance of regulation at this locus in lung cancer. PMID:27829231

  16. Recent advances in the involvement of long non-coding RNAs in neural stem cell biology and brain pathophysiology.

    PubMed

    Antoniou, Daphne; Stergiopoulos, Athanasios; Politis, Panagiotis K

    2014-01-01

    Exploration of non-coding genome has recently uncovered a growing list of formerly unknown regulatory long non-coding RNAs (lncRNAs) with important functions in stem cell pluripotency, development and homeostasis of several tissues. Although thousands of lncRNAs are expressed in mammalian brain in a highly patterned manner, their roles in brain development have just begun to emerge. Recent data suggest key roles for these molecules in gene regulatory networks controlling neuronal and glial cell differentiation. Analysis of the genomic distribution of genes encoding for lncRNAs indicates a physical association of these regulatory RNAs with transcription factors (TFs) with well-established roles in neural differentiation, suggesting that lncRNAs and TFs may form coherent regulatory networks with important functions in neural stem cells (NSCs). Additionally, many studies show that lncRNAs are involved in the pathophysiology of brain-related diseases/disorders. Here we discuss these observations and investigate the links between lncRNAs, brain development and brain-related diseases. Understanding the functions of lncRNAs in NSCs and brain organogenesis could revolutionize the basic principles of developmental biology and neuroscience.

  17. Identification of large intergenic non-coding RNAs in bovine muscle using next-generation transcriptomic sequencing.

    PubMed

    Billerey, Coline; Boussaha, Mekki; Esquerré, Diane; Rebours, Emmanuelle; Djari, Anis; Meersseman, Cédric; Klopp, Christophe; Gautheret, Daniel; Rocha, Dominique

    2014-06-19

    The advent of large-scale gene expression technologies has helped to reveal in eukaryotic cells, the existence of thousands of non-coding transcripts, whose function and significance remain mostly poorly understood. Among these non-coding transcripts, long non-coding RNAs (lncRNAs) are the least well-studied but are emerging as key regulators of diverse cellular processes. In the present study, we performed a survey in bovine Longissimus thoraci of lincRNAs (long intergenic non-coding RNAs not overlapping protein-coding transcripts). To our knowledge, this represents the first such study in bovine muscle. To identify lincRNAs, we used paired-end RNA sequencing (RNA-Seq) to explore the transcriptomes of Longissimus thoraci from nine Limousin bull calves. Approximately 14-45 million paired-end reads were obtained per library. A total of 30,548 different transcripts were identified. Using a computational pipeline, we defined a stringent set of 584 different lincRNAs with 418 lincRNAs found in all nine muscle samples. Bovine lincRNAs share characteristics seen in their mammalian counterparts: relatively short transcript and gene lengths, low exon number and significantly lower expression, compared to protein-encoding genes. As for the first time, our study identified lincRNAs from nine different samples from the same tissue, it is possible to analyse the inter-individual variability of the gene expression level of the identified lincRNAs. Interestingly, there was a significant difference when we compared the expression variation of the 418 lincRNAs with the 10,775 known selected protein-encoding genes found in all muscle samples. In addition, we found 2,083 pairs of lincRNA/protein-encoding genes showing a highly significant correlated expression. Fourteen lincRNAs were selected and 13 were validated by RT-PCR. Some of the lincRNAs expressed in muscle are located within quantitative trait loci for meat quality traits. Our study provides a glimpse into the linc

  18. The long and short of non-coding RNAs during post-natal growth and differentiation of skeletal muscles: Focus on lncRNA and miRNAs.

    PubMed

    Butchart, Lauren C; Fox, Archa; Shavlakadze, Tea; Grounds, Miranda D

    2016-12-01

    Post-natal growth of skeletal muscle is a dynamic process involving proliferation and fusion of myoblasts with elongating myofibres (hyperplasia of myonuclei) until 3 weeks post-natally in mice, with ongoing differentiation and further increases in myofibre size mostly by hypertrophy until about 12 weeks of age. The expression of mRNAs that control these events are well described, but little is known about the in vivo roles of non-coding RNAs (ncRNAs), including both microRNAs (miRNAs) and the lesser-studied long non-coding RNAs (lncRNAs). We analysed expression patterns for a broad range of lncRNAs (including Neat1, Malat1, Sra, Meg3, LncMyoD and linc-MD1), miRNAs and mRNAs in muscles of normal male C57Bl/6J mice at 2 days and 2, 4, 6 and 12 weeks after birth. These post-natal patterns were compared with expression of these RNAs during classic C2C12 myogenesis and differentiation in tissue culture. This overview of RNAs during post-natal skeletal muscle growth provides a novel focus on ncRNAs during this often overlooked growth period, with many potential applications to normal muscle growth in humans and livestock, and to childhood muscle disorders. Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

  19. Identification of proteins binding coding and non-coding human RNAs using protein microarrays

    PubMed Central

    2012-01-01

    Background The regulation and function of mammalian RNAs has been increasingly appreciated to operate via RNA-protein interactions. With the recent discovery of thousands of novel human RNA molecules by high-throughput RNA sequencing, efficient methods to uncover RNA-protein interactions are urgently required. Existing methods to study proteins associated with a given RNA are laborious and require substantial amounts of cell-derived starting material. To overcome these limitations, we have developed a rapid and large-scale approach to characterize binding of in vitro transcribed labeled RNA to ~9,400 human recombinant proteins spotted on protein microarrays. Results We have optimized methodology to probe human protein microarrays with full-length RNA molecules and have identified 137 RNA-protein interactions specific for 10 coding and non-coding RNAs. Those proteins showed strong enrichment for common human RNA binding domains such as RRM, RBD, as well as K homology and CCCH type zinc finger motifs. Previously unknown RNA-protein interactions were discovered using this technique, and these interactions were biochemically verified between TP53 mRNA and Staufen1 protein as well as between HRAS mRNA and CNBP protein. Functional characterization of the interaction between Staufen 1 protein and TP53 mRNA revealed a novel role for Staufen 1 in preserving TP53 RNA stability. Conclusions Our approach demonstrates a scalable methodology, allowing rapid and efficient identification of novel human RNA-protein interactions using RNA hybridization to human protein microarrays. Biochemical validation of newly identified interactions between TP53-Stau1 and HRAS-CNBP using reciprocal pull-down experiments, both in vitro and in vivo, demonstrates the utility of this approach to study uncharacterized RNA-protein interactions. PMID:23157412

  20. Overexpression of long non-coding RNAs following exposure to xenobiotics in the aquatic midge Chironomus riparius.

    PubMed

    Martínez-Guitarte, José-Luis; Planelló, Rosario; Morcillo, Gloria

    2012-04-01

    Non-coding RNAs (ncRNAs) represent an important transcriptional output of eukaryotic genomes. In addition to their functional relevance as housekeeping and regulatory elements, recent studies have suggested their involvement in rather unexpected cellular functions. The aim of this work was to analyse the transcriptional behaviour of non-coding RNAs in the toxic response to pollutants in Chironomus riparius, a reference organism in aquatic toxicology. Three well-characterized long non-coding sequences were studied: telomeric repeats, Cla repetitive elements and the SINE CTRT1. Transcription levels were evaluated by RT-PCR after 24-h exposures to three current aquatic contaminants: bisphenol A (BPA), benzyl butyl phthalate (BBP) and the heavy metal cadmium (Cd). Upregulation of telomeric transcripts was found after BPA treatments. Moreover, BPA significantly activated Cla transcription, which also appeared to be increased by cadmium, whereas BBP did not affect the transcription levels of these sequences. Transcription of SINE CTRT1 was not altered by any of the chemicals tested. These data are discussed in the light of previous studies that have shown a response by long ncRNAS (lncRNAs) to cellular stressors, indicating a relationship with environmental stimuli. Our results demonstrated for the first time the ability of bisphenol A to activate non-coding sequences mainly located at telomeres and centromeres. Overall, this study provides evidence that xenobiotics can induce specific responses in ncRNAs derived from repetitive sequences that could be relevant in the toxic response, and also suggests that ncRNAs could represent a novel class of potential biomarkers in toxicological assessment.

  1. Genome-Wide Identification and Characterization of Long Non-Coding RNAs from Mulberry (Morus notabilis) RNA-seq Data

    PubMed Central

    Song, Xiaobo; Sun, Liang; Luo, Haitao; Ma, Qingguo; Zhao, Yi; Pei, Dong

    2016-01-01

    Numerous sources of evidence suggest that most of the eukaryotic genome is transcribed into protein-coding mRNAs and also into a large number of non-coding RNAs (ncRNAs). Long ncRNAs (lncRNAs), a group consisting of ncRNAs longer than 200 nucleotides, have been found to play critical roles in transcriptional, post-transcriptional, and epigenetic gene regulation across all kingdoms of life. However, lncRNAs and their regulatory roles remain poorly characterized in plants, especially in woody plants. In this paper, we used a computational approach to identify novel lncRNAs from a published RNA-seq data set and analyzed their sequences and expression patterns. In total, 1133 novel lncRNAs were identified in mulberry, and 106 of these lncRNAs displayed a predominant tissue-specific expression in the five major tissues investigated. Additionally, functional predictions revealed that tissue-specific lncRNAs adjacent to protein-coding genes might play important regulatory roles in the development of floral organ and root in mulberry. The pipeline used in this study would be useful for the identification of lncRNAs obtained from other deep sequencing data. Furthermore, the predicted lncRNAs would be beneficial towards an understanding of the variations in gene expression in plants. PMID:26938562

  2. The evolution and expression of the snaR family of small non-coding RNAs

    PubMed Central

    Parrott, Andrew M.; Tsai, Michael; Batchu, Priyanka; Ryan, Karen; Ozer, Harvey L.; Tian, Bin; Mathews, Michael B.

    2011-01-01

    We recently identified the snaR family of small non-coding RNAs that associate in vivo with the nuclear factor 90 (NF90/ILF3) protein. The major human species, snaR-A, is an RNA polymerase III transcript with restricted tissue distribution and orthologs in chimpanzee but not rhesus macaque or mouse. We report their expression in human tissues and their evolution in primates. snaR genes are exclusively in African Great Apes and some are unique to humans. Two novel families of snaR-related genetic elements were found in primates: CAS (catarrhine ancestor of snaR), limited to Old World Monkeys and apes; and ASR (Alu/snaR-related), present in all monkeys and apes. ASR and CAS appear to have spread by retrotransposition, whereas most snaR genes have spread by segmental duplication. snaR-A and snaR-G2 are differentially expressed in discrete regions of the human brain and other tissues, notably including testis. snaR-A is up-regulated in transformed and immortalized human cells, and is stably bound to ribosomes in HeLa cells. We infer that snaR evolved from the left monomer of the primate-specific Alu SINE family via ASR and CAS in conjunction with major primate speciation events, and suggest that snaRs participate in tissue- and species-specific regulation of cell growth and translation. PMID:20935053

  3. An improved method for identification of small non-coding RNAs in bacteria using support vector machine.

    PubMed

    Barman, Ranjan Kumar; Mukhopadhyay, Anirban; Das, Santasabuj

    2017-04-06

    Bacterial small non-coding RNAs (sRNAs) are not translated into proteins, but act as functional RNAs. They are involved in diverse biological processes like virulence, stress response and quorum sensing. Several high-throughput techniques have enabled identification of sRNAs in bacteria, but experimental detection remains a challenge and grossly incomplete for most species. Thus, there is a need to develop computational tools to predict bacterial sRNAs. Here, we propose a computational method to identify sRNAs in bacteria using support vector machine (SVM) classifier. The primary sequence and secondary structure features of experimentally-validated sRNAs of Salmonella Typhimurium LT2 (SLT2) was used to build the optimal SVM model. We found that a tri-nucleotide composition feature of sRNAs achieved an accuracy of 88.35% for SLT2. We validated the SVM model also on the experimentally-detected sRNAs of E. coli and Salmonella Typhi. The proposed model had robustly attained an accuracy of 81.25% and 88.82% for E. coli K-12 and S. Typhi Ty2, respectively. We confirmed that this method significantly improved the identification of sRNAs in bacteria. Furthermore, we used a sliding window-based method and identified sRNAs from complete genomes of SLT2, S. Typhi Ty2 and E. coli K-12 with sensitivities of 89.09%, 83.33% and 67.39%, respectively.

  4. Co-expression analysis and identification of fecundity-related long non-coding RNAs in sheep ovaries

    PubMed Central

    Miao, Xiangyang; Luo, Qingmiao; Zhao, Huijing; Qin, Xiaoyu

    2016-01-01

    Small Tail Han sheep, including the FecBBFecBB (Han BB) and FecB+ FecB+ (Han++) genotypes, and Dorset sheep exhibit different fecundities. To identify novel long non-coding RNAs (lncRNAs) associated with sheep fecundity to better understand their molecular mechanisms, a genome-wide analysis of mRNAs and lncRNAs from Han BB, Han++ and Dorset sheep was performed. After the identification of differentially expressed mRNAs and lncRNAs, 16 significant modules were explored by using weighted gene coexpression network analysis (WGCNA) followed by functional enrichment analysis of the genes and lncRNAs in significant modules. Among these selected modules, the yellow and brown modules were significantly related to sheep fecundity. lncRNAs (e.g., NR0B1, XLOC_041882, and MYH15) in the yellow module were mainly involved in the TGF-β signalling pathway, and NYAP1 and BCORL1 were significantly associated with the oxytocin signalling pathway, which regulates several genes in the coexpression network of the brown module. Overall, we identified several gene modules associated with sheep fecundity, as well as networks consisting of hub genes and lncRNAs that may contribute to sheep prolificacy by regulating the target mRNAs related to the TGF-β and oxytocin signalling pathways. This study provides an alternative strategy for the identification of potential candidate regulatory lncRNAs. PMID:27982099

  5. The landscape of DNA methylation-mediated regulation of long non-coding RNAs in breast cancer

    PubMed Central

    Li, Xuecang; Zhao, Ning; Wang, Yihan; Han, Xiaole; Ci, Ce; Zhang, Jian; Li, Meng; Zhang, Yan

    2017-01-01

    Although systematic studies have identified a host of long non-coding RNAs (lncRNAs) which are involved in breast cancer, the knowledge about the methyla-tion-mediated dysregulation of those lncRNAs remains limited. Here, we integrated multi-omics data to analyze the methylated alteration of lncRNAs in breast invasive carcinoma (BRCA). We found that lncRNAs showed diverse methylation patterns on promoter regions in BRCA. LncRNAs were divided into two categories and four subcategories based on their promoter methylation patterns and expression levels be-tween tumor and normal samples. Through cis-regulatory analysis and gene ontology network, abnormally methylated lncRNAs were identified to be associated with can-cer regulation, proliferation or expression of transcription factors. Competing endog-enous RNA network and functional enrichment analysis of abnormally methylated lncRNAs showed that lncRNAs with different methylation patterns were involved in several hallmarks and KEGG pathways of cancers significantly. Finally, survival analysis based on mRNA modules in networks revealed that lncRNAs silenced by high methylation were associated with prognosis significantly in BRCA. This study enhances the understanding of aberrantly methylated patterns of lncRNAs and pro-vides a novel insight for identifying cancer biomarkers and potential therapeutic tar-gets in breast cancer. PMID:28881636

  6. An improved method for identification of small non-coding RNAs in bacteria using support vector machine

    PubMed Central

    Barman, Ranjan Kumar; Mukhopadhyay, Anirban; Das, Santasabuj

    2017-01-01

    Bacterial small non-coding RNAs (sRNAs) are not translated into proteins, but act as functional RNAs. They are involved in diverse biological processes like virulence, stress response and quorum sensing. Several high-throughput techniques have enabled identification of sRNAs in bacteria, but experimental detection remains a challenge and grossly incomplete for most species. Thus, there is a need to develop computational tools to predict bacterial sRNAs. Here, we propose a computational method to identify sRNAs in bacteria using support vector machine (SVM) classifier. The primary sequence and secondary structure features of experimentally-validated sRNAs of Salmonella Typhimurium LT2 (SLT2) was used to build the optimal SVM model. We found that a tri-nucleotide composition feature of sRNAs achieved an accuracy of 88.35% for SLT2. We validated the SVM model also on the experimentally-detected sRNAs of E. coli and Salmonella Typhi. The proposed model had robustly attained an accuracy of 81.25% and 88.82% for E. coli K-12 and S. Typhi Ty2, respectively. We confirmed that this method significantly improved the identification of sRNAs in bacteria. Furthermore, we used a sliding window-based method and identified sRNAs from complete genomes of SLT2, S. Typhi Ty2 and E. coli K-12 with sensitivities of 89.09%, 83.33% and 67.39%, respectively. PMID:28383059

  7. An improved method for identification of small non-coding RNAs in bacteria using support vector machine

    NASA Astrophysics Data System (ADS)

    Barman, Ranjan Kumar; Mukhopadhyay, Anirban; Das, Santasabuj

    2017-04-01

    Bacterial small non-coding RNAs (sRNAs) are not translated into proteins, but act as functional RNAs. They are involved in diverse biological processes like virulence, stress response and quorum sensing. Several high-throughput techniques have enabled identification of sRNAs in bacteria, but experimental detection remains a challenge and grossly incomplete for most species. Thus, there is a need to develop computational tools to predict bacterial sRNAs. Here, we propose a computational method to identify sRNAs in bacteria using support vector machine (SVM) classifier. The primary sequence and secondary structure features of experimentally-validated sRNAs of Salmonella Typhimurium LT2 (SLT2) was used to build the optimal SVM model. We found that a tri-nucleotide composition feature of sRNAs achieved an accuracy of 88.35% for SLT2. We validated the SVM model also on the experimentally-detected sRNAs of E. coli and Salmonella Typhi. The proposed model had robustly attained an accuracy of 81.25% and 88.82% for E. coli K-12 and S. Typhi Ty2, respectively. We confirmed that this method significantly improved the identification of sRNAs in bacteria. Furthermore, we used a sliding window-based method and identified sRNAs from complete genomes of SLT2, S. Typhi Ty2 and E. coli K-12 with sensitivities of 89.09%, 83.33% and 67.39%, respectively.

  8. Global identification and analysis of long non-coding RNAs in diploid strawberry Fragaria vesca during flower and fruit development.

    PubMed

    Kang, Chunying; Liu, Zhongchi

    2015-10-19

    Long non-coding RNAs (lncRNAs) are a new class of regulatory molecules with roles in diverse biological processes. While much effort has been invested in the analysis of lncRNAs from established plant models Arabidopsis, maize, and rice, almost nothing is known about lncRNAs from fruit crops, including those in the Rosaceae family. Here, we present a genome-scale identification and characterization of lncRNAs from a diploid strawberry, Fragaria vesca, based on rich RNA-seq datasets from 35 different flower and fruit tissues. 5,884 Fve-lncRNAs derived from 3,862 loci were identified. These lncRNAs were carefully cataloged based on expression level and whether or not they contain repetitive sequences or generate small RNAs. About one fourth of them are termed high-confidence lncRNAs (hc-lncRNAs) because they are expressed at a level of FPKM higher than 2 and produce neither small RNAs nor contain repetitive sequence. To identify regulatory interactions between lncRNAs and their potential protein-coding (PC) gene targets, pairs of lncRNAs and PC genes with positively or negatively correlated expression trends were identified based on their expression; these pairs may be candidates of cis- or trans-acting lncRNAs and their targets. Finally, blast searches within plant species indicate that lncRNAs are not well conserved. Our study identifies a large number of tissue-specifically expressed lncRNAs in F. vesca, thereby highlighting their potential contributions to strawberry flower and fruit development and paving the way for future functional studies.

  9. Paraspeckle formation during the biogenesis of long non-coding RNAs.

    PubMed

    Naganuma, Takao; Hirose, Tetsuro

    2013-03-01

    Paraspeckles are unique subnuclear structures that are built around a specific long non-coding RNA (lncRNA), NEAT1, which is comprised of two isoforms (NEAT1_1 and NEAT1_2) that are produced by alternative 3'-end processing. NEAT1 lncRNAs are unusual RNA polymerase II transcripts that lack introns. The non-polyadenylated 3'-end of NEAT1_2 is non-canonically processed by RNase P. NEAT1_2 is an essential component for paraspeckle formation. Paraspeckles form during the NEAT1_2 lncRNA biogenesis process, which encompasses transcription from its own chromosome locus through lncRNA processing and accumulation. Recent RNAi analyses of 40 paraspeckle proteins (PSPs) identified four PSPs that are required for paraspeckle formation by mediating NEAT1 processing and accumulation. In particular, HNRNPK was shown to arrest CFIm-dependent NEAT1_1 polyadenylation, leading to NEAT1_2 synthesis. The other three PSPs were required for paraspeckle formation, but did not affect NEAT1_2 expression. This observation suggests that NEAT1_2 accumulation is necessary but not sufficient for paraspeckle formation. An additional step, presumably the bundling of NEAT1 ribonucleoprotein sub-complexes, may be required for construction of the intact paraspeckle structure. NEAT1 expression is likely regulated at transcriptional and post-transcriptional steps under certain stress conditions, suggesting roles for paraspeckles in the lncRNA-mediated regulation of gene expression, such as the nucleocytoplasmic transport of mRNA in response to certain stimuli.

  10. RNA sequencing and functional analysis implicate the regulatory role of long non-coding RNAs in tomato fruit ripening.

    PubMed

    Zhu, Benzhong; Yang, Yongfang; Li, Ran; Fu, Daqi; Wen, Liwei; Luo, Yunbo; Zhu, Hongliang

    2015-08-01

    Recently, long non-coding RNAs (lncRNAs) have been shown to play critical regulatory roles in model plants, such as Arabidopsis, rice, and maize. However, the presence of lncRNAs and how they function in fleshy fruit ripening are still largely unknown because fleshy fruit ripening is not present in the above model plants. Tomato is the model system for fruit ripening studies due to its dramatic ripening process. To investigate further the role of lncRNAs in fruit ripening, it is necessary and urgent to discover and identify novel lncRNAs and understand the function of lncRNAs in tomato fruit ripening. Here it is reported that 3679 lncRNAs were discovered from wild-type tomato and ripening mutant fruit. The lncRNAs are transcribed from all tomato chromosomes, 85.1% of which came from intergenic regions. Tomato lncRNAs are shorter and have fewer exons than protein-coding genes, a situation reminiscent of lncRNAs from other model plants. It was also observed that 490 lncRNAs were significantly up-regulated in ripening mutant fruits, and 187 lncRNAs were down-regulated, indicating that lncRNAs could be involved in the regulation of fruit ripening. In line with this, silencing of two novel tomato intergenic lncRNAs, lncRNA1459 and lncRNA1840, resulted in an obvious delay of ripening of wild-type fruit. Overall, the results indicated that lncRNAs might be essential regulators of tomato fruit ripening, which sheds new light on the regulation of fruit ripening. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  11. RNA sequencing and functional analysis implicate the regulatory role of long non-coding RNAs in tomato fruit ripening

    PubMed Central

    Zhu, Benzhong; Yang, Yongfang; Li, Ran; Fu, Daqi; Wen, Liwei; Luo, Yunbo; Zhu, Hongliang

    2015-01-01

    Recently, long non-coding RNAs (lncRNAs) have been shown to play critical regulatory roles in model plants, such as Arabidopsis, rice, and maize. However, the presence of lncRNAs and how they function in fleshy fruit ripening are still largely unknown because fleshy fruit ripening is not present in the above model plants. Tomato is the model system for fruit ripening studies due to its dramatic ripening process. To investigate further the role of lncRNAs in fruit ripening, it is necessary and urgent to discover and identify novel lncRNAs and understand the function of lncRNAs in tomato fruit ripening. Here it is reported that 3679 lncRNAs were discovered from wild-type tomato and ripening mutant fruit. The lncRNAs are transcribed from all tomato chromosomes, 85.1% of which came from intergenic regions. Tomato lncRNAs are shorter and have fewer exons than protein-coding genes, a situation reminiscent of lncRNAs from other model plants. It was also observed that 490 lncRNAs were significantly up-regulated in ripening mutant fruits, and 187 lncRNAs were down-regulated, indicating that lncRNAs could be involved in the regulation of fruit ripening. In line with this, silencing of two novel tomato intergenic lncRNAs, lncRNA1459 and lncRNA1840, resulted in an obvious delay of ripening of wild-type fruit. Overall, the results indicated that lncRNAs might be essential regulators of tomato fruit ripening, which sheds new light on the regulation of fruit ripening. PMID:25948705

  12. Long Non-Coding RNAs: Key Regulators of Epithelial-Mesenchymal Transition, Tumour Drug Resistance and Cancer Stem Cells

    PubMed Central

    Heery, Richard; Finn, Stephen P.; Cuffe, Sinead; Gray, Steven G.

    2017-01-01

    Epithelial mesenchymal transition (EMT), the adoption by epithelial cells of a mesenchymal-like phenotype, is a process co-opted by carcinoma cells in order to initiate invasion and metastasis. In addition, it is becoming clear that is instrumental to both the development of drug resistance by tumour cells and in the generation and maintenance of cancer stem cells. EMT is thus a pivotal process during tumour progression and poses a major barrier to the successful treatment of cancer. Non-coding RNAs (ncRNA) often utilize epigenetic programs to regulate both gene expression and chromatin structure. One type of ncRNA, called long non-coding RNAs (lncRNAs), has become increasingly recognized as being both highly dysregulated in cancer and to play a variety of different roles in tumourigenesis. Indeed, over the last few years, lncRNAs have rapidly emerged as key regulators of EMT in cancer. In this review, we discuss the lncRNAs that have been associated with the EMT process in cancer and the variety of molecular mechanisms and signalling pathways through which they regulate EMT, and finally discuss how these EMT-regulating lncRNAs impact on both anti-cancer drug resistance and the cancer stem cell phenotype. PMID:28430163

  13. Prospective and therapeutic screening value of non-coding RNA as biomarkers in cardiovascular disease

    PubMed Central

    Busch, Albert; Eken, Suzanne M.

    2016-01-01

    Non-coding RNA (ncRNA) is a class of genetic, epigenetic and translational regulators, containing short and long transcripts with intriguing abilities for use as biomarkers due to their superordinate role in disease development. In the past five years many of these have been investigated in cardiovascular diseases (CVD), mainly myocardial infarction (MI) and heart failure. To extend this view, we summarize the existing data about ncRNA as biomarker in the whole entity of CVDs by literature-based review and comparison of the identified candidates. The myomirs miRNA-1, -133a/b, -208a, -499 with well-defined cellular functions have proven equal to classic protein biomarkers for disease detection in MI. Other microRNAs (miRNAs) were reproducibly found to correlate with disease, disease severity and outcome in heart failure, stroke, coronary artery disease (CAD) and aortic aneurysm. An additional utilization has been discovered for therapeutic monitoring. The function of long non-coding transcripts is only about to be unraveled, yet shows great potential for outcome prediction. ncRNA biomarkers have a distinct role if no alternative test is available or has is performing poorly. With increasing mechanistic understanding, circulating miRNA and long non-coding transcripts will provide useful disease information with high predictive power. PMID:27429962

  14. Identifcation of differentially expressed long non-coding RNAs in CD4+ T cells response to latent tuberculosis infection.

    PubMed

    Yi, Zhengjun; Li, Jianhua; Gao, Kunshan; Fu, Yurong

    2014-12-01

    To identify differentially expressed long non-coding RNAs (lncRNAs) in CD4(+) T cells triggered upon latent tuberculosis (TB) infection. Expression profiles of lncRNAs and mRNAs in CD4(+) T cells from individuals with latent TB infection (LTBI), active TB and healthy controls were analyzed by microarray assay and four lncRNAs were selected for validation using real time-quantitative polymerase chain reaction (RT-qPCR). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway based approaches were used to investigate biological functions and signaling pathways affected by the differentially expressed mRNAs. LncRNAs and mRNAs in CD4(+) T cells were involved in LTBI and active TB disease. Compared with healthy controls, 449 lncRNAs and 461 mRNAs were deregulated in LTBI group, 1,113 lncRNAs and 1,490 mRNAs were deregulated in active TB group, as well as 163 lncRNAs and 187 mRNAs were differentially expressed in both LTBI and active TB group. It was worth noting that 41 lncRNAs and 60 mRNAs were deregulated between three groups. Most deregulated lncRNAs were from intergenic regions (∼ 50%), natural antisense to protein-coding loci (∼ 20%), or intronic antisense to protein-coding loci (∼ 10%). Significantly enriched signaling pathways based on deregulated mRNAs were mainly involved in mitogen-activated protein kinase (MAPK) signaling pathway, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, etc. The study was the first report of differentially expressed lncRNAs in CD4(+) T cells response to TB infection and indicated that some lncRNAs may be involved in regulating host immune response to TB infection. Future studies are needed to further elucidate potential roles of these deregulated lncRNAs in LTBI and its reactivation. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  15. microRNA dependent and independent deregulation of long non-coding RNAs by an oncogenic herpesvirus

    PubMed Central

    Jain, Vaibhav

    2017-01-01

    Kaposi’s sarcoma (KS) is a highly prevalent cancer in AIDS patients, especially in sub-Saharan Africa. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of KS and other cancers like Primary Effusion Lymphoma (PEL). In KS and PEL, all tumors harbor latent KSHV episomes and express latency-associated viral proteins and microRNAs (miRNAs). The exact molecular mechanisms by which latent KSHV drives tumorigenesis are not completely understood. Recent developments have highlighted the importance of aberrant long non-coding RNA (lncRNA) expression in cancer. Deregulation of lncRNAs by miRNAs is a newly described phenomenon. We hypothesized that KSHV-encoded miRNAs deregulate human lncRNAs to drive tumorigenesis. We performed lncRNA expression profiling of endothelial cells infected with wt and miRNA-deleted KSHV and identified 126 lncRNAs as putative viral miRNA targets. Here we show that KSHV deregulates host lncRNAs in both a miRNA-dependent fashion by direct interaction and in a miRNA-independent fashion through latency-associated proteins. Several lncRNAs that were previously implicated in cancer, including MEG3, ANRIL and UCA1, are deregulated by KSHV. Our results also demonstrate that KSHV-mediated UCA1 deregulation contributes to increased proliferation and migration of endothelial cells. PMID:28715488

  16. microRNA dependent and independent deregulation of long non-coding RNAs by an oncogenic herpesvirus.

    PubMed

    Sethuraman, Sunantha; Gay, Lauren Appleby; Jain, Vaibhav; Haecker, Irina; Renne, Rolf

    2017-07-01

    Kaposi's sarcoma (KS) is a highly prevalent cancer in AIDS patients, especially in sub-Saharan Africa. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of KS and other cancers like Primary Effusion Lymphoma (PEL). In KS and PEL, all tumors harbor latent KSHV episomes and express latency-associated viral proteins and microRNAs (miRNAs). The exact molecular mechanisms by which latent KSHV drives tumorigenesis are not completely understood. Recent developments have highlighted the importance of aberrant long non-coding RNA (lncRNA) expression in cancer. Deregulation of lncRNAs by miRNAs is a newly described phenomenon. We hypothesized that KSHV-encoded miRNAs deregulate human lncRNAs to drive tumorigenesis. We performed lncRNA expression profiling of endothelial cells infected with wt and miRNA-deleted KSHV and identified 126 lncRNAs as putative viral miRNA targets. Here we show that KSHV deregulates host lncRNAs in both a miRNA-dependent fashion by direct interaction and in a miRNA-independent fashion through latency-associated proteins. Several lncRNAs that were previously implicated in cancer, including MEG3, ANRIL and UCA1, are deregulated by KSHV. Our results also demonstrate that KSHV-mediated UCA1 deregulation contributes to increased proliferation and migration of endothelial cells.

  17. Integrative analysis reveals clinical phenotypes and oncogenic potentials of long non-coding RNAs across 15 cancer types

    PubMed Central

    Piccolo, Stephen R.; Zhang, Xiao-Qin; Li, Jun-Hao; Zhou, Hui; Yang, Jian-Hua; Qu, Liang-Hu

    2016-01-01

    Long non-coding RNAs (lncRNAs) have been shown to contribute to tumorigenesis. However, surprisingly little is known about the comprehensive clinical and genomic characterization of lncRNAs across human cancer. In this study, we conducted comprehensive analyses for the expression profile, clinical outcomes, somatic copy number alterations (SCNAs) profile of lncRNAs in ~7000 clinical samples from 15 different cancer types. We identified significantly differentially expressed lncRNAs between tumor and normal tissues from each cancer. Notably, we characterized 47 lncRNAs which were extensively dysregulated in at least 10 cancer types, suggesting a conserved function in cancer development. We also analyzed the associations between lncRNA expressions and patient survival, and identified sets of lncRNAs that possessed significant prognostic values in specific cancer types. Our combined analysis of SCNA data and expression data uncovered 116 dysregulated lncRNAs are strikingly genomic altered across 15 cancer types, indicating their oncogenic potentials. Our study may lay the groundwork for future functional studies of lncRNAs and help facilitate the discovery of novel clinical biomarkers. PMID:27147563

  18. Functional analysis of long intergenic non-coding RNAs in phosphate-starved rice using competing endogenous RNA network.

    PubMed

    Xu, Xi-Wen; Zhou, Xiong-Hui; Wang, Rui-Ru; Peng, Wen-Lei; An, Yue; Chen, Ling-Ling

    2016-02-10

    Long intergenic non-coding RNAs (lincRNAs) may play widespread roles in gene regulation and other biological processes, however, a systematic examination of the functions of lincRNAs in the biological responses of rice to phosphate (Pi) starvation has not been performed. Here, we used a computational method to predict the functions of lincRNAs in Pi-starved rice. Overall, 3,170 lincRNA loci were identified using RNA sequencing data from the roots and shoots of control and Pi-starved rice. A competing endogenous RNA (ceRNA) network was constructed for each tissue by considering the competing relationships between lincRNAs and genes, and the correlations between the expression levels of RNAs in ceRNA pairs. Enrichment analyses showed that most of the communities in the networks were related to the biological processes of Pi starvation. The lincRNAs in the two tissues were individually functionally annotated based on the ceRNA networks, and the differentially expressed lincRNAs were biologically meaningful. For example, XLOC_026030 was upregulated from 3 days after Pi starvation, and its functional annotation was 'cellular response to Pi starvation'. In conclusion, we systematically annotated lincRNAs in rice and identified those involved in the biological response to Pi starvation.

  19. Transcriptional profiling identifies differential expression of long non-coding RNAs in Jo-1 associated and inclusion body myositis.

    PubMed

    Hamann, Philip D; Roux, Benoit T; Heward, James A; Love, Seth; McHugh, Neil J; Jones, Simon W; Lindsay, Mark A

    2017-08-14

    Myositis is characterised by muscle inflammation and weakness. Although generally thought to be driven by a systemic autoimmune response, increasing evidence suggests that intrinsic changes in the muscle might also contribute to the pathogenesis. Long non-coding RNAs (lncRNAs) are a family of novel genes that regulate gene transcription and translation. To determine the potential role of lncRNAs, we employed next generation sequencing to examine the transcriptome in muscle biopsies obtained from two histologically distinct patient populations, inclusion body myositis (IBM) and anti-Jo-1-associated myositis (Jo-1). 1287 mRNAs and 1068 mRNAs were differentially expressed in the muscle from Jo-1 and IBM patients, respectively. Pathway analysis showed the top canonical pathway in both Jo-1 and IBM was oxidative phosphorylation and mitochondrial dysfunction. We identified 731 known and 325 novel lncRNAs in the muscles biopsies. Comparison with controls showed 55 and 46 lncRNAs were differentially expressed in IBM and Jo-1 myositis, respectively. Of these, 16 lncRNAs were differentially expressed in both IBM and Jo-1 myositis and included upregulated H19, lncMyoD and MALAT1. Given that these are known to regulate muscle proliferation and differentiation, we speculate that changes in lncRNAs might contribute to the phenotypic changes in Jo-1 and IBM myositis.

  20. Non-coding RNAs and HIV: viral manipulation of host dark matter to shape the cellular environment

    PubMed Central

    Barichievy, Samantha; Naidoo, Jerolen; Mhlanga, Musa M.

    2015-01-01

    On October 28th 1943 Winston Churchill said “we shape our buildings, and afterward our buildings shape us” (Humes, 1994). Churchill was pondering how and when to rebuild the British House of Commons, which had been destroyed by enemy bombs on May 10th 1941. The old House had been small and insufficient to hold all its members, but was restored to its original form in 1950 in order to recapture the “convenience and dignity” that the building had shaped into its parliamentary members. The circular loop whereby buildings or dwellings are shaped and go on to shape those that reside in them is also true of pathogens and their hosts. As obligate parasites, pathogens need to alter their cellular host environments to ensure survival. Typically pathogens modify cellular transcription profiles and in doing so, the pathogen in turn is affected, thereby closing the loop. As key orchestrators of gene expression, non-coding RNAs provide a vast and extremely precise set of tools for pathogens to target in order to shape the cellular environment. This review will focus on host non-coding RNAs that are manipulated by the infamous intracellular pathogen, the human immunodeficiency virus (HIV). We will briefly describe both short and long host non-coding RNAs and discuss how HIV gains control of these factors to ensure widespread dissemination throughout the host as well as the establishment of lifelong, chronic infection. PMID:25859257

  1. Non-coding RNAs and HIV: viral manipulation of host dark matter to shape the cellular environment.

    PubMed

    Barichievy, Samantha; Naidoo, Jerolen; Mhlanga, Musa M

    2015-01-01

    On October 28th 1943 Winston Churchill said "we shape our buildings, and afterward our buildings shape us" (Humes, 1994). Churchill was pondering how and when to rebuild the British House of Commons, which had been destroyed by enemy bombs on May 10th 1941. The old House had been small and insufficient to hold all its members, but was restored to its original form in 1950 in order to recapture the "convenience and dignity" that the building had shaped into its parliamentary members. The circular loop whereby buildings or dwellings are shaped and go on to shape those that reside in them is also true of pathogens and their hosts. As obligate parasites, pathogens need to alter their cellular host environments to ensure survival. Typically pathogens modify cellular transcription profiles and in doing so, the pathogen in turn is affected, thereby closing the loop. As key orchestrators of gene expression, non-coding RNAs provide a vast and extremely precise set of tools for pathogens to target in order to shape the cellular environment. This review will focus on host non-coding RNAs that are manipulated by the infamous intracellular pathogen, the human immunodeficiency virus (HIV). We will briefly describe both short and long host non-coding RNAs and discuss how HIV gains control of these factors to ensure widespread dissemination throughout the host as well as the establishment of lifelong, chronic infection.

  2. No longer a nuisance: long non-coding RNAs join CENP-A in epigenetic centromere regulation.

    PubMed

    Rošić, Silvana; Erhardt, Sylvia

    2016-04-01

    Centromeres represent the basis for kinetochore formation, and are essential for proper chromosome segregation during mitosis. Despite these essential roles, centromeres are not defined by specific DNA sequences, but by epigenetic means. The histone variant CENP-A controls centromere identity epigenetically and is essential for recruiting kinetochore components that attach the chromosomes to the mitotic spindle during mitosis. Recently, a new player in centromere regulation has emerged: long non-coding RNAs transcribed from repetitive regions of centromeric DNA function in regulating centromeres epigenetically. This review summarizes recent findings on the essential roles that transcription, pericentromeric transcripts, and centromere-derived RNAs play in centromere biology.

  3. Identification of differentially expressed small non-coding RNAs in the legume endosymbiont Sinorhizobium meliloti by comparative genomics.

    PubMed

    del Val, Coral; Rivas, Elena; Torres-Quesada, Omar; Toro, Nicolás; Jiménez-Zurdo, José I

    2007-12-01

    Bacterial small non-coding RNAs (sRNAs) are being recognized as novel widespread regulators of gene expression in response to environmental signals. Here, we present the first search for sRNA-encoding genes in the nitrogen-fixing endosymbiont Sinorhizobium meliloti, performed by a genome-wide computational analysis of its intergenic regions. Comparative sequence data from eight related alpha-proteobacteria were obtained, and the interspecies pairwise alignments were scored with the programs eQRNA and RNAz as complementary predictive tools to identify conserved and stable secondary structures corresponding to putative non-coding RNAs. Northern experiments confirmed that eight of the predicted loci, selected among the original 32 candidates as most probable sRNA genes, expressed small transcripts. This result supports the combined use of eQRNA and RNAz as a robust strategy to identify novel sRNAs in bacteria. Furthermore, seven of the transcripts accumulated differentially in free-living and symbiotic conditions. Experimental mapping of the 5'-ends of the detected transcripts revealed that their encoding genes are organized in autonomous transcription units with recognizable promoter and, in most cases, termination signatures. These findings suggest novel regulatory functions for sRNAs related to the interactions of alpha-proteobacteria with their eukaryotic hosts.

  4. The role of non-coding RNAs in diabetic nephropathy: potential applications as biomarkers for disease development and progression.

    PubMed

    Alvarez, M Lucrecia; Distefano, Johanna K

    2013-01-01

    Diabetic nephropathy, a progressive kidney disease that develops secondary to diabetes, is the major cause of chronic kidney disease in developed countries, and contributes significantly to increased morbidity and mortality among individuals with diabetes. Although the causes of diabetic nephropathy are not fully understood, recent studies demonstrate a role for epigenetic factors in the development of the disease. For example, non-coding RNA (ncRNA) molecules, including microRNAs (miRNAs), have been shown to be functionally important in modulating renal response to hyperglycemia and progression of diabetic nephropathy. Characterization of miRNA expression in diabetic nephropathy from studies of animal models of diabetes, and in vitro investigations using different types of kidney cells also support this role. The goal of this review, therefore, is to summarize the current state of knowledge of specific ncRNAs involved in the development of diabetic nephropathy, with a focus on the potential role of miRNAs to serve as sensitive, non-invasive biomarkers of kidney disease and progression. Non-coding RNAs are currently recognized as potentially important regulators of genes involved in processes related to the development of diabetic nephropathy, and as such, represent viable targets for both clinical diagnostic strategies and therapeutic intervention.

  5. Evolutionarily divergent spliceosomal snRNAs and a conserved non-coding RNA processing motif in Giardia lamblia

    PubMed Central

    Hudson, Andrew J.; Moore, Ashley N.; Elniski, David; Joseph, Joella; Yee, Janet; Russell, Anthony G.

    2012-01-01

    Non-coding RNAs (ncRNAs) have diverse essential biological functions in all organisms, and in eukaryotes, two such classes of ncRNAs are the small nucleolar (sno) and small nuclear (sn) RNAs. In this study, we have identified and characterized a collection of sno and snRNAs in Giardia lamblia, by exploiting our discovery of a conserved 12 nt RNA processing sequence motif found in the 3′ end regions of a large number of G. lamblia ncRNA genes. RNA end mapping and other experiments indicate the motif serves to mediate ncRNA 3′ end formation from mono- and di-cistronic RNA precursor transcripts. Remarkably, we find the motif is also utilized in the processing pathway of all four previously identified trans-spliced G. lamblia introns, revealing a common RNA processing pathway for ncRNAs and trans-spliced introns in this organism. Motif sequence conservation then allowed for the bioinformatic and experimental identification of additional G. lamblia ncRNAs, including new U1 and U6 spliceosomal snRNA candidates. The U6 snRNA candidate was then used as a tool to identity novel U2 and U4 snRNAs, based on predicted phylogenetically conserved snRNA–snRNA base-pairing interactions, from a set of previously identified G. lamblia ncRNAs without assigned function. The Giardia snRNAs retain the core features of spliceosomal snRNAs but are sufficiently evolutionarily divergent to explain the difficulties in their identification. Most intriguingly, all of these snRNAs show structural features diagnostic of U2-dependent/major and U12-dependent/minor spliceosomal snRNAs. PMID:23019220

  6. Evolutionarily divergent spliceosomal snRNAs and a conserved non-coding RNA processing motif in Giardia lamblia.

    PubMed

    Hudson, Andrew J; Moore, Ashley N; Elniski, David; Joseph, Joella; Yee, Janet; Russell, Anthony G

    2012-11-01

    Non-coding RNAs (ncRNAs) have diverse essential biological functions in all organisms, and in eukaryotes, two such classes of ncRNAs are the small nucleolar (sno) and small nuclear (sn) RNAs. In this study, we have identified and characterized a collection of sno and snRNAs in Giardia lamblia, by exploiting our discovery of a conserved 12 nt RNA processing sequence motif found in the 3' end regions of a large number of G. lamblia ncRNA genes. RNA end mapping and other experiments indicate the motif serves to mediate ncRNA 3' end formation from mono- and di-cistronic RNA precursor transcripts. Remarkably, we find the motif is also utilized in the processing pathway of all four previously identified trans-spliced G. lamblia introns, revealing a common RNA processing pathway for ncRNAs and trans-spliced introns in this organism. Motif sequence conservation then allowed for the bioinformatic and experimental identification of additional G. lamblia ncRNAs, including new U1 and U6 spliceosomal snRNA candidates. The U6 snRNA candidate was then used as a tool to identity novel U2 and U4 snRNAs, based on predicted phylogenetically conserved snRNA-snRNA base-pairing interactions, from a set of previously identified G. lamblia ncRNAs without assigned function. The Giardia snRNAs retain the core features of spliceosomal snRNAs but are sufficiently evolutionarily divergent to explain the difficulties in their identification. Most intriguingly, all of these snRNAs show structural features diagnostic of U2-dependent/major and U12-dependent/minor spliceosomal snRNAs.

  7. Small Non-Coding RNAs: New Insights in Modulation of Host Immune Response by Intracellular Bacterial Pathogens

    PubMed Central

    Ahmed, Waqas; Zheng, Ke; Liu, Zheng-Fei

    2016-01-01

    Pathogenic bacteria possess intricate regulatory networks that temporally control the production of virulence factors and enable the bacteria to survive and proliferate within host cell. Small non-coding RNAs (sRNAs) have been identified as important regulators of gene expression in diverse biological contexts. Recent research has shown bacterial sRNAs involved in growth and development, cell proliferation, differentiation, metabolism, cell signaling, and immune response through regulating protein–protein interactions or via their ability to base pair with RNA and DNA. In this review, we provide a brief overview of mechanism of action employed by immune-related sRNAs, their known functions in immunity, and how they can be integrated into regulatory circuits that govern virulence, which will facilitate our understanding of pathogenesis and the development of novel, more effective therapeutic approaches to treat infections caused by intracellular bacterial pathogens. PMID:27803700

  8. Genome-wide characterization of long intergenic non-coding RNAs (lincRNAs) provides new insight into viral diseases in honey bees Apis cerana and Apis mellifera.

    PubMed

    Jayakodi, Murukarthick; Jung, Je Won; Park, Doori; Ahn, Young-Joon; Lee, Sang-Choon; Shin, Sang-Yoon; Shin, Chanseok; Yang, Tae-Jin; Kwon, Hyung Wook

    2015-09-04

    Long non-coding RNAs (lncRNAs) are a class of RNAs that do not encode proteins. Recently, lncRNAs have gained special attention for their roles in various biological process and diseases. In an attempt to identify long intergenic non-coding RNAs (lincRNAs) and their possible involvement in honey bee development and diseases, we analyzed RNA-seq datasets generated from Asian honey bee (Apis cerana) and western honey bee (Apis mellifera). We identified 2470 lincRNAs with an average length of 1011 bp from A. cerana and 1514 lincRNAs with an average length of 790 bp in A. mellifera. Comparative analysis revealed that 5 % of the total lincRNAs derived from both species are unique in each species. Our comparative digital gene expression analysis revealed a high degree of tissue-specific expression among the seven major tissues of honey bee, different from mRNA expression patterns. A total of 863 (57 %) and 464 (18 %) lincRNAs showed tissue-dependent expression in A. mellifera and A. cerana, respectively, most preferentially in ovary and fat body tissues. Importantly, we identified 11 lincRNAs that are specifically regulated upon viral infection in honey bees, and 10 of them appear to play roles during infection with various viruses. This study provides the first comprehensive set of lincRNAs for honey bees and opens the door to discover lincRNAs associated with biological and hormone signaling pathways as well as various diseases of honey bee.

  9. Transcriptome analysis reveals long intergenic non-coding RNAs involved in skeletal muscle growth and development in pig.

    PubMed

    Zou, Cheng; Li, Jingxuan; Luo, Wenzhe; Li, Long; Hu, An; Fu, Yuhua; Hou, Ye; Li, Changchun

    2017-08-18

    Long intergenic non-coding RNAs (lincRNAs) play essential roles in numerous biological processes and are widely studied. The skeletal muscle is an important tissue that plays an essential role in individual movement ability. However, lincRNAs in pig skeletal muscles are largely undiscovered and their biological functions remain elusive. In this study, we assembled transcriptomes using RNA-seq data published in previous studies of our laboratory group and identified 323 lincRNAs in porcine leg muscle. We found that these lincRNAs have shorter transcript length, fewer exons and lower expression level than protein-coding genes. Gene ontology and pathway analyses indicated that many potential target genes (PTGs) of lincRNAs were involved in skeletal-muscle-related processes, such as muscle contraction and muscle system process. Combined our previous studies, we found a potential regulatory mechanism in which the promoter methylation of lincRNAs can negatively regulate lincRNA expression and then positively regulate PTG expression, which can finally result in abnormal phenotypes of cloned piglets through a certain unknown pathway. This work detailed a number of lincRNAs and their target genes involved in skeletal muscle growth and development and can facilitate future studies on their roles in skeletal muscle growth and development.

  10. Mining Affymetrix microarray data for long non-coding RNAs: altered expression in the nucleus accumbens of heroin abusers.

    PubMed

    Michelhaugh, Sharon K; Lipovich, Leonard; Blythe, Jason; Jia, Hui; Kapatos, Gregory; Bannon, Michael J

    2011-02-01

    Although recent data suggest that some long non-coding RNAs (lncRNAs) exert widespread effects on gene expression and organelle formation, lncRNAs as a group constitute a sizable but poorly characterized fraction of the human transcriptome. We investigated whether some human lncRNA sequences were fortuitously represented on commonly used microarrays, then used this annotation to assess lncRNA expression in human brain. A computational and annotation pipeline was developed to identify lncRNA transcripts represented on Affymetrix U133 arrays. A previously published dataset derived from human nucleus accumbens was then examined for potential lncRNA expression. Twenty-three lncRNAs were determined to be represented on U133 arrays. Of these, dataset analysis revealed that five lncRNAs were consistently detected in samples of human nucleus accumbens. Strikingly, the abundance of these lncRNAs was up-regulated in human heroin abusers compared to matched drug-free control subjects, a finding confirmed by quantitative PCR. This study presents a paradigm for examining existing Affymetrix datasets for the detection and potential regulation of lncRNA expression, including changes associated with human disease. The finding that all detected lncRNAs were up-regulated in heroin abusers is consonant with the proposed role of lncRNAs as mediators of widespread changes in gene expression as occur in drug abuse.

  11. Non-coding RNAs' partitioning in the evolution of photosynthetic organisms via energy transduction and redox signaling.

    PubMed

    Kotakis, Christos

    2015-01-01

    Ars longa, vita brevis -Hippocrates Chloroplasts and mitochondria are genetically semi-autonomous organelles inside the plant cell. These constructions formed after endosymbiosis and keep evolving throughout the history of life. Experimental evidence is provided for active non-coding RNAs (ncRNAs) in these prokaryote-like structures, and a possible functional imprinting on cellular electrophysiology by those RNA entities is described. Furthermore, updated knowledge on RNA metabolism of organellar genomes uncovers novel inter-communication bridges with the nucleus. This class of RNA molecules is considered as a unique ontogeny which transforms their biological role as a genetic rheostat into a synchronous biochemical one that can affect the energetic charge and redox homeostasis inside cells. A hypothesis is proposed where such modulation by non-coding RNAs is integrated with genetic signals regulating gene transfer. The implications of this working hypothesis are discussed, with particular reference to ncRNAs involvement in the organellar and nuclear genomes evolution since their integrity is functionally coupled with redox signals in photosynthetic organisms.

  12. New Cross-Talk Layer between Ultraconserved Non-Coding RNAs, MicroRNAs and Polycomb Protein YY1 in Bladder Cancer

    PubMed Central

    Terreri, Sara; Durso, Montano; Colonna, Vincenza; Romanelli, Alessandra; Terracciano, Daniela; Ferro, Matteo; Perdonà, Sisto; Castaldo, Luigi; Febbraio, Ferdinando; de Nigris, Filomena; Cimmino, Amelia

    2016-01-01

    MicroRNAs (miRNAs) are highly conserved elements in mammals, and exert key regulatory functions. Growing evidence shows that miRNAs can interact with another class of non-coding RNAs, so-called transcribed ultraconserved regions (T-UCRs), which take part in transcriptional, post-transcriptional and epigenetic regulation processes. We report here the interaction of miRNAs and T-UCRs as a network modulating the availability of these non-coding RNAs in bladder cancer cells. In our cell system, antagomiR-596 increased the expression of T-UCR 201+. Moreover, T-UCR 8+ silencing increased miR-596 expression, which in turn reduced total T-UCR 283+, showing that the perturbation of one element in this network changes the expression of other interactors. In addition, we identify the polycomb protein Yin Yang 1 (YY1) as mediator of binding between miR-596 and T-UCR 8+. These new findings describe for the first time a network between T-UCRs, miRNAs and YY1 protein, highlighting the existence of an additional layer of gene expression regulation. PMID:27983635

  13. Long Non-coding RNAs and Their Biological Roles in Plants

    PubMed Central

    Liu, Xue; Hao, Lili; Li, Dayong; Zhu, Lihuang; Hu, Songnian

    2015-01-01

    With the development of genomics and bioinformatics, especially the extensive applications of high-throughput sequencing technology, more transcriptional units with little or no protein-coding potential have been discovered. Such RNA molecules are called non-protein-coding RNAs (npcRNAs or ncRNAs). Among them, long npcRNAs or ncRNAs (lnpcRNAs or lncRNAs) represent diverse classes of transcripts longer than 200 nucleotides. In recent years, the lncRNAs have been considered as important regulators in many essential biological processes. In plants, although a large number of lncRNA transcripts have been predicted and identified in few species, our current knowledge of their biological functions is still limited. Here, we have summarized recent studies on their identification, characteristics, classification, bioinformatics, resources, and current exploration of their biological functions in plants. PMID:25936895

  14. Systematic Identification and Characterization of Long Non-Coding RNAs in the Silkworm, Bombyx mori

    PubMed Central

    Wu, Yuqian; Cheng, Tingcai; Liu, Chun; Liu, Duolian; Zhang, Quan; Long, Renwen; Zhao, Ping; Xia, Qingyou

    2016-01-01

    Long noncoding RNAs (lncRNAs) are emerging as important regulators in various biological processes. However, to date, no systematic characterization of lncRNAs has been reported in the silkworm Bombyx mori. In the present study, we generated eighteen RNA-seq datasets with relatively high depth. Using an in-house designed lncRNA identification pipeline, 11,810 lncRNAs were identified for 5,556 loci. Among these lncRNAs, 474 transcripts were intronic lncRNAs (ilncRNAs), 6,250 transcripts were intergenic lncRNAs (lincRNAs), and 5,086 were natural antisense lncRNAs (lncNATs). Compared with protein-coding mRNAs, silkworm lncRNAs are shorter in terms of full length but longer in terms of exon and intron length. In addition, lncRNAs exhibit a lower level of sequence conservation, more repeat sequences overlapped and higher tissue specificity than protein-coding mRNAs in the silkworm. We found that 69 lncRNA transcripts from 33 gene loci may function as miRNA precursors, and 104 lncRNA transcripts from 72 gene loci may act as competing endogenous RNAs (ceRNAs). In total, 49.47% of all gene loci (2,749/5,556) for which lncRNAs were identified showed sex-biased expression. Co-expression network analysis resulted in 19 modules, 12 of which revealed relatively high tissue specificity. The highlighted darkgoldenrod module was specifically associated with middle and posterior silk glands, and the hub lncRNAs within this module were co-expressed with proteins involved in translation, translocation, and secretory processes, suggesting that these hub lncRNAs may function as regulators of the biosynthesis, translocation, and secretion of silk proteins. This study presents the first comprehensive genome-wide analysis of silkworm lncRNAs and provides an invaluable resource for genetic, evolutionary, and genomic studies of B. mori. PMID:26771876

  15. Systematic Identification and Characterization of Long Non-Coding RNAs in the Silkworm, Bombyx mori.

    PubMed

    Wu, Yuqian; Cheng, Tingcai; Liu, Chun; Liu, Duolian; Zhang, Quan; Long, Renwen; Zhao, Ping; Xia, Qingyou

    2016-01-01

    Long noncoding RNAs (lncRNAs) are emerging as important regulators in various biological processes. However, to date, no systematic characterization of lncRNAs has been reported in the silkworm Bombyx mori. In the present study, we generated eighteen RNA-seq datasets with relatively high depth. Using an in-house designed lncRNA identification pipeline, 11,810 lncRNAs were identified for 5,556 loci. Among these lncRNAs, 474 transcripts were intronic lncRNAs (ilncRNAs), 6,250 transcripts were intergenic lncRNAs (lincRNAs), and 5,086 were natural antisense lncRNAs (lncNATs). Compared with protein-coding mRNAs, silkworm lncRNAs are shorter in terms of full length but longer in terms of exon and intron length. In addition, lncRNAs exhibit a lower level of sequence conservation, more repeat sequences overlapped and higher tissue specificity than protein-coding mRNAs in the silkworm. We found that 69 lncRNA transcripts from 33 gene loci may function as miRNA precursors, and 104 lncRNA transcripts from 72 gene loci may act as competing endogenous RNAs (ceRNAs). In total, 49.47% of all gene loci (2,749/5,556) for which lncRNAs were identified showed sex-biased expression. Co-expression network analysis resulted in 19 modules, 12 of which revealed relatively high tissue specificity. The highlighted darkgoldenrod module was specifically associated with middle and posterior silk glands, and the hub lncRNAs within this module were co-expressed with proteins involved in translation, translocation, and secretory processes, suggesting that these hub lncRNAs may function as regulators of the biosynthesis, translocation, and secretion of silk proteins. This study presents the first comprehensive genome-wide analysis of silkworm lncRNAs and provides an invaluable resource for genetic, evolutionary, and genomic studies of B. mori.

  16. An overview of long non-coding RNAs in ovarian cancers

    PubMed Central

    Meryet-Figuière, Matthieu; Lambert, Bernard; Gauduchon, Pascal; Vigneron, Nicolas; Brotin, Emilie; Poulain, Laurent; Denoyelle, Christophe

    2016-01-01

    As with miRNAs a decade ago, the scientific community recently understood that lncRNAs represent a new layer of complexity in the regulation of gene expression. Although only a subset of lncRNAs has been functionally characterized, it is clear that they are deeply involved in the most critical physiological and pathological biological processes. This review shows that in ovarian carcinoma, data already available testify to the importance of lncRNAs and that the demonstration of an ever-growing role of lncRNAs in the biology of this malignancy can be expected from future studies. We also underline the importance of their relationship with associated protein partners and miRNAs. Together, the available information suggests that the emerging field of lncRNAs will pave the way for a better understanding of ovarian cancer biology and might lead to the development of innovative therapeutic approaches. Moreover, lncRNAs expression signatures either alone or in combination with other types of markers (miRNAs, mRNAs, proteins) could prove useful to predict outcome or treatment follow-up in order to improve the therapeutic care of ovarian carcinoma patients. PMID:26992233

  17. The PRC2-binding long non-coding RNAs in human and mouse genomes are associated with predictive sequence features

    NASA Astrophysics Data System (ADS)

    Tu, Shiqi; Yuan, Guo-Cheng; Shao, Zhen

    2017-01-01

    Recently, long non-coding RNAs (lncRNAs) have emerged as an important class of molecules involved in many cellular processes. One of their primary functions is to shape epigenetic landscape through interactions with chromatin modifying proteins. However, mechanisms contributing to the specificity of such interactions remain poorly understood. Here we took the human and mouse lncRNAs that were experimentally determined to have physical interactions with Polycomb repressive complex 2 (PRC2), and systematically investigated the sequence features of these lncRNAs by developing a new computational pipeline for sequences composition analysis, in which each sequence is considered as a series of transitions between adjacent nucleotides. Through that, PRC2-binding lncRNAs were found to be associated with a set of distinctive and evolutionarily conserved sequence features, which can be utilized to distinguish them from the others with considerable accuracy. We further identified fragments of PRC2-binding lncRNAs that are enriched with these sequence features, and found they show strong PRC2-binding signals and are more highly conserved across species than the other parts, implying their functional importance.

  18. In the shadow: The emerging role of long non-coding RNAs in the immune response of Atlantic salmon.

    PubMed

    Tarifeño-Saldivia, E; Valenzuela-Miranda, D; Gallardo-Escárate, C

    2017-03-31

    The genomic era has increased the research effort to uncover how the genome of an organism, and specifically the transcriptome, is modulated after interplaying with pathogenic microorganisms and ectoparasites. However, the ever-increasing accessibility of sequencing technology has also evidenced regulatory roles of long non-coding RNAs (lncRNAs) related to several biological processes including immune response. This study reports a high-confidence annotation and a comparative transcriptome analysis of lncRNAs from several tissues of Salmo salar infected with the most prevalent pathogens in the Chilean salmon aquaculture such as the infectious salmon anemia (ISA) virus, the intracellular bacterium Piscirickettsia salmonis and the ectoparasite copepod Caligus rogercresseyi. Our analyses showed that lncRNAs are widely modulated during infection. However, this modulation is pathogen-specific and highly correlated with immuno-related genes associated with innate immune response. These findings represent the first discovery for the widespread differential expression of lncRNAs in response to infections with different types of pathogens in Atlantic salmon, suggesting that lncRNAs are pivotal player during the fish immune response.

  19. The PRC2-binding long non-coding RNAs in human and mouse genomes are associated with predictive sequence features

    PubMed Central

    Tu, Shiqi; Yuan, Guo-Cheng; Shao, Zhen

    2017-01-01

    Recently, long non-coding RNAs (lncRNAs) have emerged as an important class of molecules involved in many cellular processes. One of their primary functions is to shape epigenetic landscape through interactions with chromatin modifying proteins. However, mechanisms contributing to the specificity of such interactions remain poorly understood. Here we took the human and mouse lncRNAs that were experimentally determined to have physical interactions with Polycomb repressive complex 2 (PRC2), and systematically investigated the sequence features of these lncRNAs by developing a new computational pipeline for sequences composition analysis, in which each sequence is considered as a series of transitions between adjacent nucleotides. Through that, PRC2-binding lncRNAs were found to be associated with a set of distinctive and evolutionarily conserved sequence features, which can be utilized to distinguish them from the others with considerable accuracy. We further identified fragments of PRC2-binding lncRNAs that are enriched with these sequence features, and found they show strong PRC2-binding signals and are more highly conserved across species than the other parts, implying their functional importance. PMID:28139710

  20. Long non-coding RNAs may serve as biomarkers in breast cancer combined with primary lung cancer

    PubMed Central

    Mao, Weimin; Chen, Bo; Yang, Shifeng; Ding, Xiaowen; Zou, Dehong; Mo, Wenju; He, Xiangming; Zhang, Xiping

    2017-01-01

    Long non-coding RNAs (lncRNAs) have been shown to play important regulatory role in certain type of cancers biology, including breast and lung cancers. However, the lncRNA expression in breast cancer combined with primary lung cancer remains unknown. In this study, databases of the Cancer Genome Atlas (TCGA) and the lncRNA profiler of contained candidate 192 lncRNAs were utilized. 11 lncRNAs were differentially expressed in breast cancer, 9 candidate lncRNAs were differentially expressed in lung cancer. In order to find the aberrant expression of lncRNAs in breast cancer combined with primary lung cancer, seven samples of primary breast cancer and lung cancer were studied for the expression of selected lncRNAs. The results showed that SNHG6 and NEAT1 were reversely expressed in breast cancer combined with primary lung cancer compared with primary breast or lung cancer. In addition, a significant correlation of lncRNAs was found in the patients whose age was above 56 in breast cancer. What's more, PVT1 expression was negatively correlated with the pathological stage, and the level of ER, PR, HER2, p53 in breast cancer. Furthermore, lncRNA expression did not have significant relationship with the 5-year survival of patients with breast cancer combined with primary lung cancer. The findings revealed that PVT1, SNHG6, NEAT1 may serve as a prognostic marker for breast cancer combined with primary lung cancer. Therefore, these lncRNAs are potential molecular indicators in the diagnosis and prognosis of cancer in the future. PMID:28938549

  1. Primate-specific oestrogen-responsive long non-coding RNAs regulate proliferation and viability of human breast cancer cells

    PubMed Central

    Lin, Chin-Yo; Dachet, Fabien; Cai, Juan; Ju, Donghong; Goldstone, Amanda; Wood, Emily J.; Liu, Ka; Jia, Hui; Kosir, Mary A.; Thepsuwan, Pattaraporn

    2016-01-01

    Long non-coding RNAs (lncRNAs) are transcripts of a recently discovered class of genes which do not code for proteins. LncRNA genes are approximately as numerous as protein-coding genes in the human genome. However, comparatively little remains known about lncRNA functions. We globally interrogated changes in the lncRNA transcriptome of oestrogen receptor positive human breast cancer cells following treatment with oestrogen, and identified 127 oestrogen-responsive lncRNAs. Consistent with the emerging evidence that most human lncRNA genes lack homologues outside of primates, our evolutionary analysis revealed primate-specific lncRNAs downstream of oestrogen signalling. We demonstrate, using multiple functional assays to probe gain- and loss-of-function phenotypes in two oestrogen receptor positive human breast cancer cell lines, that two primate-specific oestrogen-responsive lncRNAs identified in this study (the oestrogen-repressed lncRNA BC041455, which reduces cell viability, and the oestrogen-induced lncRNA CR593775, which increases cell viability) exert previously unrecognized functions in cell proliferation and growth factor signalling pathways. The results suggest that oestrogen-responsive lncRNAs are capable of altering the proliferation and viability of human breast cancer cells. No effects on cellular phenotypes were associated with control transfections. As heretofore unappreciated components of key signalling pathways in cancers, including the MAP kinase pathway, lncRNAs hence represent a novel mechanism of action for oestrogen effects on cellular proliferation and viability phenotypes. This finding warrants further investigation in basic and translational studies of breast and potentially other types of cancers, has broad relevance to lncRNAs in other nuclear hormone receptor pathways, and should facilitate exploiting and targeting these cell viability modulating lncRNAs in post-genomic therapeutics. PMID:28003470

  2. Role of non-coding RNAs in maintaining primary airway smooth muscle cells

    PubMed Central

    2014-01-01

    Background The airway smooth muscle (ASM) cell maintains its own proliferative rate and contributes to the inflammatory response in the airways, effects that are inhibited by corticosteroids, used in the treatment of airways diseases. Objective We determined the differential expression of mRNAs, microRNAs (miRNAs) and long noncoding RNA species (lncRNAs) in primary ASM cells following treatment with a corticosteroid, dexamethasone, and fetal calf serum (FCS). Methods mRNA, miRNA and lncRNA expression was measured by microarray and quantitative real-time PCR. Results A small number of miRNAs (including miR-150, −371-5p, −718, −940, −1181, −1207-5p, −1915, and −3663-3p) were decreased following exposure to dexamethasone and FCS. The mRNA targets of these miRNAs were increased in expression. The changes in mRNA expression were associated with regulation of ASM actin cytoskeleton. We also observed changes in expression of lncRNAs, including natural antisense, pseudogenes, intronic lncRNAs, and intergenic lncRNAs following dexamethasone and FCS. We confirmed the change in expression of three of these, LINC00882, LINC00883, PVT1, and its transcriptional activator, c-MYC. We propose that four of these lincRNAs (RP11-46A10.4, LINC00883, BCYRN1, and LINC00882) act as miRNA ‘sponges’ for 4 miRNAs (miR-150, −371-5p, −940, −1207-5p). Conclusion This in-vitro model of primary ASM cell phenotype was associated with the regulation of several ncRNAs. Their identification allows for in-vitro functional experimentation to establish causality with the primary ASM phenotype, and in airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). PMID:24886442

  3. LincSNP: a database of linking disease-associated SNPs to human large intergenic non-coding RNAs.

    PubMed

    Ning, Shangwei; Zhao, Zuxianglan; Ye, Jingrun; Wang, Peng; Zhi, Hui; Li, Ronghong; Wang, Tingting; Li, Xia

    2014-05-20

    Genome-wide association studies (GWAS) have successfully identified a large number of single nucleotide polymorphisms (SNPs) that are associated with a wide range of human diseases. However, many of these disease-associated SNPs are located in non-coding regions and have remained largely unexplained. Recent findings indicate that disease-associated SNPs in human large intergenic non-coding RNA (lincRNA) may lead to susceptibility to diseases through their effects on lincRNA expression. There is, therefore, a need to specifically record these SNPs and annotate them as potential candidates for disease. We have built LincSNP, an integrated database, to identify and annotate disease-associated SNPs in human lincRNAs. The current release of LincSNP contains approximately 140,000 disease-associated SNPs (or linkage disequilibrium SNPs), which can be mapped to around 5,000 human lincRNAs, together with their comprehensive functional annotations. The database also contains annotated, experimentally supported SNP-lincRNA-disease associations and disease-associated lincRNAs. It provides flexible search options for data extraction and searches can be performed by disease/phenotype name, SNP ID, lincRNA name and chromosome region. In addition, we provide users with a link to download all the data from LincSNP and have developed a web interface for the submission of novel identified SNP-lincRNA-disease associations. The LincSNP database aims to integrate disease-associated SNPs and human lincRNAs, which will be an important resource for the investigation of the functions and mechanisms of lincRNAs in human disease. The database is available at http://bioinfo.hrbmu.edu.cn/LincSNP.

  4. RNA sequencing of transcriptomes in human brain regions: protein-coding and non-coding RNAs, isoforms and alleles.

    PubMed

    Webb, Amy; Papp, Audrey C; Curtis, Amanda; Newman, Leslie C; Pietrzak, Maciej; Seweryn, Michal; Handelman, Samuel K; Rempala, Grzegorz A; Wang, Daqing; Graziosa, Erica; Tyndale, Rachel F; Lerman, Caryn; Kelsoe, John R; Mash, Deborah C; Sadee, Wolfgang

    2015-11-23

    We used RNA sequencing to analyze transcript profiles of ten autopsy brain regions from ten subjects. RNA sequencing techniques were designed to detect both coding and non-coding RNA, splice isoform composition, and allelic expression. Brain regions were selected from five subjects with a documented history of smoking and five non-smokers. Paired-end RNA sequencing was performed on SOLiD instruments to a depth of >40 million reads, using linearly amplified, ribosomally depleted RNA. Sequencing libraries were prepared with both poly-dT and random hexamer primers to detect all RNA classes, including long non-coding (lncRNA), intronic and intergenic transcripts, and transcripts lacking poly-A tails, providing additional data not previously available. The study was designed to generate a database of the complete transcriptomes in brain region for gene network analyses and discovery of regulatory variants. Of 20,318 protein coding and 18,080 lncRNA genes annotated from GENCODE and lncipedia, 12 thousand protein coding and 2 thousand lncRNA transcripts were detectable at a conservative threshold. Of the aligned reads, 52 % were exonic, 34 % intronic and 14 % intergenic. A majority of protein coding genes (65 %) was expressed in all regions, whereas ncRNAs displayed a more restricted distribution. Profiles of RNA isoforms varied across brain regions and subjects at multiple gene loci, with neurexin 3 (NRXN3) a prominent example. Allelic RNA ratios deviating from unity were identified in > 400 genes, detectable in both protein-coding and non-coding genes, indicating the presence of cis-acting regulatory variants. Mathematical modeling was used to identify RNAs stably expressed in all brain regions (serving as potential markers for normalizing expression levels), linked to basic cellular functions. An initial analysis of differential expression analysis between smokers and nonsmokers implicated a number of genes, several previously associated with nicotine exposure. RNA

  5. Non-Coding RNAs: Functional Aspects and Diagnostic Utility in Oncology

    PubMed Central

    Kim, Taiho; Reitmair, Armin

    2013-01-01

    Noncoding RNAs (ncRNAs) have been found to have roles in a large variety of biological processes. Recent studies indicate that ncRNAs are far more abundant and important than initially imagined, holding great promise for use in diagnostic, prognostic, and therapeutic applications. Within ncRNAs, microRNAs (miRNAs) are the most widely studied and characterized. They have been implicated in initiation and progression of a variety of human malignancies, including major pathologies such as cancers, arthritis, neurodegenerative disorders, and cardiovascular diseases. Their surprising stability in serum and other bodily fluids led to their rapid ascent as a novel class of biomarkers. For example, several properties of stable miRNAs, and perhaps other classes of ncRNAs, make them good candidate biomarkers for early cancer detection and for determining which preneoplastic lesions are likely to progress to cancer. Of particular interest is the identification of biomarker signatures, which may include traditional protein-based biomarkers, to improve risk assessment, detection, and prognosis. Here, we offer a comprehensive review of the ncRNA biomarker literature and discuss state-of-the-art technologies for their detection. Furthermore, we address the challenges present in miRNA detection and quantification, and outline future perspectives for development of next-generation biodetection assays employing multicolor alternating-laser excitation (ALEX) fluorescence spectroscopy. PMID:23455466

  6. Genome Wide Identification and Functional Prediction of Long Non-Coding RNAs Responsive to Sclerotinia sclerotiorum Infection in Brassica napus

    PubMed Central

    Joshi, Raj Kumar; Megha, Swati; Basu, Urmila; Rahman, Muhammad H.; Kav, Nat N. V.

    2016-01-01

    Sclerotinia stem rot caused by Sclerotinia sclerotiorum affects canola production worldwide. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the regulation of gene expression in plants, in response to both abiotic and biotic stress. So far, identification of lncRNAs has been limited to a few model plant species, and their roles in mediating responses to biotic stresses are yet to be characterized in Brassica napus. The present study reports the identification of novel lncRNAs responsive to S. sclerotiorum infection in B. napus at two time points after infection (24 hpi and 48 hpi) using a stranded RNA-Sequencing technique and a detection pipeline for lncRNAs. Of the total 3,181 lncRNA candidates, 2,821 lncRNAs were intergenic, 111 were natural antisense transcripts, 76 possessed exonic overlap with the reference coding transcripts while the remaining 173 represented novel lnc- isoforms. Forty one lncRNAs were identified as the precursors for microRNAs (miRNAs) including miR156, miR169 and miR394, with significant roles in mediating plant responses to fungal phytopathogens. A total of 931 differentially expressed lncRNAs were identified in response to S. sclerotiorum infection and the expression of 12 such lncRNAs was further validated using qRT-PCR. B. napus antisense lncRNA, TCONS_00000966, having 90% overlap with a plant defensin gene, showed significant induction at both infection stages, suggesting its involvement in the transcriptional regulation of defense responsive genes under S. sclerotiorum infection. Additionally, nine lncRNAs showed overlap with cis-regulatory regions of differentially expressed genes of B. napus. Quantitative RT-PCR verification of a set of S. sclerotiorum responsive sense/antisense transcript pairs revealed contrasting expression patterns, supporting the hypothesis that steric clashes of transcriptional machinery may lead to inactivation of sense promoter. Our findings highlight the potential

  7. Germ cell-specific sustained activation of Wnt signalling perturbs spermatogenesis in aged mice, possibly through non-coding RNAs

    PubMed Central

    Kumar, Manish; Atkins, Joshua; Cairns, Murray; Ali, Ayesha; Tanwar, Pradeep S.

    2016-01-01

    Dysregulated Wnt signalling is associated with human infertility and testicular cancer. However, the role of Wnt signalling in male germ cells remains poorly understood. In this study, we first confirmed the activity of Wnt signalling in mouse, dog and human testes. To determine the physiological importance of the Wnt pathway, we developed a mouse model with germ cell-specific constitutive activation of βcatenin. In young mutants, similar to controls, germ cell development was normal. However, with age, mutant testes showed defective spermatogenesis, progressive germ cell loss, and flawed meiotic entry of spermatogonial cells. Flow sorting confirmed reduced germ cell populations at the leptotene/zygotene stages of meiosis in mutant group. Using thymidine analogues-based DNA double labelling technique, we further established decline in germ cell proliferation and differentiation. Overactivation of Wnt/βcatenin signalling in a spermatogonial cell line resulted in reduced cell proliferation, viability and colony formation. RNA sequencing analysis of testes revealed significant alterations in the non-coding regions of mutant mouse genome. One of the novel non-coding RNAs was switched on in mutant testes compared to controls. QPCR analysis confirmed upregulation of this unique non-coding RNA in mutant testis. In summary, our results highlight the significance of Wnt signalling in male germ cells. PMID:27992363

  8. BI-03GLIOBLASTOMA-SPECIFIC AND GLIOBLASTOMA STEM CELL SUBTYPE-SPECIFIC SIGNATURES OF LONG, NON-CODING RNAs

    PubMed Central

    Bronisz, Agnieszka; Mineo, Marco; Ansari, Khairul; Rooj, Arun; Nakano, Ichiro; Antonio Chiocca, E.; Godlewski, Jakub

    2014-01-01

    Long-non coding RNAs (lncRNAs) are large and heterogeneous group of non-protein coding RNAs larger than 200nt. They regulate the expression of their target genes by multiple mechanisms including regulation of transcription, splicing, translation and epigenetic regulation. There is growing evidence of important role of lncRNAs in carcinogenesis, including glioblastoma multiforme (GBM). To profile lncRNAs in GBM patient samples and cells, we designed a platform using NanoString system to detect 73 lncRNAs that has been implicated in cancer pathophysiology. We used our collection of matched samples (i.e. from the same patient) of GBM tumors and adjacent brain tissue. We showed that 27-lncRNA signature (10 GBM-low and 17 GBM-high) clustered these samples. Glioblastoma stem cells (GSCs) are highly tumorigenic and therapy-resistant sub-population of glioblastoma. We characterized our large collection of patient-derived GSCs maintained in serum-free culture. Based on 10-gene signature we ascribed them to either proneural (PN), mesenchymal (MES) subtype. We demonstrated that 28-lncRNA signature (7 PN-low and 21 PN-high) clustered PN and MES GSCs. Testing the functionality of lncRNAs, we showed that PN-MES subtype switch achieved by de-regulation of important regulator of GSC self-renewal - miR-128, was concurrent with the shift in lncRNA signature. Finally, based on 29-lncRNA signature, we were able to establish that, irradiated PN GSCs acquired more mesenchymal characteristics. Our results thus suggest broad involvement of lncRNAs in the regulation of pathophysiological processes in GBM/GSC cells.

  9. Long non-coding RNAs as novel expression signatures modulate DNA damage and repair in cadmium toxicology

    PubMed Central

    Zhou, Zhiheng; Liu, Haibai; Wang, Caixia; Lu, Qian; Huang, Qinhai; Zheng, Chanjiao; Lei, Yixiong

    2015-01-01

    Increasing evidence suggests that long non-coding RNAs (lncRNAs) are involved in a variety of physiological and pathophysiological processes. Our study was to investigate whether lncRNAs as novel expression signatures are able to modulate DNA damage and repair in cadmium(Cd) toxicity. There were aberrant expression profiles of lncRNAs in 35th Cd-induced cells as compared to untreated 16HBE cells. siRNA-mediated knockdown of ENST00000414355 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA-damage related genes (ATM, ATR and ATRIP), while increased the expressions of DNA-repair related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, RAD50, XRCC1 and BARD1). Cadmium increased ENST00000414355 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000414355 expression and urinary/blood Cd concentrations, and there were significant correlations of lncRNA-ENST00000414355 expression with the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd exposed workers. These results indicate that some lncRNAs are aberrantly expressed in Cd-treated 16HBE cells. lncRNA-ENST00000414355 may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity. PMID:26472689

  10. SINEUPs: A new class of natural and synthetic antisense long non-coding RNAs that activate translation

    PubMed Central

    Zucchelli, S; Cotella, D; Takahashi, H; Carrieri, C; Cimatti, L; Fasolo, F; Jones, MH; Sblattero, D; Sanges, R; Santoro, C; Persichetti, F; Carninci, P; Gustincich, S

    2015-01-01

    Over the past 10 years, it has emerged that pervasive transcription in mammalian genomes has a tremendous impact on several biological functions. Most of transcribed RNAs are lncRNAs and repetitive elements. In this review, we will detail the discovery of a new functional class of natural and synthetic antisense lncRNAs that stimulate translation of sense mRNAs. These molecules have been named SINEUPs since their function requires the activity of an embedded inverted SINEB2 sequence to UP-regulate translation. Natural SINEUPs suggest that embedded Transposable Elements may represent functional domains in long non-coding RNAs. Synthetic SINEUPs may be designed by targeting the antisense sequence to the mRNA of choice representing the first scalable tool to increase protein synthesis of potentially any gene of interest. We will discuss potential applications of SINEUP technology in the field of molecular biology experiments, in protein manufacturing as well as in therapy of haploinsufficiencies. PMID:26259533

  11. Non-coding RNAs derived from an alternatively spliced REST transcript (REST-003) regulate breast cancer invasiveness

    PubMed Central

    Sook Lee, Nan; Evgrafov, Oleg V.; Souaiaia, Tade; Bonyad, Adrineh; Herstein, Jennifer; Yeun Lee, Joo; Kim, Jihong; Ning, Yan; Sixto, Marcos; Weitz, Andrew C.; Lenz, Heinz-Josef; Wang, Kai; Knowles, James A.; Press, Michael F.; Salvaterra, Paul M.; Kirk Shung, K.; Chow, Robert H.

    2015-01-01

    RE1-Silencing Transcription factor (REST) has a well-established role in regulating transcription of genes important for neuronal development. Its role in cancer, though significant, is less well understood. We show that REST downregulation in weakly invasive MCF-7 breast cancer cells converts them to a more invasive phenotype, while REST overexpression in highly invasive MDA-MB-231 cells suppresses invasiveness. Surprisingly, the mechanism responsible for these phenotypic changes does not depend directly on the transcriptional function of REST protein. Instead, it is driven by previously unstudied mid-size (30–200 nt) non-coding RNAs (ncRNAs) derived from the first exon of an alternatively spliced REST transcript: REST-003. We show that processing of REST-003 into ncRNAs is controlled by an uncharacterized serine/arginine repeat-related protein, SRRM3. SRRM3 expression may be under REST-mediated transcriptional control, as it increases following REST downregulation. The SRRM3-dependent regulation of REST-003 processing into ncRNAs has many similarities to recently described promoter-associated small RNA-like processes. Targeting ncRNAs that control invasiveness could lead to new therapeutic approaches to limit breast cancer metastasis. PMID:26053433

  12. Non-coding RNAs derived from an alternatively spliced REST transcript (REST-003) regulate breast cancer invasiveness.

    PubMed

    Lee, Nan Sook; Evgrafov, Oleg V; Souaiaia, Tade; Bonyad, Adrineh; Herstein, Jennifer; Lee, Joo Yeun; Kim, Jihong; Ning, Yan; Sixto, Marcos; Weitz, Andrew C; Lenz, Heinz-Josef; Wang, Kai; Knowles, James A; Press, Michael F; Salvaterra, Paul M; Shung, K Kirk; Chow, Robert H

    2015-06-08

    RE1-Silencing Transcription factor (REST) has a well-established role in regulating transcription of genes important for neuronal development. Its role in cancer, though significant, is less well understood. We show that REST downregulation in weakly invasive MCF-7 breast cancer cells converts them to a more invasive phenotype, while REST overexpression in highly invasive MDA-MB-231 cells suppresses invasiveness. Surprisingly, the mechanism responsible for these phenotypic changes does not depend directly on the transcriptional function of REST protein. Instead, it is driven by previously unstudied mid-size (30-200 nt) non-coding RNAs (ncRNAs) derived from the first exon of an alternatively spliced REST transcript: REST-003. We show that processing of REST-003 into ncRNAs is controlled by an uncharacterized serine/arginine repeat-related protein, SRRM3. SRRM3 expression may be under REST-mediated transcriptional control, as it increases following REST downregulation. The SRRM3-dependent regulation of REST-003 processing into ncRNAs has many similarities to recently described promoter-associated small RNA-like processes. Targeting ncRNAs that control invasiveness could lead to new therapeutic approaches to limit breast cancer metastasis.

  13. Long non-coding RNAs as novel expression signatures modulate DNA damage and repair in cadmium toxicology

    NASA Astrophysics Data System (ADS)

    Zhou, Zhiheng; Liu, Haibai; Wang, Caixia; Lu, Qian; Huang, Qinhai; Zheng, Chanjiao; Lei, Yixiong

    2015-10-01

    Increasing evidence suggests that long non-coding RNAs (lncRNAs) are involved in a variety of physiological and pathophysiological processes. Our study was to investigate whether lncRNAs as novel expression signatures are able to modulate DNA damage and repair in cadmium(Cd) toxicity. There were aberrant expression profiles of lncRNAs in 35th Cd-induced cells as compared to untreated 16HBE cells. siRNA-mediated knockdown of ENST00000414355 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA-damage related genes (ATM, ATR and ATRIP), while increased the expressions of DNA-repair related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, RAD50, XRCC1 and BARD1). Cadmium increased ENST00000414355 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000414355 expression and urinary/blood Cd concentrations, and there were significant correlations of lncRNA-ENST00000414355 expression with the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd exposed workers. These results indicate that some lncRNAs are aberrantly expressed in Cd-treated 16HBE cells. lncRNA-ENST00000414355 may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity.

  14. lncRScan-SVM: A Tool for Predicting Long Non-Coding RNAs Using Support Vector Machine.

    PubMed

    Sun, Lei; Liu, Hui; Zhang, Lin; Meng, Jia

    2015-01-01

    Functional long non-coding RNAs (lncRNAs) have been bringing novel insight into biological study, however it is still not trivial to accurately distinguish the lncRNA transcripts (LNCTs) from the protein coding ones (PCTs). As various information and data about lncRNAs are preserved by previous studies, it is appealing to develop novel methods to identify the lncRNAs more accurately. Our method lncRScan-SVM aims at classifying PCTs and LNCTs using support vector machine (SVM). The gold-standard datasets for lncRScan-SVM model training, lncRNA prediction and method comparison were constructed according to the GENCODE gene annotations of human and mouse respectively. By integrating features derived from gene structure, transcript sequence, potential codon sequence and conservation, lncRScan-SVM outperforms other approaches, which is evaluated by several criteria such as sensitivity, specificity, accuracy, Matthews correlation coefficient (MCC) and area under curve (AUC). In addition, several known human lncRNA datasets were assessed using lncRScan-SVM. LncRScan-SVM is an efficient tool for predicting the lncRNAs, and it is quite useful for current lncRNA study.

  15. Long non-coding RNAs and human X-chromosome regulation: a coat for the active X chromosome.

    PubMed

    Vallot, Céline; Rougeulle, Claire

    2013-08-01

    In mammals, the genic disequilibrium between males (XY) and females (XX) is resolved through the inactivation of one of the X-chromosomes in females. X-chromosome inactivation (XCI) takes place in all mammalian species, but has mainly been studied in the mouse model where it was shown to be controlled by the interplay of several long non-coding RNA (lncRNA). However, recent data point toward the existence of species divergences among mammals in the strategies used to achieve XCI. The recent discovery of XACT, a novel lncRNA that coats the active X-chromosome specifically in human pluripotent cells, further highlights the existence of human-specific mechanisms of X-chromosome regulation. Here, we discuss the roles of lncRNAs in defining species-specific mechanisms controlling X-inactivation and explore the potential role of large lncRNAs in gene activation.

  16. Beyond Thymidylate Synthase and Dihydrofolate Reductase: Impact of Non-coding microRNAs in Anticancer Chemoresistance.

    PubMed

    Ju, Jingfang

    2012-09-01

    Chemoresistance is one of the major reasons for the failure of anticancer chemotherapy in treating advanced stage cancer. The mechanism of chemoresistance to fluoropyrimidines and antifolates has been extensively investigated in the past 40 years. It has been well established that thymidylate synthase (TYMS, TS) and dihydrofolate reductase (DHFR) are two major targets for fluoropyrimidines and antifolates, respectively. The regulatory mechanism of TS and DHFR expression is rather complex involving transcriptional, post-transcriptional and translational regulations. Our recent understanding of the chemoresistance mechanism has been extended beyond the simple one target/drug view. In this review, we will focus on the recent advancement of non-coding microRNAs (miRNAs) in contributing to the regulations of TS and DHFR expression, and to the chemoresistance mechanism of fluoropyrimidines and antifolates.

  17. Aberrantly Expressed Long Non-Coding RNAs In CD8(+) T Cells Response to Active Tuberculosis.

    PubMed

    Fu, Yurong; Gao, Kunshan; Tao, Enxue; Li, Ruifang; Yi, Zhengjun

    2017-04-19

    Dysregulated expression of long noncoding RNAs (lncRNAs) has been demonstrated as being implicated in a variety of human diseases. In the study we aimed to determine lncRNA profile in CD8(+) T cells response to active tuberculosis (TB). We examined the lncRNA expression by microarray in circulating CD8(+) T cells isolated from patients with active TB and healthy controls. Change predictions to analysis was used to address functional roles of the deregulated mRNAs. Real-time quantitative PCR (RT-qPCR) was used to validate the microarray result. In total, 328 lncRNAs and 356 mRNAs were differentially expressed in TB CD8(+) T cells. Upregulated mRNAs were mainly enriched in cAMP signaling pathway, calcium signaling pathway, and TGF-beta signaling pathway, while downregulated mRNAs were enriched in antigen processing and presentation and natural killer cell mediated cytotoxicity in TB CD8(+) T cells. Interestingly, we found that heme oxygenase 1 (HMOX1) was decreased in active TB CD8(+) T cells, while its nearby lincRNA XLOC_014219 was upregulated. Subsequent RT-qPCR results confirmed the changes. This is the first research addressing lncRNA expression profiles in active TB CD8(+) T cells. The aberrantly expressed lncRNAs observed in the study may provide clues to the dysfunction of CD8(+) T cells and so to the pathophysiological properties of active TB. Further studies should focus on the function of lncRNAs involved in active TB. J. Cell. Biochem. 9999: 1-10, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. The SLE transcriptome exhibits evidence of chronic endotoxin exposure and has widespread dysregulation of non-coding and coding RNAs.

    PubMed

    Shi, Lihua; Zhang, Zhe; Yu, Angela M; Wang, Wei; Wei, Zhi; Akhter, Ehtisham; Maurer, Kelly; Costa Reis, Patrícia; Song, Li; Petri, Michelle; Sullivan, Kathleen E

    2014-01-01

    Gene expression studies of peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE) have demonstrated a type I interferon signature and increased expression of inflammatory cytokine genes. Studies of patients with Aicardi Goutières syndrome, commonly cited as a single gene model for SLE, have suggested that accumulation of non-coding RNAs may drive some of the pathologic gene expression, however, no RNA sequencing studies of SLE patients have been performed. This study was designed to define altered expression of coding and non-coding RNAs and to detect globally altered RNA processing in SLE. Purified monocytes from eight healthy age/gender matched controls and nine SLE patients (with low-moderate disease activity and lack of biologic drug use or immune suppressive treatment) were studied using RNA-seq. Quantitative RT-PCR was used to validate findings. Serum levels of endotoxin were measured by ELISA. We found that SLE patients had diminished expression of most endogenous retroviruses and small nucleolar RNAs, but exhibited increased expression of pri-miRNAs. Splicing patterns and polyadenylation were significantly altered. In addition, SLE monocytes expressed novel transcripts, an effect that was replicated by LPS treatment of control monocytes. We further identified increased circulating endotoxin in SLE patients. Monocytes from SLE patients exhibit globally dysregulated gene expression. The transcriptome is not simply altered by the transcriptional activation of a set of genes, but is qualitatively different in SLE. The identification of novel loci, inducible by LPS, suggests that chronic microbial translocation could contribute to the immunologic dysregulation in SLE, a new potential disease mechanism.

  19. Determining Associations between Human Diseases and non-coding RNAs with Critical Roles in Network Control.

    PubMed

    Kagami, Haruna; Akutsu, Tatsuya; Maegawa, Shingo; Hosokawa, Hiroshi; Nacher, Jose C

    2015-10-13

    Deciphering the association between life molecules and human diseases is currently an important task in systems biology. Research over the past decade has unveiled that the human genome is almost entirely transcribed, producing a vast number of non-protein-coding RNAs (ncRNAs) with potential regulatory functions. More recent findings suggest that many diseases may not be exclusively linked to mutations in protein-coding genes. The combination of these arguments poses the question of whether ncRNAs that play a critical role in network control are also enriched with disease-associated ncRNAs. To address this question, we mapped the available annotated information of more than 350 human disorders to the largest collection of human ncRNA-protein interactions, which define a bipartite network of almost 93,000 interactions. Using a novel algorithmic-based controllability framework applied to the constructed bipartite network, we found that ncRNAs engaged in critical network control are also statistically linked to human disorders (P-value of P = 9.8 × 10(-109)). Taken together, these findings suggest that the addition of those genes that encode optimized subsets of ncRNAs engaged in critical control within the pool of candidate genes could aid disease gene prioritization studies.

  20. Determining Associations between Human Diseases and non-coding RNAs with Critical Roles in Network Control

    NASA Astrophysics Data System (ADS)

    Kagami, Haruna; Akutsu, Tatsuya; Maegawa, Shingo; Hosokawa, Hiroshi; Nacher, Jose C.

    2015-10-01

    Deciphering the association between life molecules and human diseases is currently an important task in systems biology. Research over the past decade has unveiled that the human genome is almost entirely transcribed, producing a vast number of non-protein-coding RNAs (ncRNAs) with potential regulatory functions. More recent findings suggest that many diseases may not be exclusively linked to mutations in protein-coding genes. The combination of these arguments poses the question of whether ncRNAs that play a critical role in network control are also enriched with disease-associated ncRNAs. To address this question, we mapped the available annotated information of more than 350 human disorders to the largest collection of human ncRNA-protein interactions, which define a bipartite network of almost 93,000 interactions. Using a novel algorithmic-based controllability framework applied to the constructed bipartite network, we found that ncRNAs engaged in critical network control are also statistically linked to human disorders (P-value of P = 9.8 × 10-109). Taken together, these findings suggest that the addition of those genes that encode optimized subsets of ncRNAs engaged in critical control within the pool of candidate genes could aid disease gene prioritization studies.

  1. A Transgenic Transcription Factor (TaDREB3) in Barley Affects the Expression of MicroRNAs and Other Small Non-Coding RNAs

    PubMed Central

    Hackenberg, Michael; Shi, Bu-Jun; Gustafson, Perry; Langridge, Peter

    2012-01-01

    Transcription factors (TFs), microRNAs (miRNAs), small interfering RNAs (siRNAs) and other functional non-coding small RNAs (sRNAs) are important gene regulators. Comparison of sRNA expression profiles between transgenic barley over-expressing a drought tolerant TF (TaDREB3) and non-transgenic control barley revealed many group-specific sRNAs. In addition, 42% of the shared sRNAs were differentially expressed between the two groups (|log2| >1). Furthermore, TaDREB3-derived sRNAs were only detected in transgenic barley despite the existence of homologous genes in non-transgenic barley. These results demonstrate that the TF strongly affects the expression of sRNAs and siRNAs could in turn affect the TF stability. The TF also affects size distribution and abundance of sRNAs including miRNAs. About half of the sRNAs in each group were derived from chloroplast. A sRNA derived from tRNA-His(GUG) encoded by the chloroplast genome is the most abundant sRNA, accounting for 42.2% of the total sRNAs in transgenic barley and 28.9% in non-transgenic barley. This sRNA, which targets a gene (TC245676) involved in biological processes, was only present in barley leaves but not roots. 124 and 136 miRNAs were detected in transgenic and non-transgenic barley, respectively. miR156 was the most abundant miRNA and up-regulated in transgenic barley, while miR168 was the most abundant miRNA and up-regulated in non-transgenic barley. Eight out of 20 predicted novel miRNAs were differentially expressed between the two groups. All the predicted novel miRNA targets were validated using a degradome library. Our data provide an insight into the effect of TF on the expression of sRNAs in barley. PMID:22870277

  2. Non-coding Y RNAs associate with early replicating euchromatin in concordance with the origin recognition complex.

    PubMed

    Kheir, Eyemen; Krude, Torsten

    2017-04-01

    Non-coding Y RNAs are essential for the initiation of chromosomal DNA replication in vertebrates, yet their association with chromatin during the cell cycle is not characterised. Here, we quantify human Y RNA levels in soluble and chromatin-associated intracellular fractions and investigate, topographically, their dynamic association with chromatin during the cell cycle. We find that, on average, about a million Y RNA molecules are present in the soluble fraction of a proliferating cell, and 5-10-fold less are in association with chromatin. These levels decrease substantially during quiescence. No significant differences are apparent between cancer and non-cancer cell lines. Y RNAs associate with euchromatin throughout the cell cycle. Their levels are 2-4-fold higher in S phase than in G1 phase or mitosis. Y RNAs are not detectable at active DNA replication foci, and re-associate with replicated euchromatin during mid and late S phase. The dynamics and sites of Y1 RNA association with chromatin are in concordance with those of the origin recognition complex (ORC). Our data therefore suggest a functional role of Y RNAs in a common pathway with ORC. © 2017. Published by The Company of Biologists Ltd.

  3. Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions

    PubMed Central

    Vojtech, Lucia; Woo, Sangsoon; Hughes, Sean; Levy, Claire; Ballweber, Lamar; Sauteraud, Renan P.; Strobl, Johanna; Westerberg, Katharine; Gottardo, Raphael; Tewari, Muneesh; Hladik, Florian

    2014-01-01

    Semen contains relatively ill-defined regulatory components that likely aid fertilization, but which could also interfere with defense against infection. Each ejaculate contains trillions of exosomes, membrane-enclosed subcellular microvesicles, which have immunosuppressive effects on cells important in the genital mucosa. Exosomes in general are believed to mediate inter-cellular communication, possibly by transferring small RNA molecules. We found that seminal exosome (SE) preparations contain a substantial amount of RNA from 20 to 100 nucleotides (nts) in length. We sequenced 20–40 and 40–100 nt fractions of SE RNA separately from six semen donors. We found various classes of small non-coding RNA, including microRNA (21.7% of the RNA in the 20–40 nt fraction) as well as abundant Y RNAs and tRNAs present in both fractions. Specific RNAs were consistently present in all donors. For example, 10 (of ∼2600 known) microRNAs constituted over 40% of mature microRNA in SE. Additionally, tRNA fragments were strongly enriched for 5’-ends of 18–19 or 30–34 nts in length; such tRNA fragments repress translation. Thus, SE could potentially deliver regulatory signals to the recipient mucosa via transfer of small RNA molecules. PMID:24838567

  4. Microarray analysis of long non-coding RNAs in COPD lung tissue.

    PubMed

    Bi, Hui; Zhou, Ji; Wu, Dandan; Gao, Wei; Li, Lingling; Yu, Like; Liu, Feng; Huang, Mao; Adcock, Ian M; Barnes, Peter J; Yao, Xin

    2015-02-01

    Long noncoding RNAs (lncRNAs) play an important role in the pathogenesis of many human diseases. In this study, we provide the description of genome-wide lncRNA expression in the lung tissue of non-smokers without Chronic obstructive pulmonary disease (COPD), of smokers without COPD and of smokers with COPD. RNA was extracted from human lung tissue and analysed using an Agilent Human lncRNA + mRNA Array v2.0 system. 39,253 distinct lncRNA transcripts were detected in the lung tissues of all subjects. In smokers without COPD 87 lncRNAs were significantly up-regulated and 244 down-regulated compared to non-smokers without COPD with RNA50010|UCSC-9199-1005 and RNA58351| CombinedLit_316_550, the most over- and under-regulated, respectively. In contrast, in COPD patients 120 lncRNAs were over-expressed and 43 under-expressed compared with smokers without COPD with RNA44121|UCSC-2000-3182 and RNA43510|UCSC-1260-3754 being the most over- and under-regulated, respectively. Gene Ontology (GO) and pathway analysis indicated that cigarette smoking was associated with activation of metabolic pathways, whereas COPD transcripts were associated with 'hematopoietic cell lineage', intermediary metabolism and immune system processes. We conclude that the altered expression of lncRNAs might play partial role in pathways implicated in COPD onset and progression such as intermediary metabolism and the immune response.

  5. Small non-coding RNAs (sncRNA) regulate gene silencing and modify homeostatic status in animals faced with porcine reproductive and respiratory syndrome virus (PRRSV)

    USDA-ARS?s Scientific Manuscript database

    It has been established that reduced susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) has a genetic component. This genetic component may take the form of small non-coding RNAs (sncRNA), which are molecules that function as regulators of gene expression. Various sncRNAs ...

  6. Identification and characterization of three Vibrio alginolyticus non-coding RNAs involved in adhesion, chemotaxis, and motility processes

    PubMed Central

    Huang, Lixing; Hu, Jiao; Su, Yongquan; Qin, Yingxue; Kong, Wendi; Ma, Ying; Xu, Xiaojin; Lin, Mao; Yan, Qingpi

    2015-01-01

    The capability of Vibrio alginolyticus to adhere to fish mucus is a key virulence factor of the bacteria. Our previous research showed that stress conditions, such as Cu2+, Pb2+, Hg2+, and low pH, can reduce this adhesion ability. Non-coding (nc) RNAs play a crucial role in regulating bacterial gene expression, affecting the bacteria's pathogenicity. To investigate the mechanism(s) underlying the decline in adhesion ability caused by stressors, we combined high-throughput sequencing with computational techniques to detect stressed ncRNA dynamics. These approaches yielded three commonly altered ncRNAs that are predicted to regulate the bacterial chemotaxis pathway, which plays a key role in the adhesion process of bacteria. We hypothesized they play a key role in the adhesion process of V. alginolyticus. In this study, we validated the effects of these three ncRNAs on their predicted target genes and their role in the V. alginolyticus adhesion process with RNA interference (i), quantitative real-time polymerase chain reaction (qPCR), northern blot, capillary assay, and in vitro adhesion assays. The expression of these ncRNAs and their predicted target genes were confirmed by qPCR and northern blot, which reinforced the reliability of the sequencing data and the target prediction. Overexpression of these ncRNAs was capable of reducing the chemotactic and adhesion ability of V. alginolyticus, and the expression levels of their target genes were also significantly reduced. Our results indicated that these three ncRNAs: (1) are able to regulate the bacterial chemotaxis pathway, and (2) play a key role in the adhesion process of V. alginolyticus. PMID:26217589

  7. Identification and characterization of three Vibrio alginolyticus non-coding RNAs involved in adhesion, chemotaxis, and motility processes.

    PubMed

    Huang, Lixing; Hu, Jiao; Su, Yongquan; Qin, Yingxue; Kong, Wendi; Ma, Ying; Xu, Xiaojin; Lin, Mao; Yan, Qingpi

    2015-01-01

    The capability of Vibrio alginolyticus to adhere to fish mucus is a key virulence factor of the bacteria. Our previous research showed that stress conditions, such as Cu(2+), Pb(2+), Hg(2+), and low pH, can reduce this adhesion ability. Non-coding (nc) RNAs play a crucial role in regulating bacterial gene expression, affecting the bacteria's pathogenicity. To investigate the mechanism(s) underlying the decline in adhesion ability caused by stressors, we combined high-throughput sequencing with computational techniques to detect stressed ncRNA dynamics. These approaches yielded three commonly altered ncRNAs that are predicted to regulate the bacterial chemotaxis pathway, which plays a key role in the adhesion process of bacteria. We hypothesized they play a key role in the adhesion process of V. alginolyticus. In this study, we validated the effects of these three ncRNAs on their predicted target genes and their role in the V. alginolyticus adhesion process with RNA interference (i), quantitative real-time polymerase chain reaction (qPCR), northern blot, capillary assay, and in vitro adhesion assays. The expression of these ncRNAs and their predicted target genes were confirmed by qPCR and northern blot, which reinforced the reliability of the sequencing data and the target prediction. Overexpression of these ncRNAs was capable of reducing the chemotactic and adhesion ability of V. alginolyticus, and the expression levels of their target genes were also significantly reduced. Our results indicated that these three ncRNAs: (1) are able to regulate the bacterial chemotaxis pathway, and (2) play a key role in the adhesion process of V. alginolyticus.

  8. Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non-coding RNAs in T cells.

    PubMed

    Lai, N-S; Koo, M; Yu, C-L; Lu, M-C

    2017-03-01

    Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are RNA molecules that do not translate into protein. Both miRNAs and lncRNAs are known to regulate gene expression and to play an essential role in T cell differentiation and function. Both systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease, and rheumatoid arthritis (RA), a representative disease of inflammatory arthritis, are characterized by a complex dysfunction in the innate and adaptive immunity. T cells play a central role in cell-mediated immune response and multiple defects in T cells from patients with SLE and RA have been observed. Abnormality in T cell signalling, cytokine and chemokine production, T cell activation and apoptosis, T cell differentiation and DNA methylation that are associated closely with the aberrant expression of a number of miRNAs and lncRNAs have been implicated in the immunopathogenesis of SLE and RA. This review aims to provide an overview of the current state of research on the abnormal expression of miRNAs and lncRNAs in T cells and their roles in the immunopathogenesis of SLE and RA. In addition, by comparing the differences in aberrant expression of miRNAs and lncRNAs in T cells between patients with SLE and RA, controversial areas are highlighted that warrant further investigation.

  9. Analysis of non-coding transcriptome in rice and maize uncovers roles of conserved lncRNAs associated with agriculture traits.

    PubMed

    Wang, Huan; Niu, Qi-Wen; Wu, Hui-Wen; Liu, Jun; Ye, Jian; Yu, Niu; Chua, Nam-Hai

    2015-10-01

    Long non-coding RNAs (lncRNAs) have recently been found to widely exist in eukaryotes and play important roles in key biological processes. To extend our knowledge of lncRNAs in crop plants we performed both non-directional and strand-specific RNA-sequencing experiments to profile non-coding transcriptomes of various rice and maize organs at different developmental stages. Analysis of more than 3 billion reads identified 22 334 long intergenic non-coding RNAs (lincRNAs) and 6673 pairs of sense and natural antisense transcript (NAT). Many lincRNA genes were associated with epigenetic marks. Expression of rice lincRNA genes was significantly correlated with that of nearby protein-coding genes. A set of NAT genes also showed expression correlation with their sense genes. More than 200 rice lincRNA genes had homologous non-coding sequences in the maize genome. Much more lincRNA and NAT genes were derived from conserved genomic regions between the two cereals presenting positional conservation. Protein-coding genes flanking or having a sense-antisense relationship to these conserved lncRNA genes were mainly involved in development and stress responses, suggesting that the associated lncRNAs might have similar functions. Integrating previous genome-wide association studies (GWAS), we found that hundreds of lincRNAs contain trait-associated SNPs (single nucleotide polymorphisms [SNPs]) suggesting their putative contributions to developmental and agriculture traits.

  10. MicroRNAs: short non-coding players in cancer chemoresistance.

    PubMed

    Donzelli, Sara; Mori, Federica; Biagioni, Francesca; Bellissimo, Teresa; Pulito, Claudio; Muti, Paola; Strano, Sabrina; Blandino, Giovanni

    2014-01-01

    Chemoresistance is one of the main problems in the therapy of cancer. There are a number of different molecular mechanisms through which a cancer cell acquires resistance to a specific treatment, such as alterations in drug uptake, drug metabolism and drug targets. There are several lines of evidence showing that miRNAs are involved in drug sensitivity of cancer cells in different tumor types and by different treatments. In this review, we provide an overview of the more recent and significant findings on the role of miRNAs in cancer cell drug resistance. In particular, we focus on specific miRNA mechanisms of action that in various steps lead from drug cell sensitivity to drug cell resistance. We also provide evidence on how miRNA profiling may unveil relevant predictive biomarkers for therapy outcomes.

  11. The Use of Three Long Non-Coding RNAs as Potential Prognostic Indicators of Astrocytoma.

    PubMed

    Zhi, Feng; Wang, Qiang; Xue, Lian; Shao, Naiyuan; Wang, Rong; Deng, Danni; Wang, Suinuan; Xia, Xiwei; Yang, Yilin

    2015-01-01

    Long noncoding RNAs (lncRNAs) are pervasively transcribed and play a key role in tumorigenesis. The aim of the study was to determine the lncRNA expression profile in astrocytomas and to assess its potential clinical value. We performed a three-step analysis to establish the lncRNA profile for astrocytoma: a) the lncRNA expression was examined on 3 astrocytomas as well as 3 NATs (normal adjacent tissues) using the lncRNA microarray; b) the top-hits were validated in 40 astrocytomas (WHO grade II-IV) by quantitative real time-PCR (qRT-PCR); c) the hits with significant differences were re-evaluated using qRT-PCR in 90 astrocytomas. Finally, 7 lncRNAs were found to have a significantly different expression profile in astrocytoma samples compared to the NAT samples. Unsupervised clustering analysis further revealed the potential of the 7-lncRNA profile to differentiate between tumors and NAT samples. The upregulation of ENST00000545440 and NR_002809 was associated with advanced clinical stages of astrocytoma. Using Kaplan-Meier survival analysis, we showed that the low expression of BC002811 or XLOC_010967, or the high expression of NR_002809 was significantly associated with poor patient survival. Moreover, Cox proportional hazard regression analysis revealed that this prognostic impact was independent of other clinicopathological factors. Our results indicate that the lncRNA profile may be a potential prognostic biomarker for the prediction of post-surgical outcomes.

  12. Polymorphisms at long non-coding RNAs and prostate cancer risk in an eastern Chinese population.

    PubMed

    Cao, D-L; Gu, C-Y; Zhu, Y; Dai, B; Zhang, H-L; Shi, G-H; Shen, Y-J; Zhu, Y-P; Ma, C-G; Xiao, W-J; Qin, X-J; Lin, G-W; Ye, D-W

    2014-12-01

    Controversial data on the association of single-nucleotide polymorphisms (SNPs, rs3787016G>A and rs10773338G>A) in long non-coding RNA (lncRNA) with prostate cancer risk were emerged. Considering possible genetic differences among populations, we conducted the present study to clarify these discrepancies and re-validate these results in an eastern Chinese population and thus provide clues for new therapeutic targets of prostate cancer. Genotypes of these two SNPs from 1015 ethnic Han Chinese patients with prostate cancer and 1032 cancer-free controls were determined by Taqman assays. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations. The association of rs3787016 A variant genotypes with a significantly higher prostate cancer risk were found (adjusted OR = 1.418, 95% CI = 1.090-1.844 for AA vs GG). Stratification analysis indicated that the risk of rs3787016 variant AG/AA genotypes was more evident in younger subjects, ever smoking, patients with Gleason score ⩾ 7(4+3) and highly aggressive status. All these risks were not present for rs10773338G>A. These findings suggested that lncRNA SNPs may contribute to prostate cancer risk in an eastern Chinese population. Larger and well-designed studies with different ethnic populations are warranted to validate our findings.

  13. Long non-coding RNAs, ASAP1-IT1, FAM215A, and LINC00472, in epithelial ovarian cancer.

    PubMed

    Fu, Yuanyuan; Biglia, Nicoletta; Wang, Zhanwei; Shen, Yi; Risch, Harvey A; Lu, Lingeng; Canuto, Emilie Marion; Jia, Wei; Katsaros, Dionyssios; Yu, Herbert

    2016-12-01

    Long non-coding RNAs (lncRNAs) are a class of non-protein coding transcripts that has gained significant attention lately due to their important biological actions and potential involvement in cancer. Ovarian cancer is a devastating disease with poor prognosis, and our understanding of lncRNA's involvement in the malignancy is limited. To further our knowledge, we measured the expression of three lncRNAs, ASAP1-IT1, FAM215A, and LINC00472, in tumor samples, and analyzed their associations with disease characteristics and patient survival. Two hundred sixty-six patients diagnosed with primary epithelial ovarian cancers were recruited for the study. Fresh-frozen tumor samples were obtained from the patients at tumor resection and analyzed by RT-qPCR for expression of ASAP1-IT1, FAM215A, and LINC00472. Associations of lncRNA expression with patient survival were determined using Cox proportional hazards regression models. We observed high expression of ASAP1-IT1, FAM215A and LINC00472 more frequently in low grade tumors and early stage disease compared to high grade tumors and late stage disease, respectively. High expression of ASAP1-IT1 and FAM215A were associated with favorable overall survival, and the survival association with ASAP1-IT1 was independent of tumor grade and disease stage. Analyses of online data also demonstrated similar survival associations with ASAP1-IT1 and FAM215A, suggesting that these lncRNAs may be involved in ovarian cancer progression. LncRNAs may play appreciable roles in ovarian cancer and more research is needed to elucidate their biological mechanisms and clinical implications in tumor characterization as well as disease prognosis and treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Specific expression of novel long non-coding RNAs in high-hyperdiploid childhood acute lymphoblastic leukemia

    PubMed Central

    Drouin, Simon; Caron, Maxime; St-Onge, Pascal; Gioia, Romain; Richer, Chantal; Oualkacha, Karim; Droit, Arnaud; Sinnett, Daniel

    2017-01-01

    Pre-B cell childhood acute lymphoblastic leukemia (pre-B cALL) is a heterogeneous disease involving many subtypes typically stratified using a combination of cytogenetic and molecular-based assays. These methods, although widely used, rely on the presence of known chromosomal translocations, which is a limiting factor. There is therefore a need for robust, sensitive, and specific molecular biomarkers unaffected by such limitations that would allow better risk stratification and consequently better clinical outcome. In this study we performed a transcriptome analysis of 56 pre-B cALL patients to identify expression signatures in different subtypes. In both protein-coding and long non-coding RNAs (lncRNA), we identified subtype-specific gene signatures distinguishing pre-B cALL subtypes, particularly in t(12;21) and hyperdiploid cases. The genes up-regulated in pre-B cALL subtypes were enriched in bivalent chromatin marks in their promoters. LncRNAs is a new and under-studied class of transcripts. The subtype-specific nature of lncRNAs suggests they may be suitable clinical biomarkers to guide risk stratification and targeted therapies in pre-B cALL patients. PMID:28346506

  15. Specific expression of novel long non-coding RNAs in high-hyperdiploid childhood acute lymphoblastic leukemia.

    PubMed

    Lajoie, Mathieu; Drouin, Simon; Caron, Maxime; St-Onge, Pascal; Ouimet, Manon; Gioia, Romain; Lafond, Marie-Hélène; Vidal, Ramon; Richer, Chantal; Oualkacha, Karim; Droit, Arnaud; Sinnett, Daniel

    2017-01-01

    Pre-B cell childhood acute lymphoblastic leukemia (pre-B cALL) is a heterogeneous disease involving many subtypes typically stratified using a combination of cytogenetic and molecular-based assays. These methods, although widely used, rely on the presence of known chromosomal translocations, which is a limiting factor. There is therefore a need for robust, sensitive, and specific molecular biomarkers unaffected by such limitations that would allow better risk stratification and consequently better clinical outcome. In this study we performed a transcriptome analysis of 56 pre-B cALL patients to identify expression signatures in different subtypes. In both protein-coding and long non-coding RNAs (lncRNA), we identified subtype-specific gene signatures distinguishing pre-B cALL subtypes, particularly in t(12;21) and hyperdiploid cases. The genes up-regulated in pre-B cALL subtypes were enriched in bivalent chromatin marks in their promoters. LncRNAs is a new and under-studied class of transcripts. The subtype-specific nature of lncRNAs suggests they may be suitable clinical biomarkers to guide risk stratification and targeted therapies in pre-B cALL patients.

  16. DNA methylation patterns of protein-coding genes and long non-coding RNAs in males with schizophrenia.

    PubMed

    Liao, Qi; Wang, Yunliang; Cheng, Jia; Dai, Dongjun; Zhou, Xingyu; Zhang, Yuzheng; Li, Jinfeng; Yin, Honglei; Gao, Shugui; Duan, Shiwei

    2015-11-01

    Schizophrenia (SCZ) is one of the most complex mental illnesses affecting ~1% of the population worldwide. SCZ pathogenesis is considered to be a result of genetic as well as epigenetic alterations. Previous studies have aimed to identify the causative genes of SCZ. However, DNA methylation of long non-coding RNAs (lncRNAs) involved in SCZ has not been fully elucidated. In the present study, a comprehensive genome-wide analysis of DNA methylation was conducted using samples from two male patients with paranoid and undifferentiated SCZ, respectively. Methyl-CpG binding domain protein-enriched genome sequencing was used. In the two patients with paranoid and undifferentiated SCZ, 1,397 and 1,437 peaks were identified, respectively. Bioinformatic analysis demonstrated that peaks were enriched in protein-coding genes, which exhibited nervous system and brain functions. A number of these peaks in gene promoter regions may affect gene expression and, therefore, influence SCZ-associated pathways. Furthermore, 7 and 20 lncRNAs, respectively, in the Refseq database were hypermethylated. According to the lncRNA dataset in the NONCODE database, ~30% of intergenic peaks overlapped with novel lncRNA loci. The results of the present study demonstrated that aberrant hypermethylation of lncRNA genes may be an important epigenetic factor associated with SCZ. However, further studies using larger sample sizes are required.

  17. Non-coding RNAs in Host-Pathogen Interactions: Subversion of Mammalian Cell Functions by Protozoan Parasites.

    PubMed

    Bayer-Santos, Ethel; Marini, Marjorie M; da Silveira, José F

    2017-01-01

    Pathogens have evolved mechanisms to modulate host cell functions and avoid recognition and destruction by the host damage response. For many years, researchers have focused on proteins as the main effectors used by pathogens to hijack host cell pathways, but only recently with the development of deep RNA sequencing these molecules were brought to light as key players in infectious diseases. Protozoan parasites such as those from the genera Plasmodium, Toxoplasma, Leishmania, and Trypanosoma cause life-threatening diseases and are responsible for 1000s of deaths worldwide every year. Some of these parasites replicate intracellularly when infecting mammalian hosts, whereas others can survive and replicate extracellularly in the bloodstream. Each of these parasites uses specific evasion mechanisms to avoid being killed by the host defense system. An increasing number of studies have shown that these pathogens can transfer non-coding RNA molecules to the host cells to modulate their functions. This transference usually happens via extracellular vesicles, which are small membrane vesicles secreted by the microorganism. In this mini-review we will combine published work regarding several protozoan parasites that were shown to use non-coding RNAs in inter-kingdom communication and briefly discuss future perspectives in the field.

  18. Non-coding RNAs in Host–Pathogen Interactions: Subversion of Mammalian Cell Functions by Protozoan Parasites

    PubMed Central

    Bayer-Santos, Ethel; Marini, Marjorie M.; da Silveira, José F.

    2017-01-01

    Pathogens have evolved mechanisms to modulate host cell functions and avoid recognition and destruction by the host damage response. For many years, researchers have focused on proteins as the main effectors used by pathogens to hijack host cell pathways, but only recently with the development of deep RNA sequencing these molecules were brought to light as key players in infectious diseases. Protozoan parasites such as those from the genera Plasmodium, Toxoplasma, Leishmania, and Trypanosoma cause life-threatening diseases and are responsible for 1000s of deaths worldwide every year. Some of these parasites replicate intracellularly when infecting mammalian hosts, whereas others can survive and replicate extracellularly in the bloodstream. Each of these parasites uses specific evasion mechanisms to avoid being killed by the host defense system. An increasing number of studies have shown that these pathogens can transfer non-coding RNA molecules to the host cells to modulate their functions. This transference usually happens via extracellular vesicles, which are small membrane vesicles secreted by the microorganism. In this mini-review we will combine published work regarding several protozoan parasites that were shown to use non-coding RNAs in inter-kingdom communication and briefly discuss future perspectives in the field. PMID:28377760

  19. Non-coding RNAs match the deleted genomic regions in humans

    PubMed Central

    Byeon, Boseon; Kovalchuk, Igor

    2016-01-01

    RNA is transcribed from DNA, and therefore, there should be no RNA transcript from the deleted DNA region. Our study attempted to analyse whether any RNA cache that maps the deleted regions is present in human cells. Using data from the 1000 genome project, we selected 41 CEPH (CEU) and 38 Yoruba (YRI) samples that included the data for the entire genome sequence and ncRNA and mRNA sequences. Aligning the ncRNA reads against the genomic DNA in individual samples has revealed that 229 out of 1114 homozygous deletions have ncRNA reads that map to them. Further analysis has revealed that ncRNA reads that map the deleted regions are enriched around the deletion ends and at genic regions of the genome. The read enrichment at deletion ends suggests that these ncRNAs are likely some form of double-strand break induced RNAs. Our analysis suggests that human cells may contain a residual ncRNA cache that is possibly propagated across generations. PMID:27853310

  20. Identification of mRNA-like non-coding RNAs and validation of a mighty one named MAR in Panax ginseng.

    PubMed

    Wang, Meizhen; Wu, Bin; Chen, Chao; Lu, Shanfa

    2015-03-01

    Increasing evidence suggests that long non-coding RNAs (lncRNAs) play significant roles in plants. However, little is known about lncRNAs in Panax ginseng C. A. Meyer, an economically significant medicinal plant species. A total of 3,688 mRNA-like non-coding RNAs (mlncRNAs), a class of lncRNAs, were identified in P. ginseng. Approximately 40% of the identified mlncRNAs were processed into small RNAs, implying their regulatory roles via small RNA-mediated mechanisms. Eleven miRNA-generating mlncRNAs also produced siRNAs, suggesting the coordinated production of miRNAs and siRNAs in P. ginseng. The mlncRNA-derived small RNAs might be 21-, 22-, or 24-nt phased and could be generated from both or only one strand of mlncRNAs, or from super long hairpin structures. A full-length mlncRNA, termed MAR (multiple-function-associated mlncRNA), was cloned. It generated the most abundant siRNAs. The MAR siRNAs were predominantly 24-nt and some of them were distributed in a phased pattern. A total of 228 targets were predicted for 71 MAR siRNAs. Degradome sequencing validated 68 predicted targets involved in diverse metabolic pathways, suggesting the significance of MAR in P. ginseng. Consistently, MAR was detected in all tissues analyzed and responded to methyl jasmonate (MeJA) treatment. It sheds light on the function of mlncRNAs in plants. © 2014 Institute of Botany, Chinese Academy of Sciences.

  1. Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington's disease.

    PubMed

    Soldati, Chiara; Bithell, Angela; Johnston, Caroline; Wong, Kee-Yew; Stanton, Lawrence W; Buckley, Noel J

    2013-02-01

    Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in Huntington's disease (HD) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element-1 Silencing Transcription Factor (REST) is a repressor whose association with Htt in the cytoplasm is disrupted in HD, leading to increased nuclear REST and concomitant repression of several neuronal-specific genes, including brain-derived neurotrophic factor (Bdnf). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock-down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock-down. We also identified several microRNAs (miRNAs) whose aberrant repression is directly mediated by REST, including miR-137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST-mediated transcriptional repression to the widespread changes in coding and non-coding gene expression in a cellular model of HD that may affect normal neuronal function and survival.

  2. Determination of the differential expression of mitochondrial long non-coding RNAs as a noninvasive diagnosis of bladder cancer

    PubMed Central

    2012-01-01

    Background Bladder cancer is a significant cause of morbidity and mortality with a high recurrence rate. Early detection of bladder cancer is essential in order to remove the tumor, to preserve the organ and to avoid metastasis. The aim of this study was to analyze the differential expression of mitochondrial non-coding RNAs (sense and antisense) in cells isolated from voided urine of patients with bladder cancer as a noninvasive diagnostic assay. Methods The differential expression of the sense (SncmtRNA) and the antisense (ASncmtRNAs) transcripts in cells isolated from voided urine was determined by fluorescent in situ hybridization. The test uses a multiprobe mixture labeled with different fluorophores and takes about 1 hour to complete. We examined the expression of these transcripts in cells isolated from urine of 24 patients with bladder cancer and from 15 healthy donors. Results This study indicates that the SncmtRNA and the ASncmtRNAs are stable in cells present in urine. The test reveals that the expression pattern of the mitochondrial transcripts can discriminate between normal and tumor cells. The analysis of 24 urine samples from patients with bladder cancer revealed expression of the SncmtRNA and down-regulation of the ASncmtRNAs. Exfoliated cells recovered from the urine of healthy donors do not express these mitochondrial transcripts. This is the first report showing that the differential expression of these mitochondrial transcripts can detect tumor cells in the urine of patients with low and high grade bladder cancer. Conclusion This pilot study indicates that fluorescent in situ hybridization of cells from urine of patients with different grades of bladder cancer confirmed the tumor origin of these cells. Samples from the 24 patients with bladder cancer contain cells that express the SncmtRNA and down-regulate the ASncmtRNAs. In contrast, the hybridization of the few exfoliated cells recovered from healthy donors revealed no expression of these

  3. Long Non-Coding RNAs (lncRNAs) of Sea Cucumber: Large-Scale Prediction, Expression Profiling, Non-Coding Network Construction, and lncRNA-microRNA-Gene Interaction Analysis of lncRNAs in Apostichopus japonicus and Holothuria glaberrima During LPS Challenge and Radial Organ Complex Regeneration.

    PubMed

    Mu, Chuang; Wang, Ruijia; Li, Tianqi; Li, Yuqiang; Tian, Meilin; Jiao, Wenqian; Huang, Xiaoting; Zhang, Lingling; Hu, Xiaoli; Wang, Shi; Bao, Zhenmin

    2016-08-01

    Long non-coding RNA (lncRNA) structurally resembles mRNA but cannot be translated into protein. Although the systematic identification and characterization of lncRNAs have been increasingly reported in model species, information concerning non-model species is still lacking. Here, we report the first systematic identification and characterization of lncRNAs in two sea cucumber species: (1) Apostichopus japonicus during lipopolysaccharide (LPS) challenge and in heathy tissues and (2) Holothuria glaberrima during radial organ complex regeneration, using RNA-seq datasets and bioinformatics analysis. We identified A. japonicus and H. glaberrima lncRNAs that were differentially expressed during LPS challenge and radial organ complex regeneration, respectively. Notably, the predicted lncRNA-microRNA-gene trinities revealed that, in addition to targeting protein-coding transcripts, miRNAs might also target lncRNAs, thereby participating in a potential novel layer of regulatory interactions among non-coding RNA classes in echinoderms. Furthermore, the constructed coding-non-coding network implied the potential involvement of lncRNA-gene interactions during the regulation of several important genes (e.g., Toll-like receptor 1 [TLR1] and transglutaminase-1 [TGM1]) in response to LPS challenge and radial organ complex regeneration in sea cucumbers. Overall, this pioneer systematic identification, annotation, and characterization of lncRNAs in echinoderm pave the way for similar studies and future genetic, genomic, and evolutionary research in non-model species.

  4. Genome-wide long non-coding RNA screening, identification and characterization in a model microorganism Chlamydomonas reinhardtii

    PubMed Central

    Li, Hui; Wang, Yuting; Chen, Meirong; Xiao, Peng; Hu, Changxing; Zeng, Zhiyong; Wang, Chaogang; Wang, Jiangxin; Hu, Zhangli

    2016-01-01

    Microalgae are regarded as the most promising biofuel candidates and extensive metabolic engineering were conducted but very few improvements were achieved. Long non-coding RNA (lncRNA) investigation and manipulation may provide new insights for this issue. LncRNAs refer to transcripts that are longer than 200 nucleotides, do not encode proteins but play important roles in eukaryotic gene regulation. However, no information of potential lncRNAs has been reported in eukaryotic alga. Recently, we performed RNA sequencing in Chlamydomonas reinhardtii, and obtained totally 3,574 putative lncRNAs. 1440 were considered as high-confidence lncRNAs, including 936 large intergenic, 310 intronic and 194 anti-sense lncRNAs. The average transcript length, ORF length and numbers of exons for lncRNAs are much less than for genes in this green alga. In contrast with human lncRNAs of which more than 98% are spliced, the percentage in C. reinhardtii is only 48.1%. In addition, we identified 367 lncRNAs responsive to sulfur deprivation, including 36 photosynthesis-related lncRNAs. This is the first time that lncRNAs were explored in the unicellular model organism C. reinhardtii. The lncRNA data could also provide new insights into C. reinhardtii hydrogen production under sulfur deprivation. PMID:27659799

  5. Genome-wide long non-coding RNA screening, identification and characterization in a model microorganism Chlamydomonas reinhardtii.

    PubMed

    Li, Hui; Wang, Yuting; Chen, Meirong; Xiao, Peng; Hu, Changxing; Zeng, Zhiyong; Wang, Chaogang; Wang, Jiangxin; Hu, Zhangli

    2016-09-23

    Microalgae are regarded as the most promising biofuel candidates and extensive metabolic engineering were conducted but very few improvements were achieved. Long non-coding RNA (lncRNA) investigation and manipulation may provide new insights for this issue. LncRNAs refer to transcripts that are longer than 200 nucleotides, do not encode proteins but play important roles in eukaryotic gene regulation. However, no information of potential lncRNAs has been reported in eukaryotic alga. Recently, we performed RNA sequencing in Chlamydomonas reinhardtii, and obtained totally 3,574 putative lncRNAs. 1440 were considered as high-confidence lncRNAs, including 936 large intergenic, 310 intronic and 194 anti-sense lncRNAs. The average transcript length, ORF length and numbers of exons for lncRNAs are much less than for genes in this green alga. In contrast with human lncRNAs of which more than 98% are spliced, the percentage in C. reinhardtii is only 48.1%. In addition, we identified 367 lncRNAs responsive to sulfur deprivation, including 36 photosynthesis-related lncRNAs. This is the first time that lncRNAs were explored in the unicellular model organism C. reinhardtii. The lncRNA data could also provide new insights into C. reinhardtii hydrogen production under sulfur deprivation.

  6. Evolutionary modeling and prediction of non-coding RNAs in Drosophila.

    PubMed

    Bradley, Robert K; Uzilov, Andrew V; Skinner, Mitchell E; Bendaña, Yuri R; Barquist, Lars; Holmes, Ian

    2009-08-11

    We performed benchmarks of phylogenetic grammar-based ncRNA gene prediction, experimenting with eight different models of structural evolution and two different programs for genome alignment. We evaluated our models using alignments of twelve Drosophila genomes. We find that ncRNA prediction performance can vary greatly between different gene predictors and subfamilies of ncRNA gene. Our estimates for false positive rates are based on simulations which preserve local islands of conservation; using these simulations, we predict a higher rate of false positives than previous computational ncRNA screens have reported. Using one of the tested prediction grammars, we provide an updated set of ncRNA predictions for D. melanogaster and compare them to previously-published predictions and experimental data. Many of our predictions show correlations with protein-coding genes. We found significant depletion of intergenic predictions near the 3' end of coding regions and furthermore depletion of predictions in the first intron of protein-coding genes. Some of our predictions are colocated with larger putative unannotated genes: for example, 17 of our predictions showing homology to the RFAM family snoR28 appear in a tandem array on the X chromosome; the 4.5 Kbp spanned by the predicted tandem array is contained within a FlyBase-annotated cDNA.

  7. Differential transcription profiles of long non-coding RNAs in primary human brain microvascular endothelial cells in response to meningitic Escherichia coli

    PubMed Central

    Yang, Ruicheng; Huang, Fei; Fu, Jiyang; Dou, Beibei; Xu, Bojie; Miao, Ling; Liu, Wentong; Yang, Xiaopei; Tan, Chen; Chen, Huanchun; Wang, Xiangru

    2016-01-01

    Accumulating studies have indicated the influence of long non-coding RNAs (lncRNAs) on various biological processes as well as disease development and progression. However, the lncRNAs involved in bacterial meningitis and their regulatory effects are largely unknown. By RNA-sequencing, the transcriptional profiles of host lncRNAs in primary human brain microvascular endothelial cells (hBMECs) in response to meningitic Escherichia coli were demonstrated. Here, 25,257 lncRNAs were identified, including 24,645 annotated lncRNAs and 612 newly found ones. A total of 895 lncRNAs exhibited significant differences upon infection, among which 382 were upregulated and 513 were downregulated (≥2-fold, p < 0.05). Via bioinformatic analysis, the features of these lncRNAs, their possible functions, and the potential regulatory relationships between lncRNAs and mRNAs were predicted. Moreover, we compared the transcriptional specificity of these differential lncRNAs among hBMECs, human astrocyte cell U251, and human umbilical vein endothelial cells, and demonstrated the novel regulatory effects of proinflammatory cytokines on these differential lncRNAs. To our knowledge, this is the first time the transcriptional profiles of host lncRNAs involved in E. coli-induced meningitis have been reported, which shall provide novel insight into the regulatory mechanisms behind bacterial meningitis involving lncRNAs, and contribute to better prevention and therapy of CNS infection. PMID:27958323

  8. Identification of Potential Key Long Non-Coding RNAs and Target Genes Associated with Pneumonia Using Long Non-Coding RNA Sequencing (lncRNA-Seq): A Preliminary Study

    PubMed Central

    Huang, Sai; Feng, Cong; Chen, Li; Huang, Zhi; Zhou, Xuan; Li, Bei; Wang, Li-li; Chen, Wei; Lv, Fa-qin; Li, Tan-shi

    2016-01-01

    Background This study aimed to identify the potential key long non-coding RNAs (lncRNAs) and target genes associated with pneumonia using lncRNA sequencing (lncRNA-seq). Material/Methods A total of 9 peripheral blood samples from patients with mild pneumonia (n=3) and severe pneumonia (n=3), as well as volunteers without pneumonia (n=3), were received for lncRNA-seq. Based on the sequencing data, differentially expressed lncRNAs (DE-lncRNAs) were identified by the limma package. After the functional enrichment analysis, target genes of DE-lncRNAs were predicted, and the regulatory network was constructed. Results In total, 99 DE-lncRNAs (14 upregulated and 85 downregulated ones) were identified in the mild pneumonia group and 85 (72 upregulated and 13 downregulated ones) in the severe pneumonia group, compared with the control group. Among these DE-lncRNAs, 9 lncRNAs were upregulated in both the mild and severe pneumonia groups. A set of 868 genes were predicted to be targeted by these 9 DE-lncRNAs. In the network, RP11-248E9.5 and RP11-456D7.1 targeted the majority of genes. RP11-248E9.5 regulated several genes together with CTD-2300H10.2, such as QRFP and EPS8. Both upregulated RP11-456D7.1 and RP11-96C23.9 regulated several genes, such as PDK2. RP11-456D7.1 also positively regulated CCL21. Conclusions These novel lncRNAs and their target genes may be closely associated with the progression of pneumonia. PMID:27663962

  9. Genome-wide identification and functional prediction of nitrogen-responsive intergenic and intronic long non-coding RNAs in maize (Zea mays L.).

    PubMed

    Lv, Yuanda; Liang, Zhikai; Ge, Min; Qi, Weicong; Zhang, Tifu; Lin, Feng; Peng, Zhaohua; Zhao, Han

    2016-05-11

    Nitrogen (N) is an essential and often limiting nutrient to plant growth and development. Previous studies have shown that the mRNA expressions of numerous genes are regulated by nitrogen supplies; however, little is known about the expressed non-coding elements, for example long non-coding RNAs (lncRNAs) that control the response of maize (Zea mays L.) to nitrogen. LncRNAs are a class of non-coding RNAs larger than 200 bp, which have emerged as key regulators in gene expression. In this study, we surveyed the intergenic/intronic lncRNAs in maize B73 leaves at the V7 stage under conditions of N-deficiency and N-sufficiency using ribosomal RNA depletion and ultra-deep total RNA sequencing approaches. By integration with mRNA expression profiles and physiological evaluations, 7245 lncRNAs and 637 nitrogen-responsive lncRNAs were identified that exhibited unique expression patterns. Co-expression network analysis showed that the nitrogen-responsive lncRNAs were enriched mainly in one of the three co-expressed modules. The genes in the enriched module are mainly involved in NADH dehydrogenase activity, oxidative phosphorylation and the nitrogen compounds metabolic process. We identified a large number of lncRNAs in maize and illustrated their potential regulatory roles in response to N stress. The results lay the foundation for further in-depth understanding of the molecular mechanisms of lncRNAs' role in response to nitrogen stresses.

  10. Comprehensive analysis of long non-coding RNAs highlights their spatio-temporal expression patterns and evolutional conservation in Sus scrofa.

    PubMed

    Tang, Zhonglin; Wu, Yang; Yang, Yalan; Yang, Yu-Cheng T; Wang, Zishuai; Yuan, Jiapei; Yang, Yang; Hua, Chaoju; Fan, Xinhao; Niu, Guanglin; Zhang, Yubo; Lu, Zhi John; Li, Kui

    2017-02-24

    Despite modest sequence conservation and rapid evolution, long non-coding RNAs (lncRNAs) appear to be conserved in expression pattern and function. However, analysis of lncRNAs across tissues and developmental stages remains largely uncharacterized in mammals. Here, we systematically investigated the lncRNAs of the Guizhou miniature pig (Sus scrofa), which was widely used as biomedical model. We performed RNA sequencing across 9 organs and 3 developmental skeletal muscle, and developed a filtering pipeline to identify 10,813 lncRNAs (9,075 novel). Conservation patterns analysis revealed that 57% of pig lncRNAs showed homology to humans and mice based on genome alignment. 5,455 lncRNAs exhibited typical hallmarks of regulatory molecules, such as high spatio-temporal specificity. Notably, conserved lncRNAs exhibited higher tissue specificity than pig-specific lncRNAs and were significantly enriched in testis and ovary. Weighted co-expression network analysis revealed a set of conserved lncRNAs that are likely involved in postnatal muscle development. Based on the high degree of similarity in the structure, organization, and dynamic expression of pig lncRNAs compared with human and mouse lncRNAs, we propose that these lncRNAs play an important role in organ physiology and development in mammals. Our results provide a resource for studying animal evolution, morphological complexity, breeding, and biomedical research.

  11. Comprehensive analysis of long non-coding RNAs highlights their spatio-temporal expression patterns and evolutional conservation in Sus scrofa

    PubMed Central

    Tang, Zhonglin; Wu, Yang; Yang, Yalan; Yang, Yu-Cheng T.; Wang, Zishuai; Yuan, Jiapei; Yang, Yang; Hua, Chaoju; Fan, Xinhao; Niu, Guanglin; Zhang, Yubo; Lu, Zhi John; Li, Kui

    2017-01-01

    Despite modest sequence conservation and rapid evolution, long non-coding RNAs (lncRNAs) appear to be conserved in expression pattern and function. However, analysis of lncRNAs across tissues and developmental stages remains largely uncharacterized in mammals. Here, we systematically investigated the lncRNAs of the Guizhou miniature pig (Sus scrofa), which was widely used as biomedical model. We performed RNA sequencing across 9 organs and 3 developmental skeletal muscle, and developed a filtering pipeline to identify 10,813 lncRNAs (9,075 novel). Conservation patterns analysis revealed that 57% of pig lncRNAs showed homology to humans and mice based on genome alignment. 5,455 lncRNAs exhibited typical hallmarks of regulatory molecules, such as high spatio-temporal specificity. Notably, conserved lncRNAs exhibited higher tissue specificity than pig-specific lncRNAs and were significantly enriched in testis and ovary. Weighted co-expression network analysis revealed a set of conserved lncRNAs that are likely involved in postnatal muscle development. Based on the high degree of similarity in the structure, organization, and dynamic expression of pig lncRNAs compared with human and mouse lncRNAs, we propose that these lncRNAs play an important role in organ physiology and development in mammals. Our results provide a resource for studying animal evolution, morphological complexity, breeding, and biomedical research. PMID:28233874

  12. Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain

    PubMed Central

    Scheckel, Claudia; Drapeau, Elodie; Frias, Maria A; Park, Christopher Y; Fak, John; Zucker-Scharff, Ilana; Kou, Yan; Haroutunian, Vahram; Ma'ayan, Avi

    2016-01-01

    Neuronal ELAV-like (nELAVL) RNA binding proteins have been linked to numerous neurological disorders. We performed crosslinking-immunoprecipitation and RNAseq on human brain, and identified nELAVL binding sites on 8681 transcripts. Using knockout mice and RNAi in human neuroblastoma cells, we showed that nELAVL intronic and 3' UTR binding regulates human RNA splicing and abundance. We validated hundreds of nELAVL targets among which were important neuronal and disease-associated transcripts, including Alzheimer's disease (AD) transcripts. We therefore investigated RNA regulation in AD brain, and observed differential splicing of 150 transcripts, which in some cases correlated with differential nELAVL binding. Unexpectedly, the most significant change of nELAVL binding was evident on non-coding Y RNAs. nELAVL/Y RNA complexes were specifically remodeled in AD and after acute UV stress in neuroblastoma cells. We propose that the increased nELAVL/Y RNA association during stress may lead to nELAVL sequestration, redistribution of nELAVL target binding, and altered neuronal RNA splicing. DOI: http://dx.doi.org/10.7554/eLife.10421.001 PMID:26894958

  13. The essential Drosophila CLAMP protein differentially regulates non-coding roX RNAs in male and females.

    PubMed

    Urban, Jennifer A; Doherty, Caroline A; Jordan, William T; Bliss, Jacob E; Feng, Jessica; Soruco, Marcela M; Rieder, Leila E; Tsiarli, Maria A; Larschan, Erica N

    2017-06-01

    Heterogametic species require chromosome-wide gene regulation to compensate for differences in sex chromosome gene dosage. In Drosophila melanogaster, transcriptional output from the single male X-chromosome is equalized to that of XX females by recruitment of the male-specific lethal (MSL) complex, which increases transcript levels of active genes 2-fold. The MSL complex contains several protein components and two non-coding RNA on the X ( roX) RNAs that are transcriptionally activated by the MSL complex. We previously discovered that targeting of the MSL complex to the X-chromosome is dependent on the chromatin-linked adapter for MSL proteins (CLAMP) zinc finger protein. To better understand CLAMP function, we used the CRISPR/Cas9 genome editing system to generate a frameshift mutation in the clamp gene that eliminates expression of the CLAMP protein. We found that clamp null females die at the third instar larval stage, while almost all clamp null males die at earlier developmental stages. Moreover, we found that in clamp null females roX gene expression is activated, whereas in clamp null males roX gene expression is reduced. Therefore, CLAMP regulates roX abundance in a sex-specific manner. Our results provide new insights into sex-specific gene regulation by an essential transcription factor.

  14. Identification of non-coding RNAs with a new composite feature in the Hybrid Random Forest Ensemble algorithm

    PubMed Central

    Lertampaiporn, Supatcha; Thammarongtham, Chinae; Nukoolkit, Chakarida; Kaewkamnerdpong, Boonserm; Ruengjitchatchawalya, Marasri

    2014-01-01

    To identify non-coding RNA (ncRNA) signals within genomic regions, a classification tool was developed based on a hybrid random forest (RF) with a logistic regression model to efficiently discriminate short ncRNA sequences as well as long complex ncRNA sequences. This RF-based classifier was trained on a well-balanced dataset with a discriminative set of features and achieved an accuracy, sensitivity and specificity of 92.11%, 90.7% and 93.5%, respectively. The selected feature set includes a new proposed feature, SCORE. This feature is generated based on a logistic regression function that combines five significant features—structure, sequence, modularity, structural robustness and coding potential—to enable improved characterization of long ncRNA (lncRNA) elements. The use of SCORE improved the performance of the RF-based classifier in the identification of Rfam lncRNA families. A genome-wide ncRNA classification framework was applied to a wide variety of organisms, with an emphasis on those of economic, social, public health, environmental and agricultural significance, such as various bacteria genomes, the Arthrospira (Spirulina) genome, and rice and human genomic regions. Our framework was able to identify known ncRNAs with sensitivities of greater than 90% and 77.7% for prokaryotic and eukaryotic sequences, respectively. Our classifier is available at http://ncrna-pred.com/HLRF.htm. PMID:24771344

  15. The systematic analysis of coding and long non-coding RNAs in the sub-chronic and chronic stages of spinal cord injury

    PubMed Central

    Duran, Raquel Cuevas-Diaz; Yan, Han; Zheng, Yiyan; Huang, Xingfan; Grill, Raymond; Kim, Dong H.; Cao, Qilin; Wu, Jia Qian

    2017-01-01

    Spinal cord injury (SCI) remains one of the most debilitating neurological disorders and the majority of SCI patients are in the chronic phase. Previous studies of SCI have usually focused on few genes and pathways at a time. In particular, the biological roles of long non-coding RNAs (lncRNAs) have never been characterized in SCI. Our study is the first to comprehensively investigate alterations in the expression of both coding and long non-coding genes in the sub-chronic and chronic stages of SCI using RNA-Sequencing. Through pathway analysis and network construction, the functions of differentially expressed genes were analyzed systematically. Furthermore, we predicted the potential regulatory function of non-coding transcripts, revealed enriched motifs of transcription factors in the upstream regulatory regions of differentially expressed lncRNAs, and identified differentially expressed lncRNAs homologous to human genomic regions which contain single-nucleotide polymorphisms associated with diseases. Overall, these results revealed critical pathways and networks that exhibit sustained alterations at the sub-chronic and chronic stages of SCI, highlighting the temporal regulation of pathological processes including astrogliosis. This study also provided an unprecedented resource and a new catalogue of lncRNAs potentially involved in the regulation and progression of SCI. PMID:28106101

  16. Long non-coding RNAs differentially expressed between normal versus primary breast tumor tissues disclose converse changes to breast cancer-related protein-coding genes.

    PubMed

    Reiche, Kristin; Kasack, Katharina; Schreiber, Stephan; Lüders, Torben; Due, Eldri U; Naume, Bjørn; Riis, Margit; Kristensen, Vessela N; Horn, Friedemann; Børresen-Dale, Anne-Lise; Hackermüller, Jörg; Baumbusch, Lars O

    2014-01-01

    Breast cancer, the second leading cause of cancer death in women, is a highly heterogeneous disease, characterized by distinct genomic and transcriptomic profiles. Transcriptome analyses prevalently assessed protein-coding genes; however, the majority of the mammalian genome is expressed in numerous non-coding transcripts. Emerging evidence supports that many of these non-coding RNAs are specifically expressed during development, tumorigenesis, and metastasis. The focus of this study was to investigate the expression features and molecular characteristics of long non-coding RNAs (lncRNAs) in breast cancer. We investigated 26 breast tumor and 5 normal tissue samples utilizing a custom expression microarray enclosing probes for mRNAs as well as novel and previously identified lncRNAs. We identified more than 19,000 unique regions significantly differentially expressed between normal versus breast tumor tissue, half of these regions were non-coding without any evidence for functional open reading frames or sequence similarity to known proteins. The identified non-coding regions were primarily located in introns (53%) or in the intergenic space (33%), frequently orientated in antisense-direction of protein-coding genes (14%), and commonly distributed at promoter-, transcription factor binding-, or enhancer-sites. Analyzing the most diverse mRNA breast cancer subtypes Basal-like versus Luminal A and B resulted in 3,025 significantly differentially expressed unique loci, including 682 (23%) for non-coding transcripts. A notable number of differentially expressed protein-coding genes displayed non-synonymous expression changes compared to their nearest differentially expressed lncRNA, including an antisense lncRNA strongly anticorrelated to the mRNA coding for histone deacetylase 3 (HDAC3), which was investigated in more detail. Previously identified chromatin-associated lncRNAs (CARs) were predominantly downregulated in breast tumor samples, including CARs located in the

  17. Long Non-Coding RNAs Differentially Expressed between Normal versus Primary Breast Tumor Tissues Disclose Converse Changes to Breast Cancer-Related Protein-Coding Genes

    PubMed Central

    Reiche, Kristin; Kasack, Katharina; Schreiber, Stephan; Lüders, Torben; Due, Eldri U.; Naume, Bjørn; Riis, Margit; Kristensen, Vessela N.; Horn, Friedemann; Børresen-Dale, Anne-Lise; Hackermüller, Jörg; Baumbusch, Lars O.

    2014-01-01

    Breast cancer, the second leading cause of cancer death in women, is a highly heterogeneous disease, characterized by distinct genomic and transcriptomic profiles. Transcriptome analyses prevalently assessed protein-coding genes; however, the majority of the mammalian genome is expressed in numerous non-coding transcripts. Emerging evidence supports that many of these non-coding RNAs are specifically expressed during development, tumorigenesis, and metastasis. The focus of this study was to investigate the expression features and molecular characteristics of long non-coding RNAs (lncRNAs) in breast cancer. We investigated 26 breast tumor and 5 normal tissue samples utilizing a custom expression microarray enclosing probes for mRNAs as well as novel and previously identified lncRNAs. We identified more than 19,000 unique regions significantly differentially expressed between normal versus breast tumor tissue, half of these regions were non-coding without any evidence for functional open reading frames or sequence similarity to known proteins. The identified non-coding regions were primarily located in introns (53%) or in the intergenic space (33%), frequently orientated in antisense-direction of protein-coding genes (14%), and commonly distributed at promoter-, transcription factor binding-, or enhancer-sites. Analyzing the most diverse mRNA breast cancer subtypes Basal-like versus Luminal A and B resulted in 3,025 significantly differentially expressed unique loci, including 682 (23%) for non-coding transcripts. A notable number of differentially expressed protein-coding genes displayed non-synonymous expression changes compared to their nearest differentially expressed lncRNA, including an antisense lncRNA strongly anticorrelated to the mRNA coding for histone deacetylase 3 (HDAC3), which was investigated in more detail. Previously identified chromatin-associated lncRNAs (CARs) were predominantly downregulated in breast tumor samples, including CARs located in the

  18. A Tale of Two RNAs during Viral Infection: How Viruses Antagonize mRNAs and Small Non-Coding RNAs in The Host Cell

    PubMed Central

    Herbert, Kristina M.; Nag, Anita

    2016-01-01

    Viral infection initiates an array of changes in host gene expression. Many viruses dampen host protein expression and attempt to evade the host anti-viral defense machinery. Host gene expression is suppressed at several stages of host messenger RNA (mRNA) formation including selective degradation of translationally competent messenger RNAs. Besides mRNAs, host cells also express a variety of noncoding RNAs, including small RNAs, that may also be subject to inhibition upon viral infection. In this review we focused on different ways viruses antagonize coding and noncoding RNAs in the host cell to its advantage. PMID:27271653

  19. A Tale of Two RNAs during Viral Infection: How Viruses Antagonize mRNAs and Small Non-Coding RNAs in The Host Cell.

    PubMed

    Herbert, Kristina M; Nag, Anita

    2016-06-02

    Viral infection initiates an array of changes in host gene expression. Many viruses dampen host protein expression and attempt to evade the host anti-viral defense machinery. Host gene expression is suppressed at several stages of host messenger RNA (mRNA) formation including selective degradation of translationally competent messenger RNAs. Besides mRNAs, host cells also express a variety of noncoding RNAs, including small RNAs, that may also be subject to inhibition upon viral infection. In this review we focused on different ways viruses antagonize coding and noncoding RNAs in the host cell to its advantage.

  20. A novel protein coding potential of long intergenic non-coding RNAs (lincRNAs) in the kinetoplastid protozoan parasite Leishmania major.

    PubMed

    Pawar, Harsh; Pai, Kalpana; Patole, Milind S

    2017-03-01

    Cutaneous leishmaniasis (CL) is caused by a kinetoplastid protozoan parasite Leishmania major, as a skin ulcer at the site of the sandfly bite. CL is curable and in most cases ulcers heal spontaneously within three to six months leaving a scar and disfiguration. Complete genome of L. major was reported in 2005 at the very initial phase of kinetoplastid parasite genome sequencing project. Presently, L. major genome is most studied and comprehensively annotated genome and therefore, it is being used as a reference genome for annotating recently sequenced Leishmanial genomes. A recent study reporting global transcriptome of L. major promastigotes, identified 1884 uniquely expressed non-coding RNAs (ncRNA) in L. major. In the current study, an in-depth analysis of the 1884 novel ncRNAs was carried out using a proteogenomic approach to identify their protein coding potential. Our analysis resulted in identification of eight novel protein coding genes based on mass spectrometry data. We have analyzed each of these eight novel CDS and in the process have improved the genome annotation of L. major on the basis of mass spectrometry derived peptide data. Although sequenced a decade ago, the improvement in the L. major genome annotation thus is an ongoing process. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Genome-wide analysis of long non-coding RNAs at the mature stage of sea buckthorn (Hippophae rhamnoides Linn) fruit.

    PubMed

    Zhang, Guoyun; Duan, Aiguo; Zhang, Jianguo; He, Caiyun

    2017-01-05

    Long non-coding RNAs (lncRNAs), which are >200nt longer transcripts, potentially play important roles in almost all biological processes in plants and mammals. However, the functions and profiles of lncRNAs in fruit is less understood. Therefore, it is urgent and necessary to identify and analyze the functions of lncRNAs in sea buckthorns. Using RNA-sequencing, we synthetically identified lncRNAs in mature fruit from the red and yellow sea buckthorn. We obtained 567,778,938 clean reads from six samples and identified 3428 lncRNAs in mature fruit, including 2498 intergenic lncRNAs, 593 anti-sense lncRNAs, and 337 intronic lncRNAs. We also identified 3819 and 2295 circular RNAs in red and yellow sea buckthorn Fruit. In the aspects of gene architecture and expression, our results showed significant differences among the three lncRNA subtypes. We also investigated the effect of lncRNAs on its cis and trans target genes. Based on target genes analysis, we obtained 61 different expression lncRNAs (DE-lncRNAs) between these two sea buckthorns, including 23 special expression lncRNAs in red fruit and 22 special expression lncRNAs in yellow fruit. Importantly, we found a few DE-lncRNAs play cis and trans roles for genes in the Carotenoid biosynthesis, ascorbate and aldarate metabolism and fatty acid metabolism pathways. Our study provides a resource for lncRNA studies in mature fruit. It probably encourages researchers to deeply study fruit-coloring. It expands our knowledge about lncRNA biology and the annotation of the sea buckthorn genome. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a non-coding transcript at the progesterone receptor promoter

    PubMed Central

    Chu, Yongjun; Yue, Xuan; Younger, Scott T.; Janowski, Bethany A.; Corey, David R.

    2010-01-01

    Double-stranded RNAs that are complementary to non-coding transcripts at gene promoters can activate or inhibit gene expression in mammalian cells. Understanding the mechanism for modulating gene expression by promoter-targeted antigene RNAs (agRNAs) will require identification of the proteins involved in recognition. Previous reports have implicated argonaute (AGO) proteins, but identifications have differed with involvement of AGO1, AGO2, or both AGO1 and AGO2 being reported by different studies. The roles of AGO3 and AGO4 have not been investigated. Here, we examine the role of AGO 1–4 in gene silencing and activation of the progesterone receptor (PR) gene. Expression of AGO2 is necessary for efficient gene silencing or activation and AGO2 is recruited to the non-coding transcript that overlaps the promoter during both gene silencing and activation. Expression of AGO1, AGO3 and AGO4 are not necessary for gene silencing or activation nor are AGO1, AGO3, or AGO4 recruited to the target non-coding transcript during gene activation. These data indicate that AGO2 is the primary AGO variant involved in modulating expression of PR by agRNAs. PMID:20675357

  3. The expression level of small non-coding RNAs derived from the first exon of protein-coding genes is predictive of cancer status.

    PubMed

    Zovoilis, Athanasios; Mungall, Andrew J; Moore, Richard; Varhol, Richard; Chu, Andy; Wong, Tina; Marra, Marco; Jones, Steven J M

    2014-04-01

    Small non-coding RNAs (smRNAs) are known to be significantly enriched near the transcriptional start sites of genes. However, the functional relevance of these smRNAs remains unclear, and they have not been associated with human disease. Within the cancer genome atlas project (TCGA), we have generated small RNA datasets for many tumor types. In prior cancer studies, these RNAs have been regarded as transcriptional "noise," due to their apparent chaotic distribution. In contrast, we demonstrate their striking potential to distinguish efficiently between cancer and normal tissues and classify patients with cancer to subgroups of distinct survival outcomes. This potential to predict cancer status is restricted to a subset of these smRNAs, which is encoded within the first exon of genes, highly enriched within CpG islands and negatively correlated with DNA methylation levels. Thus, our data show that genome-wide changes in the expression levels of small non-coding RNAs within first exons are associated with cancer.

  4. The Schistosoma mansoni genome encodes thousands of long non-coding RNAs predicted to be functional at different parasite life-cycle stages.

    PubMed

    Vasconcelos, Elton J R; daSilva, Lucas F; Pires, David S; Lavezzo, Guilherme M; Pereira, Adriana S A; Amaral, Murilo S; Verjovski-Almeida, Sergio

    2017-09-05

    Next Generation Sequencing (NGS) strategies, like RNA-Seq, have revealed the transcription of a wide variety of long non-coding RNAs (lncRNAs) in the genomes of several organisms. In the present work we assessed the lncRNAs complement of Schistosoma mansoni, the blood fluke that causes schistosomiasis, ranked among the most prevalent parasitic diseases worldwide. We focused on the long intergenic/intervening ncRNAs (lincRNAs), hidden within the large amount of information obtained through RNA-Seq in S. mansoni (88 libraries). Our computational pipeline identified 7029 canonically-spliced putative lincRNA genes on 2596 genomic loci (at an average 2.7 isoforms per lincRNA locus), as well as 402 spliced lncRNAs that are antisense to protein-coding (PC) genes. Hundreds of lincRNAs showed traits for being functional, such as the presence of epigenetic marks at their transcription start sites, evolutionary conservation among other schistosome species and differential expression across five different life-cycle stages of the parasite. Real-time qPCR has confirmed the differential life-cycle stage expression of a set of selected lincRNAs. We have built PC gene and lincRNA co-expression networks, unraveling key biological processes where lincRNAs might be involved during parasite development. This is the first report of a large-scale identification and structural annotation of lncRNAs in the S. mansoni genome.

  5. Genome wide discovery of long intergenic non-coding RNAs in Diamondback moth (Plutella xylostella) and their expression in insecticide resistant strains.

    PubMed

    Etebari, Kayvan; Furlong, Michael J; Asgari, Sassan

    2015-09-28

    Long non-coding RNAs (lncRNAs) play important roles in genomic imprinting, cancer, differentiation and regulation of gene expression. Here, we identified 3844 long intergenic ncRNAs (lincRNA) in Plutella xylostella, which is a notorious pest of cruciferous plants that has developed field resistance to all classes of insecticides, including Bacillus thuringiensis (Bt) endotoxins. Further, we found that some of those lincRNAs may potentially serve as precursors for the production of small ncRNAs. We found 280 and 350 lincRNAs that are differentially expressed in Chlorpyrifos and Fipronil resistant larvae. A survey on P. xylostella midgut transcriptome data from Bt-resistant populations revealed 59 altered lincRNA in two resistant strains compared with the susceptible population. We validated the transcript levels of a number of putative lincRNAs in deltamethrin-resistant larvae that were exposed to deltamethrin, which indicated that this group of lincRNAs might be involved in the response to xenobiotics in this insect. To functionally characterize DBM lincRNAs, gene ontology (GO) enrichment of their associated protein-coding genes was extracted and showed over representation of protein, DNA and RNA binding GO terms. The data presented here will facilitate future studies to unravel the function of lincRNAs in insecticide resistance or the response to xenobiotics of eukaryotic cells.

  6. Dengue virus genomic variation associated with mosquito adaptation defines the pattern of viral non-coding RNAs and fitness in human cells.

    PubMed

    Filomatori, Claudia V; Carballeda, Juan M; Villordo, Sergio M; Aguirre, Sebastian; Pallarés, Horacio M; Maestre, Ana M; Sánchez-Vargas, Irma; Blair, Carol D; Fabri, Cintia; Morales, Maria A; Fernandez-Sesma, Ana; Gamarnik, Andrea V

    2017-03-01

    The Flavivirus genus includes a large number of medically relevant pathogens that cycle between humans and arthropods. This host alternation imposes a selective pressure on the viral population. Here, we found that dengue virus, the most important viral human pathogen transmitted by insects, evolved a mechanism to differentially regulate the production of viral non-coding RNAs in mosquitos and humans, with a significant impact on viral fitness in each host. Flavivirus infections accumulate non-coding RNAs derived from the viral 3'UTRs (known as sfRNAs), relevant in viral pathogenesis and immune evasion. We found that dengue virus host adaptation leads to the accumulation of different species of sfRNAs in vertebrate and invertebrate cells. This process does not depend on differences in the host machinery; but it was found to be dependent on the selection of specific mutations in the viral 3'UTR. Dissecting the viral population and studying phenotypes of cloned variants, the molecular determinants for the switch in the sfRNA pattern during host change were mapped to a single RNA structure. Point mutations selected in mosquito cells were sufficient to change the pattern of sfRNAs, induce higher type I interferon responses and reduce viral fitness in human cells, explaining the rapid clearance of certain viral variants after host change. In addition, using epidemic and pre-epidemic Zika viruses, similar patterns of sfRNAs were observed in mosquito and human infected cells, but they were different from those observed during dengue virus infections, indicating that distinct selective pressures act on the 3'UTR of these closely related viruses. In summary, we present a novel mechanism by which dengue virus evolved an RNA structure that is under strong selective pressure in the two hosts, as regulator of non-coding RNA accumulation and viral fitness. This work provides new ideas about the impact of host adaptation on the variability and evolution of flavivirus 3'UTRs with

  7. Circulating long-non coding RNAs as biomarkers of left ventricular diastolic function and remodelling in patients with well-controlled type 2 diabetes

    PubMed Central

    de Gonzalo-Calvo, D.; Kenneweg, F.; Bang, C.; Toro, R.; van der Meer, R. W.; Rijzewijk, L. J.; Smit, J. W.; Lamb, H. J.; Llorente-Cortes, V.; Thum, T.

    2016-01-01

    Contractile dysfunction is underdiagnosed in early stages of diabetic cardiomyopathy. We evaluated the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers of subclinical cardiac abnormalities in type 2 diabetes. Forty-eight men with well-controlled type 2 diabetes and 12 healthy age-matched volunteers were enrolled in the study. Left ventricular (LV) parameters were measured by magnetic resonance imaging. A panel of lncRNAs was quantified in serum by RT-qPCR. No differences in expression levels of lncRNAs were observed between type 2 diabetes patients and healthy volunteers. In patients with type 2 diabetes, long intergenic non-coding RNA predicting cardiac remodeling (LIPCAR) was inversely associated with diastolic function, measured as E/A peak flow (P < 0.050 for all linear models). LIPCAR was positively associated with grade I diastolic dysfunction (P < 0.050 for all logistic models). Myocardial infarction-associated transcript (MIAT) and smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA (SENCR) were directly associated with LV mass to LV end-diastolic volume ratio, a marker of cardiac remodelling (P < 0.050 for all linear models). These findings were validated in a sample of 30 patients with well-controlled type 2 diabetes. LncRNAs are independent predictors of diastolic function and remodelling in patients with type 2 diabetes. PMID:27874027

  8. Circulating long-non coding RNAs as biomarkers of left ventricular diastolic function and remodelling in patients with well-controlled type 2 diabetes.

    PubMed

    de Gonzalo-Calvo, D; Kenneweg, F; Bang, C; Toro, R; van der Meer, R W; Rijzewijk, L J; Smit, J W; Lamb, H J; Llorente-Cortes, V; Thum, T

    2016-11-22

    Contractile dysfunction is underdiagnosed in early stages of diabetic cardiomyopathy. We evaluated the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers of subclinical cardiac abnormalities in type 2 diabetes. Forty-eight men with well-controlled type 2 diabetes and 12 healthy age-matched volunteers were enrolled in the study. Left ventricular (LV) parameters were measured by magnetic resonance imaging. A panel of lncRNAs was quantified in serum by RT-qPCR. No differences in expression levels of lncRNAs were observed between type 2 diabetes patients and healthy volunteers. In patients with type 2 diabetes, long intergenic non-coding RNA predicting cardiac remodeling (LIPCAR) was inversely associated with diastolic function, measured as E/A peak flow (P < 0.050 for all linear models). LIPCAR was positively associated with grade I diastolic dysfunction (P < 0.050 for all logistic models). Myocardial infarction-associated transcript (MIAT) and smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA (SENCR) were directly associated with LV mass to LV end-diastolic volume ratio, a marker of cardiac remodelling (P < 0.050 for all linear models). These findings were validated in a sample of 30 patients with well-controlled type 2 diabetes. LncRNAs are independent predictors of diastolic function and remodelling in patients with type 2 diabetes.

  9. The Novel Landscape of Long Non-Coding RNAs in Response to Human Foamy Virus Infection Characterized by RNA-Seq.

    PubMed

    Xu, Shanshan; Dong, Lanlan; Shi, Yingying; Chen, Liujun; Yuan, Peipei; Wang, Shuang; Li, Zhi; Sun, Yan; Han, Song; Yin, Jun; Peng, Biwen; He, Xiaohua; Liu, Wanhong

    2017-05-01

    Human foamy virus (HFV) is a complex and unique retrovirus with the longest genomes among retroviruses that are used as vectors for gene therapy. Long non-coding RNAs (lncRNAs) are regarded as key regulators that are involved in diverse biological processes during viral infection. However, the role of lncRNAs in HFV infection remains unknown. In this study, we utilized next-generation sequencing to first characterize lncRNAs in 293T cells after HFV infection, evaluating length distribution, exon number distribution, volcano picture, and lncRNA class distribution. We identified 11,336 lncRNAs (4,729 upregulated lncRNAs and 6,588 downregulated lncRNAs) and 61,367 mRNAs (30,133 upregulated mRNAs and 31,220 downregulated mRNAs), which were differentially expressed in the HFV-infected 293T cells. Subsequently, six differentially expressed lncRNAs characterized using RNA-seq were confirmed by quantitative real-time polymerase chain reaction assays. Interestingly, Gene Ontology (GO)/Gene Ontology Tree Machine (GOTM) and Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analyses indicated that positive regulation of interleukin 8 (IL8) production and cytokine-cytokine receptor interaction might be involved in the functional enrichment of lncRNAs. Moreover, cis-acting and trans-acting regulatory networks show that NR_028036 may target the fas gene in a cis-acting manner and that ENST00000354838 may target the IL18 gene in a trans-acting manner. Overall, these results not only provide novel insights into the relationship between HFV and lncRNAs in the host response to infection but also have implications for the future wider application of HFV as a vector.

  10. Characteristics of long non-coding RNAs in the Brown Norway rat and alterations in the Dahl salt-sensitive rat.

    PubMed

    Wang, Feng; Li, Liping; Xu, Haiming; Liu, Yong; Yang, Chun; Cowley, Allen W; Wang, Niansong; Liu, Pengyuan; Liang, Mingyu

    2014-11-21

    Long non-coding RNAs (lncRNAs) are potentially important mediators of genomic regulation. lncRNAs, however, remain poorly characterized in the rat model organism widely used in biomedical research. Using poly(A)-independent and strand-specific RNA-seq, we identified 1,500 to 1,800 lncRNAs expressed in each of the following tissues of Brown Norway rats: the renal cortex, renal outer medulla, liver, cardiac left ventricle, adrenal gland, and hypothalamus. Expression and the binding of histone H3K4me3 to promoter regions were confirmed for several lncRNAs. Rat lncRNA expression appeared to be more tissue-specific than mRNA. Rat lncRNAs had 4.5 times fewer exons and 29% shorter transcripts than mRNA. The median cumulative abundance of rat lncRNAs was 53% of that of mRNA. Approximately 28% of the lncRNAs identified in the renal outer medulla appeared to lack a poly(A) tail. Differential expression of 74 lncRNAs was detected in the renal outer medulla between Dahl SS rats, a model of salt-sensitive hypertension, and salt-insensitive, congenic SS.13(BN26) rats fed a high-salt diet. Two of the differentially expressed lncRNAs, which were confirmed, were located within the congenic region and contained several sequence variants. The study identified genome-wide characteristics of lncRNAs in the rat model and suggested a role of lncRNAs in hypertension.

  11. Using machine learning and high-throughput RNA sequencing to classify the precursors of small non-coding RNAs.

    PubMed

    Ryvkin, Paul; Leung, Yuk Yee; Ungar, Lyle H; Gregory, Brian D; Wang, Li-San

    2014-05-01

    Recent advances in high-throughput sequencing allow researchers to examine the transcriptome in more detail than ever before. Using a method known as high-throughput small RNA-sequencing, we can now profile the expression of small regulatory RNAs such as microRNAs and small interfering RNAs (siRNAs) with a great deal of sensitivity. However, there are many other types of small RNAs (<50nt) present in the cell, including fragments derived from snoRNAs (small nucleolar RNAs), snRNAs (small nuclear RNAs), scRNAs (small cytoplasmic RNAs), tRNAs (transfer RNAs), and transposon-derived RNAs. Here, we present a user's guide for CoRAL (Classification of RNAs by Analysis of Length), a computational method for discriminating between different classes of RNA using high-throughput small RNA-sequencing data. Not only can CoRAL distinguish between RNA classes with high accuracy, but it also uses features that are relevant to small RNA biogenesis pathways. By doing so, CoRAL can give biologists a glimpse into the characteristics of different RNA processing pathways and how these might differ between tissue types, biological conditions, or even different species. CoRAL is available at http://wanglab.pcbi.upenn.edu/coral/.

  12. Deep Sequencing Reveals Predominant Expression of miR-21 Amongst the Small Non-Coding RNAs in Retinal Microvascular Endothelial Cells

    PubMed Central

    Guduric-Fuchs, Jasenka; O'Connor, Anna; Cullen, Angela; Harwood, Laura; Medina, Reinhold J; O'Neill, Christina L; Stitt, Alan W; Curtis, Tim M; Simpson, David A

    2012-01-01

    The retinal vascular endothelium is essential for angiogenesis and is involved in maintaining barrier selectivity and vascular tone. The aim of this study was to identify and quantify microRNAs and other small regulatory non-coding RNAs (ncRNAs) which may regulate these crucial functions. Primary bovine retinal microvascular endothelial cells (RMECs) provide a well-characterized in vitro system for studying angiogenesis. RNA extracted from RMECs was used to prepare a small RNA library for deep sequencing (Illumina Genome Analyzer). A total of 6.8 million reads were mapped to 250 known microRNAs in miRBase (release 16). In many cases, the most frequent isomiR differed from the sequence reported in miRBase. In addition, five novel microRNAs, 13 novel bovine orthologs of known human microRNAs and multiple new members of the miR-2284/2285 family were detected. Several ∼30 nucleotide sno-miRNAs were identified, with the most highly expressed being derived from snoRNA U78. Highly expressed microRNAs previously associated with endothelial cells included miR-126 and miR-378, but the most highly expressed was miR-21, comprising more than one-third of all mapped reads. Inhibition of miR-21 with an LNA inhibitor significantly reduced proliferation, migration, and tube-forming capacity of RMECs. The independence from prior sequence knowledge provided by deep sequencing facilitates analysis of novel microRNAs and other small RNAs. This approach also enables quantitative evaluation of microRNA expression, which has highlighted the predominance of a small number of microRNAs in RMECs. Knockdown of miR-21 suggests a role for this microRNA in regulation of angiogenesis in the retinal microvasculature. J. Cell. Biochem. 113: 2098–2111, 2012. © 2012 Wiley Periodicals, Inc. PMID:22298343

  13. Genome-Wide Detection of Predicted Non-coding RNAs Related to the Adhesion Process in Vibrio alginolyticus Using High-Throughput Sequencing

    PubMed Central

    Huang, Lixing; Hu, Jiao; Su, Yongquan; Qin, Yingxue; Kong, Wendi; Zhao, Lingmin; Ma, Ying; Xu, Xiaojin; Lin, Mao; Zheng, Jiang; Yan, Qingpi

    2016-01-01

    The ability of bacteria to adhere to fish mucus can be affected by environmental conditions and is considered to be a key virulence factor of Vibrio alginolyticus. However, the molecular mechanism underlying this ability remains unclear. Our previous study showed that stress conditions such as exposure to Cu, Pb, Hg, and low pH are capable of reducing the adhesion ability of V. alginolyticus. Non-coding RNAs (ncRNAs) play a crucial role in the intricate regulation of bacterial gene expression, thereby affecting bacterial pathogenicity. Thus, we hypothesized that ncRNAs play a key role in the V. alginolyticus adhesion process. To validate this, we combined high-throughput sequencing with computational techniques to detect ncRNA dynamics in samples after stress treatments. The expression of randomly selected novel ncRNAs was confirmed by QPCR. Among the significantly altered ncRNAs, 30 were up-regulated and 2 down-regulated by all stress treatments. The QPCR results reinforced the reliability of the sequencing data. Target prediction and KEGG pathway analysis indicated that these ncRNAs are closely related to pathways associated with in vitro adhesion, and our results indicated that chemical stress-induced reductions in the adhesion ability of V. alginolyticus might be due to the perturbation of ncRNA expression. Our findings provide important information for further functional characterization of ncRNAs during the adhesion process of V. alginolyticus. PMID:27199948

  14. Global assessment of small RNAs reveals a non-coding transcript involved in biofilm formation and attachment in Acinetobacter baumannii ATCC 17978

    PubMed Central

    Pérez, Astrid; Gómez, Manuel J.; Gayoso, Carmen; Vallejo, Juan A.; Ohneck, Emily J.; Valle, Jaione; Actis, Luis A.; Beceiro, Alejandro; Bou, Germán

    2017-01-01

    Many strains of Acinetobacter baumannii have been described as being able to form biofilm. Small non-coding RNAs (sRNAs) control gene expression in many regulatory circuits in bacteria. The aim of the present work was to provide a global description of the sRNAs produced both by planktonic and biofilm-associated (sessile) cells of A. baumannii ATCC 17978, and to compare the corresponding gene expression profiles to identify sRNAs molecules associated to biofilm formation and virulence. sRNA was extracted from both planktonic and sessile cells and reverse transcribed. cDNA was subjected to 454-pyrosequencing using the GS-FLX Titanium chemistry. The global analysis of the small RNA transcriptome revealed different sRNA expression patterns in planktonic and biofilm associated cells, with some of the transcripts only expressed or repressed in sessile bacteria. A total of 255 sRNAs were detected, with 185 of them differentially expressed in the different types of cells. A total of 9 sRNAs were expressed only in biofilm cells, while the expression of other 21 coding regions were repressed only in biofilm cells. Strikingly, the expression level of the sRNA 13573 was 120 times higher in biofilms than in planktonic cells, an observation that prompted us to further investigate the biological role of this non-coding transcript. Analyses of an isogenic mutant and over-expressing strains revealed that the sRNA 13573 gene is involved in biofilm formation and attachment to A549 human alveolar epithelial cells. The present work serves as a basis for future studies examining the complex regulatory network that regulate biofilm biogenesis and attachment to eukaryotic cells in A. baumannii ATCC 17978. PMID:28763494

  15. Genome-wide analysis of long non-coding RNAs at early stage of skin pigmentation in goats (Capra hircus).

    PubMed

    Ren, Hangxing; Wang, Gaofu; Chen, Lei; Jiang, Jing; Liu, Liangjia; Li, Nianfu; Zhao, Jinhong; Sun, Xiaoyan; Zhou, Peng

    2016-01-19

    Long noncoding RNAs (lncRNAs) play roles in almost all biological processes; however, their function and profile in skin development and pigmentation is less understood. In addition, because lncRNAs are species-specific, their function in goats has not been established. We systematically identified lncRNAs in 100-day-old fetal skin by deep RNA-sequencing using the Youzhou dark goat (dark skin) and Yudong white goat (white skin) as a model of skin pigmentation. A total of 841,895,634 clean reads were obtained from six libraries (samples). We identified 1336 specific lncRNAs in fetal skin that belonged to three subtypes, including 999 intergenic lncRNAs (lincRNAs), 218 anti-sense lncRNAs, and 119 intronic lncRNAs. Our results demonstrated significant differences in gene architecture and expression among the three lncRNA subtypes, particularly in terms of density and position bias of transpose elements near the transcription start site. We also investigated the impact of lncRNAs on its target genes in cis and trans, indicating that these lncRNAs have a strict tissue specificity and functional conservation during skin development and pigmentation. The present study provides a resource for lncRNA studies in diseases involved in pigmentation and skin development. It expands our knowledge about lncRNA biology as well as contributes to the annotation of the goat genome.

  16. Structural and functional analysis of four non-coding Y RNAs from Chinese hamster cells: identification, molecular dynamics simulations and DNA replication initiation assays.

    PubMed

    de Lima Neto, Quirino Alves; Duarte Junior, Francisco Ferreira; Bueno, Paulo Sérgio Alves; Seixas, Flavio Augusto Vicente; Kowalski, Madzia Pauline; Kheir, Eyemen; Krude, Torsten; Fernandez, Maria Aparecida

    2016-01-05

    The genes coding for Y RNAs are evolutionarily conserved in vertebrates. These non-coding RNAs are essential for the initiation of chromosomal DNA replication in vertebrate cells. However thus far, no information is available about Y RNAs in Chinese hamster cells, which have already been used to detect replication origins and alternative DNA structures around these sites. Here, we report the gene sequences and predicted structural characteristics of the Chinese hamster Y RNAs, and analyze their ability to support the initiation of chromosomal DNA replication in vitro. We identified DNA sequences in the Chinese hamster genome of four Y RNAs (chY1, chY3, chY4 and chY5) with upstream promoter sequences, which are homologous to the four main types of vertebrate Y RNAs. The chY1, chY3 and chY5 genes were highly conserved with their vertebrate counterparts, whilst the chY4 gene showed a relatively high degree of diversification from the other vertebrate Y4 genes. Molecular dynamics simulations suggest that chY4 RNA is structurally stable despite its evolutionarily divergent predicted stem structure. Of the four Y RNA genes present in the hamster genome, we found that only the chY1 and chY3 RNA were strongly expressed in the Chinese hamster GMA32 cell line, while expression of the chY4 and chY5 RNA genes was five orders of magnitude lower, suggesting that they may in fact not be expressed. We synthesized all four chY RNAs and showed that any of these four could support the initiation of DNA replication in an established human cell-free system. These data therefore establish that non-coding chY RNAs are stable structures and can substitute for human Y RNAs in a reconstituted cell-free DNA replication initiation system. The pattern of Y RNA expression and functionality is consistent with Y RNAs of other rodents, including mouse and rat.

  17. Expression and clinical significance of estrogen-regulated long non-coding RNAs in estrogen receptor α-positive ovarian cancer progression.

    PubMed

    Qiu, Jun-Jun; Ye, Le-Chi; Ding, Jing-Xin; Feng, Wei-Wei; Jin, Hong-Yan; Zhang, Ying; Li, Qing; Hua, Ke-Qin

    2014-04-01

    Estrogen (E2) has long been implicated in epithelial ovarian cancer (EOC) progression. The effects of E2 on cancer progression can be mediated by numerous target genes, including coding RNAs and, more recently, non-coding RNAs (ncRNAs). Among the ncRNAs, long ncRNAs (lncRNAs) have emerged as new regulators in cancer progression; therefore, our aim was to determine whether the expression of any lncRNAs is regulated by E2 and, if so, whether a subset of these lncRNAs have some clinical significance in EOC progression. A microarray was performed to identify E2-regulated lncRNAs in E2 receptor (ER) α-positive EOC cells. Bioinformatics analyses of lncRNAs were conducted, focusing on gene ontology and pathway analyses. Quantitative real-time polymerase chain reactions were performed to confirm the expression of certain lncRNAs in ERα-positive EOC tissues. The correlation between certain lncRNA expression and clinicopathological factors as well as prognosis in ERα-positive EOC patients was then analyzed. We showed that 115 lncRNAs exhibited significant changes in E2-treated SKOV3 cells compared with untreated controls. Most of these lncRNAs were predicated to have potential to contribute to cancer progression. Notably, three candidates (TC0100223, TC0101686 and TC0101441) were aberrantly expressed in ERα-positive compared to ERα-negative EOC tissues, showing correlations with some malignant cancer phenotypes such as advanced FIGO stage and/or high histological grade. Furthermore, multivariate analysis indicated that TC0101441 was an independent prognostic factor for overall survival. Taken together, these results indicate for the first time that E2 can modulate lncRNA expression in ERα-positive EOC cells and that certain lncRNAs are correlated with advanced cancer progression and suggestive of a prognostic indicator in ERα-positive EOC patients. Knowledge of these E2-regulated lncRNAs could aid in the future understanding of the estrogenic effect on EOC progression

  18. Differential expression of long non-coding RNAs in three genetic lines of rainbow trout in response to infection with Flavobacterium psychrophilum

    PubMed Central

    Paneru, Bam; Al-Tobasei, Rafet; Palti, Yniv; Wiens, Gregory D.; Salem, Mohamed

    2016-01-01

    Bacterial cold-water disease caused by Flavobacterium psychrophilum is one of the major causes of mortality of salmonids. Three genetic lines of rainbow trout designated as ARS-Fp-R (resistant), ARS-Fp-C (control) and ARS-Fp-S (susceptible) have significant differences in survival rate following F. psychrophilum infection. Previous study identified transcriptome differences of immune-relevant protein-coding genes at basal and post infection levels among these genetic lines. Using RNA-Seq approach, we quantified differentially expressed (DE) long non-coding RNAs (lncRNAs) in response to F. psychrophilum challenge in these genetic lines. Pairwise comparison between genetic lines and different infection statuses identified 556 DE lncRNAs. A positive correlation existed between the number of the differentially regulated lncRNAs and that of the protein-coding genes. Several lncRNAs showed strong positive and negative expression correlation with their overlapped, neighboring and distant immune related protein-coding genes including complement components, cytokines, chemokines and several signaling molecules involved in immunity. The correlated expressions and genome-wide co-localization suggested that some lncRNAs may be involved in regulating immune-relevant protein-coding genes. This study provides the first evidence of lncRNA-mediated regulation of the anti-bacterial immune response in a commercially important aquaculture species and will likely help developing new genetic markers for rainbow trout disease resistance. PMID:27786264

  19. Linc-ing Circulating Long Non-coding RNAs to the Diagnosis and Malignant Prediction of Intraductal Papillary Mucinous Neoplasms of the Pancreas.

    PubMed

    Permuth, Jennifer B; Chen, Dung-Tsa; Yoder, Sean J; Li, Jiannong; Smith, Andrew T; Choi, Jung W; Kim, Jongphil; Balagurunathan, Yoganand; Jiang, Kun; Coppola, Domenico; Centeno, Barbara A; Klapman, Jason; Hodul, Pam; Karreth, Florian A; Trevino, Jose G; Merchant, Nipun; Magliocco, Anthony; Malafa, Mokenge P; Gillies, Robert

    2017-09-05

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective biomarkers for early detection. We hypothesized that circulating long non-coding RNAs (lncRNAs) may act as diagnostic markers of incidentally-detected cystic PDAC precursors known as intraductal papillary mucinous neoplasms (IPMNs) and predictors of their pathology/histological classification. Using NanoString nCounter® technology, we measured the abundance of 28 candidate lncRNAs in pre-operative plasma from a cohort of pathologically-confirmed IPMN cases of various grades of severity and non-diseased controls. Results showed that two lncRNAs (GAS5 and SRA) aided in differentiating IPMNs from controls. An 8-lncRNA signature (including ADARB2-AS1, ANRIL, GLIS3-AS1, LINC00472, MEG3, PANDA, PVT1, and UCA1) had greater accuracy than standard clinical and radiologic features in distinguishing 'aggressive/malignant' IPMNs that warrant surgical removal from 'indolent/benign' IPMNs that can be observed. When the 8-lncRNA signature was combined with plasma miRNA data and quantitative 'radiomic' imaging features, the accuracy of predicting IPMN pathological classification improved. Our findings provide novel information on the ability to detect lncRNAs in plasma from patients with IPMNs and suggest that an lncRNA-based blood test may have utility as a diagnostic adjunct for identifying IPMNs and their pathology, especially when incorporated with biomarkers such as miRNAs, quantitative imaging features, and clinical data.

  20. LncRNApred: Classification of Long Non-Coding RNAs and Protein-Coding Transcripts by the Ensemble Algorithm with a New Hybrid Feature

    PubMed Central

    Chen, Zhi; Chen, Yuanyuan; Zhang, Jin; Yang, Tao; Zhang, Liangyun

    2016-01-01

    As a novel class of noncoding RNAs, long noncoding RNAs (lncRNAs) have been verified to be associated with various diseases. As large scale transcripts are generated every year, it is significant to accurately and quickly identify lncRNAs from thousands of assembled transcripts. To accurately discover new lncRNAs, we develop a classification tool of random forest (RF) named LncRNApred based on a new hybrid feature. This hybrid feature set includes three new proposed features, which are MaxORF, RMaxORF and SNR. LncRNApred is effective for classifying lncRNAs and protein coding transcripts accurately and quickly. Moreover,our RF model only requests the training using data on human coding and non-coding transcripts. Other species can also be predicted by using LncRNApred. The result shows that our method is more effective compared with the Coding Potential Calculate (CPC). The web server of LncRNApred is available for free at http://mm20132014.wicp.net:57203/LncRNApred/home.jsp. PMID:27228152

  1. Identification and functional analysis of long non-coding RNAs in human and mouse early embryos based on single-cell transcriptome data

    PubMed Central

    Qiu, Jia-jun; Ren, Zhao-rui; Yan, Jing-bin

    2016-01-01

    Epigenetics regulations have an important role in fertilization and proper embryonic development, and several human diseases are associated with epigenetic modification disorders, such as Rett syndrome, Beckwith-Wiedemann syndrome and Angelman syndrome. However, the dynamics and functions of long non-coding RNAs (lncRNAs), one type of epigenetic regulators, in human pre-implantation development have not yet been demonstrated. In this study, a comprehensive analysis of human and mouse early-stage embryonic lncRNAs was performed based on public single-cell RNA sequencing data. Expression profile analysis revealed that lncRNAs are expressed in a developmental stage–specific manner during human early-stage embryonic development, whereas a more temporal-specific expression pattern was identified in mouse embryos. Weighted gene co-expression network analysis suggested that lncRNAs involved in human early-stage embryonic development are associated with several important functions and processes, such as oocyte maturation, zygotic genome activation and mitochondrial functions. We also found that the network of lncRNAs involved in zygotic genome activation was highly preservative between human and mouse embryos, whereas in other stages no strong correlation between human and mouse embryo was observed. This study provides insight into the molecular mechanism underlying lncRNA involvement in human pre-implantation embryonic development. PMID:27542205

  2. The Tetraodon nigroviridis reference transcriptome: developmental transition, length retention and microsynteny of long non-coding RNAs in a compact vertebrate genome

    PubMed Central

    Basu, Swaraj; Hadzhiev, Yavor; Petrosino, Giuseppe; Nepal, Chirag; Gehrig, Jochen; Armant, Olivier; Ferg, Marco; Strahle, Uwe; Sanges, Remo; Müller, Ferenc

    2016-01-01

    Pufferfish such as fugu and tetraodon carry the smallest genomes among all vertebrates and are ideal for studying genome evolution. However, comparative genomics using these species is hindered by the poor annotation of their genomes. We performed RNA sequencing during key stages of maternal to zygotic transition of Tetraodon nigroviridis and report its first developmental transcriptome. We assembled 61,033 transcripts (23,837 loci) representing 80% of the annotated gene models and 3816 novel coding transcripts from 2667 loci. We demonstrate the similarities of gene expression profiles between pufferfish and zebrafish during maternal to zygotic transition and annotated 1120 long non-coding RNAs (lncRNAs) many of which differentially expressed during development. The promoters for 60% of the assembled transcripts result validated by CAGE-seq. Despite the extreme compaction of the tetraodon genome and the dramatic loss of transposons, the length of lncRNA exons remain comparable to that of other vertebrates and a small set of lncRNAs appears enriched for transposable elements suggesting a selective pressure acting on lncRNAs length and composition. Finally, a set of lncRNAs are microsyntenic between teleost and vertebrates, which indicates potential regulatory interactions between lncRNAs and their flanking coding genes. Our work provides a fundamental molecular resource for vertebrate comparative genomics and embryogenesis studies. PMID:27628538

  3. Dengue virus genomic variation associated with mosquito adaptation defines the pattern of viral non-coding RNAs and fitness in human cells

    PubMed Central

    Aguirre, Sebastian; Pallarés, Horacio M.; Blair, Carol D.; Fabri, Cintia; Morales, Maria A.; Fernandez-Sesma, Ana; Gamarnik, Andrea V.

    2017-01-01

    The Flavivirus genus includes a large number of medically relevant pathogens that cycle between humans and arthropods. This host alternation imposes a selective pressure on the viral population. Here, we found that dengue virus, the most important viral human pathogen transmitted by insects, evolved a mechanism to differentially regulate the production of viral non-coding RNAs in mosquitos and humans, with a significant impact on viral fitness in each host. Flavivirus infections accumulate non-coding RNAs derived from the viral 3’UTRs (known as sfRNAs), relevant in viral pathogenesis and immune evasion. We found that dengue virus host adaptation leads to the accumulation of different species of sfRNAs in vertebrate and invertebrate cells. This process does not depend on differences in the host machinery; but it was found to be dependent on the selection of specific mutations in the viral 3’UTR. Dissecting the viral population and studying phenotypes of cloned variants, the molecular determinants for the switch in the sfRNA pattern during host change were mapped to a single RNA structure. Point mutations selected in mosquito cells were sufficient to change the pattern of sfRNAs, induce higher type I interferon responses and reduce viral fitness in human cells, explaining the rapid clearance of certain viral variants after host change. In addition, using epidemic and pre-epidemic Zika viruses, similar patterns of sfRNAs were observed in mosquito and human infected cells, but they were different from those observed during dengue virus infections, indicating that distinct selective pressures act on the 3’UTR of these closely related viruses. In summary, we present a novel mechanism by which dengue virus evolved an RNA structure that is under strong selective pressure in the two hosts, as regulator of non-coding RNA accumulation and viral fitness. This work provides new ideas about the impact of host adaptation on the variability and evolution of flavivirus 3

  4. Active role of small non-coding RNAs derived from SINE/B1 retrotransposon during early mouse development.

    PubMed

    Ohnishi, Yusuke; Totoki, Yasushi; Toyoda, Atsushi; Watanabe, Toshiaki; Yamamoto, Yasuhiro; Tokunaga, Katsushi; Sakaki, Yoshiyuki; Sasaki, Hiroyuki; Hohjoh, Hirohiko

    2012-02-01

    Small RNAs derived from repetitive sequences appear to play essential roles in mammalian gametogenesis and early development. In this study we focused on the short interspersed nucleotide element B1 (SINE/B1) small RNAs, which were zygotically expressed in pre-implantation mouse embryos; and we investigated whether the SINE/B1 small RNAs played an active role in gene silencing during early mouse development. The results indicated that the level of silencing activity involving the SINE/B1 small RNAs as mediators was significantly reduced in Dicer-knockdown mouse embryos. In addition, when the SINE/B1 small RNAs were mapped to a full-length SINE/B1 sequence, phase-distribution of the small RNAs appeared, suggesting possible enzymatic involvement. Therefore, our present study suggested that the zygotically expressed SINE/B1 small RNAs in pre-implantation mouse embryos contain active small RNAs, which were presumably processed by Dicer and involved in gene silencing.

  5. Mechanisms of the alternative activation of macrophages and non-coding RNAs in the development of radiation-induced lung fibrosis

    PubMed Central

    Duru, Nadire; Wolfson, Benjamin; Zhou, Qun

    2016-01-01

    Radiation-induced lung fibrosis (RILF) is a common side effect of thoracic irradiation therapy and leads to high mortality rates after cancer treatment. Radiation injury induces inflammatory M1 macrophage polarization leading to radiation pneumonitis, the first stage of RILF progression. Fibrosis occurs due to the transition of M1 macrophages to the anti-inflammatory pro-fibrotic M2 phenotype, and the resulting imbalance of macrophage regulated inflammatory signaling. Non-coding RNA signaling has been shown to play a large role in the regulation of the M2 mediated signaling pathways that are associated with the development and progression of fibrosis. While many studies show the link between M2 macrophages and fibrosis, there are only a few that explore their distinct role and the regulation of their signaling by non-coding RNA in RILF. In this review we summarize the current body of knowledge describing the roles of M2 macrophages in RILF, with an emphasis on the expression and functions of non-coding RNAs. PMID:27957248

  6. Mechanisms of the alternative activation of macrophages and non-coding RNAs in the development of radiation-induced lung fibrosis.

    PubMed

    Duru, Nadire; Wolfson, Benjamin; Zhou, Qun

    2016-11-26

    Radiation-induced lung fibrosis (RILF) is a common side effect of thoracic irradiation therapy and leads to high mortality rates after cancer treatment. Radiation injury induces inflammatory M1 macrophage polarization leading to radiation pneumonitis, the first stage of RILF progression. Fibrosis occurs due to the transition of M1 macrophages to the anti-inflammatory pro-fibrotic M2 phenotype, and the resulting imbalance of macrophage regulated inflammatory signaling. Non-coding RNA signaling has been shown to play a large role in the regulation of the M2 mediated signaling pathways that are associated with the development and progression of fibrosis. While many studies show the link between M2 macrophages and fibrosis, there are only a few that explore their distinct role and the regulation of their signaling by non-coding RNA in RILF. In this review we summarize the current body of knowledge describing the roles of M2 macrophages in RILF, with an emphasis on the expression and functions of non-coding RNAs.

  7. MALAT1 and HOTAIR Long Non-Coding RNAs Play Opposite Role in Estrogen-Mediated Transcriptional Regulation in Prostate Cancer Cells

    PubMed Central

    Aiello, Aurora; Bacci, Lorenza; Re, Agnese; Ripoli, Cristian; Pierconti, Francesco; Pinto, Francesco; Masetti, Riccardo; Grassi, Claudio; Gaetano, Carlo; Bassi, Pier Francesco; Pontecorvi, Alfredo; Nanni, Simona; Farsetti, Antonella

    2016-01-01

    In the complex network of nuclear hormone receptors, the long non-coding RNAs (lncRNAs) are emerging as critical determinants of hormone action. Here we investigated the involvement of selected cancer-associated lncRNAs in Estrogen Receptor (ER) signaling. Prior studies by Chromatin Immunoprecipitation (ChIP) Sequencing showed that in prostate cancer cells ERs form a complex with the endothelial nitric oxide synthase (eNOS) and that in turn these complexes associate with chromatin in an estrogen-dependent fashion. Among these associations (peaks) we focused our attention on those proximal to the regulatory region of HOTAIR and MALAT1. These transcripts appeared regulated by estrogens and able to control ERs function by interacting with ERα/ERβ as indicated by RNA-ChIP. Further studies performed by ChIRP revealed that in unstimulated condition, HOTAIR and MALAT1 were present on pS2, hTERT and HOTAIR promoters at the ERE/eNOS peaks. Interestingly, upon treatment with17β-estradiol HOTAIR recruitment to chromatin increased significantly while that of MALAT1 was reduced, suggesting an opposite regulation and function for these lncRNAs. Similar results were obtained in cells and in an ex vivo prostate organotypic slice cultures. Overall, our data provide evidence of a crosstalk between lncRNAs, estrogens and estrogen receptors in prostate cancer with important consequences on gene expression regulation. PMID:27922078

  8. Microarray Expression Profile Analysis of Long Non-Coding RNAs in Umbilical Cord Plasma Reveals their Potential Role in Gestational Diabetes-Induced Macrosomia.

    PubMed

    Shi, Zhonghua; Zhao, Chun; Long, Wei; Ding, Hongjuan; Shen, Rong

    2015-01-01

    Fetal macrosomia and its associated complications are the most frequent and serious morbidities for infants associated with gestational diabetes mellitus (GDM). The associations between long non-coding RNAs (lncRNAs) and macrosomia have been rarely reported; therefore, we investigated the umbilical cord lncRNA profiles in GDM macrosomia. Thirty pairs of GDM macrosomia and normal controls were divided into three subgroups randomly, and the umbilical cord vein blood from each subgroup was mixed, and hybridized to a microarray containing probes representing 33,000 lncRNA genes. Quantitative real-time polymerase chain reaction (qPCR) was used to validate selected differentially expressed lncRNAs. The gene ontology (GO), pathway and network analysis were performed. The microarray identified 8814 lncRNAs that were expressed in the umbilical cord blood, of which 349 were significantly upregulated and 892 were significantly downregulated (fold-change ≥ 2.0) in GDM group. The highest enriched GOs targeted by downregulated transcripts were biological regulation. Pathway analysis indicated that nine pathways corresponded to downregulated transcripts. Certain lncRNAs that were aberrantly expressed in the umbilical cord blood from GDM macrosomia might play a partial or key role in GDM macrosomia development. This study provided potential targets for treatment of macrosomia and novel insights into macrosomia biology. © 2015 S. Karger AG, Basel.

  9. Non-Coding RNAs at the Gnas and Snrpn-Ube3a Imprinted Gene Loci and Their Involvement in Hereditary Disorders

    PubMed Central

    Plagge, Antonius

    2012-01-01

    Non-coding RNAs (ncRNAs) have long been recognized at imprinted gene loci and provided early paradigms to investigate their functions and molecular mechanisms of action. The characteristic feature of imprinted genes, their monoallelic, parental-origin-dependent expression, is achieved through complex epigenetic regulation, which is modulated by ncRNAs. This minireview focuses on two imprinted gene clusters, in which changes in ncRNA expression contribute to human disorders. At the GNAS locus loss of NESP RNA can cause autosomal dominant Pseudohypoparathyroidism type 1b (AD-PHP-Ib), while at the SNRPN-UBE3A locus a long ncRNA and processed snoRNAs play a role in Angelman-Syndrome (AS) and Prader–Willi-Syndrome (PWS). The ncRNAs silence overlapping protein-coding transcripts in sense or anti-sense orientation through changes in histone modifications as well as DNA methylation at CpG-rich sequence motifs. Their epigenetic modulatory functions are required in early development in the pre-implantation embryo or already in the parental germ cells. However, it remains unclear whether the sequence homology-carrying ncRNA itself is required, or whether the process of its transcription through other promoters causes the silencing effect. PMID:23226156

  10. Expression profiles of long non-coding RNAs located in autoimmune disease-associated regions reveal immune cell-type specificity.

    PubMed

    Hrdlickova, Barbara; Kumar, Vinod; Kanduri, Kartiek; Zhernakova, Daria V; Tripathi, Subhash; Karjalainen, Juha; Lund, Riikka J; Li, Yang; Ullah, Ubaid; Modderman, Rutger; Abdulahad, Wayel; Lähdesmäki, Harri; Franke, Lude; Lahesmaa, Riitta; Wijmenga, Cisca; Withoff, Sebo

    2014-01-01

    Although genome-wide association studies (GWAS) have identified hundreds of variants associated with a risk for autoimmune and immune-related disorders (AID), our understanding of the disease mechanisms is still limited. In particular, more than 90% of the risk variants lie in non-coding regions, and almost 10% of these map to long non-coding RNA transcripts (lncRNAs). lncRNAs are known to show more cell-type specificity than protein-coding genes. We aimed to characterize lncRNAs and protein-coding genes located in loci associated with nine AIDs which have been well-defined by Immunochip analysis and by transcriptome analysis across seven populations of peripheral blood leukocytes (granulocytes, monocytes, natural killer (NK) cells, B cells, memory T cells, naive CD4(+) and naive CD8(+) T cells) and four populations of cord blood-derived T-helper cells (precursor, primary, and polarized (Th1, Th2) T-helper cells). We show that lncRNAs mapping to loci shared between AID are significantly enriched in immune cell types compared to lncRNAs from the whole genome (α <0.005). We were not able to prioritize single cell types relevant for specific diseases, but we observed five different cell types enriched (α <0.005) in five AID (NK cells for inflammatory bowel disease, juvenile idiopathic arthritis, primary biliary cirrhosis, and psoriasis; memory T and CD8(+) T cells in juvenile idiopathic arthritis, primary biliary cirrhosis, psoriasis, and rheumatoid arthritis; Th0 and Th2 cells for inflammatory bowel disease, juvenile idiopathic arthritis, primary biliary cirrhosis, psoriasis, and rheumatoid arthritis). Furthermore, we show that co-expression analyses of lncRNAs and protein-coding genes can predict the signaling pathways in which these AID-associated lncRNAs are involved. The observed enrichment of lncRNA transcripts in AID loci implies lncRNAs play an important role in AID etiology and suggests that lncRNA genes should be studied in more detail to interpret GWAS

  11. In silico screening of the chicken genome for overlaps between genomic regions: microRNA genes, coding and non-coding transcriptional units, QTL, and genetic variations.

    PubMed

    Zorc, Minja; Kunej, Tanja

    2016-05-01

    MicroRNAs (miRNAs) are a class of non-coding RNAs involved in posttranscriptional regulation of target genes. Regulation requires complementarity between target mRNA and the mature miRNA seed region, responsible for their recognition and binding. It has been estimated that each miRNA targets approximately 200 genes, and genetic variability of miRNA genes has been reported to affect phenotypic variability and disease susceptibility in humans, livestock species, and model organisms. Polymorphisms in miRNA genes could therefore represent biomarkers for phenotypic traits in livestock animals. In our previous study, we collected polymorphisms within miRNA genes in chicken. In the present study, we identified miRNA-related genomic overlaps to prioritize genomic regions of interest for further functional studies and biomarker discovery. Overlapping genomic regions in chicken were analyzed using the following bioinformatics tools and databases: miRNA SNiPer, Ensembl, miRBase, NCBI Blast, and QTLdb. Out of 740 known pre-miRNA genes, 263 (35.5 %) contain polymorphisms; among them, 35 contain more than three polymorphisms The most polymorphic miRNA genes in chicken are gga-miR-6662, containing 23 single nucleotide polymorphisms (SNPs) within the pre-miRNA region, including five consecutive SNPs, and gga-miR-6688, containing ten polymorphisms including three consecutive polymorphisms. Several miRNA-related genomic hotspots have been revealed in chicken genome; polymorphic miRNA genes are located within protein-coding and/or non-coding transcription units and quantitative trait loci (QTL) associated with production traits. The present study includes the first description of an exonic miRNA in a chicken genome, an overlap between the miRNA gene and the exon of the protein-coding gene (gga-miR-6578/HADHB), and the first report of a missense polymorphism located within a mature miRNA seed region. Identified miRNA-related genomic hotspots in chicken can serve researchers as a

  12. From Discovery to Function: The Expanding Roles of Long NonCoding RNAs in Physiology and Disease

    PubMed Central

    Sun, Miao

    2015-01-01

    Long noncoding RNAs (lncRNAs) are a relatively poorly understood class of RNAs with little or no coding capacity transcribed from a set of incompletely annotated genes. They have received considerable attention in the past few years and are emerging as potentially important players in biological regulation. Here we discuss the evolving understanding of this new class of molecular regulators that has emerged from ongoing research, which continues to expand our databases of annotated lncRNAs and provide new insights into their physical properties, molecular mechanisms of action, and biological functions. We outline the current strategies and approaches that have been employed to identify and characterize lncRNAs, which have been instrumental in revealing their multifaceted roles ranging from cis- to trans-regulation of gene expression and from epigenetic modulation in the nucleus to posttranscriptional control in the cytoplasm. In addition, we highlight the molecular and biological functions of some of the best characterized lncRNAs in physiology and disease, especially those relevant to endocrinology, reproduction, metabolism, immunology, neurobiology, muscle biology, and cancer. Finally, we discuss the tremendous diagnostic and therapeutic potential of lncRNAs in cancer and other diseases. PMID:25426780

  13. Quantification of Small Non-Coding RNAs Allows an Accurate Comparison of miRNA Expression Profiles

    PubMed Central

    Masotti, Andrea; Caputo, Viviana; Da Sacco, Letizia; Pizzuti, Antonio; Dallapiccola, Bruno; Bottazzo, Gian Franco

    2009-01-01

    MicroRNAs (miRNAs) are highly conserved ∼22-mer RNA molecules, encoded by plants and animals that regulate the expression of genes binding to the 3′-UTR of specific target mRNAs. The amount of miRNAs in a total RNA sample depends on the recovery efficiency that may be significantly affected by the different purification methods employed. Traditional approaches may be inefficient at recovering small RNAs, and common spectrophotometric determination is not adequate to quantify selectively these low molecular weight (LMW) species from total RNA samples. Here, we describe the use of qualitative and quantitative lab-on-a-chip tools for the analysis of these LMW RNA species. Our data emphasize the close correlation of LMW RNAs with the expression levels of some miRNAs. We therefore applied our result to the comparison of some miRNA expression profiles in different tissues. Finally, the methods we used in this paper allowed us to analyze the efficiency of extraction protocols, to study the small (but significant) differences among various preparations and to allow a proper comparison of some miRNA expression profiles in various tissues. PMID:19727414

  14. Experimental RNomics in Aquifex aeolicus: identification of small non-coding RNAs and the putative 6S RNA homolog

    PubMed Central

    Willkomm, Dagmar K.; Minnerup, Jens; Hüttenhofer, Alexander; Hartmann, Roland K.

    2005-01-01

    By an experimental RNomics approach, we have generated a cDNA library from small RNAs expressed from the genome of the hyperthermophilic bacterium Aquifex aeolicus. The library included RNAs that were antisense to mRNAs and tRNAs as well as RNAs encoded in intergenic regions. Substantial steady-state levels in A.aeolicus cells were confirmed for several of the cloned RNAs by northern blot analysis. The most abundant intergenic RNA of the library was identified as the 6S RNA homolog of A.aeolicus. Although shorter in size (150 nt) than its γ-proteobacterial homologs (∼185 nt), it is predicted to have the most stable structure among known 6S RNAs. As in the γ-proteobacteria, the A.aeolicus 6S RNA gene (ssrS) is located immediately upstream of the ygfA gene encoding a widely conserved 5-formyltetrahydrofolate cyclo-ligase. We identifed novel 6S RNA candidates within the γ-proteobacteria but were unable to identify reasonable 6S RNA candidates in other bacterial branches, utilizing mfold analyses of the region immediately upstream of ygfA combined with 6S RNA blastn searches. By RACE experiments, we mapped the major transcription initiation site of A.aeolicus 6S RNA primary transcripts, located within the pheT gene preceding ygfA, as well as three processing sites. PMID:15814812

  15. Integrated Analysis of Long Non-coding RNAs (LncRNAs) and mRNA Expression Profiles Reveals the Potential Role of LncRNAs in Skeletal Muscle Development of the Chicken

    PubMed Central

    Li, Zhenhui; Ouyang, Hongjia; Zheng, Ming; Cai, Bolin; Han, Peigong; Abdalla, Bahareldin A.; Nie, Qinghua; Zhang, Xiquan

    2017-01-01

    Long non-coding RNAs (lncRNAs) play important roles in transcriptional and post-transcriptional regulation. However, little is currently known about the mechanisms by which they regulate skeletal muscle development in the chicken. In this study, we used RNA sequencing to profile the leg muscle transcriptome (lncRNA and mRNA) at three stages of skeletal muscle development in the chicken: embryonic day 11 (E11), embryonic day 16 (E16), and 1 day after hatching (D1). In total, 129, 132, and 45 differentially expressed lncRNAs, and 1798, 3072, and 1211 differentially expressed mRNAs were identified in comparisons of E11 vs. E16, E11 vs. D1, and E16 vs. D1, respectively. Moreover, we identified the cis- and trans-regulatory target genes of differentially expressed lncRNAs, and constructed lncRNA-gene interaction networks. In total, 126 and 200 cis-targets, and two and three trans-targets were involved in lncRNA-gene interaction networks that were constructed based on the E11 vs. E16, and E11 vs. D1 comparisons, respectively. The comparison of the E16 vs. D1 lncRNA-gene network comprised 25 cis-targets. We determined that lncRNA target genes are potentially involved in cellular development, and cellular growth and proliferation using Ingenuity Pathway Analysis. The gene networks identified for the E11 vs. D1 comparison were involved in embryonic development, organismal development and tissue development. The present study provides an RNA sequencing based evaluation of lncRNA function during skeletal muscle development in the chicken. Comprehensive analysis facilitated the identification of lncRNAs and target genes that might contribute to the regulation of different stages of skeletal muscle development. PMID:28119630

  16. The identification and characterization of non-coding and coding RNAs and their modified nucleosides by mass spectrometry.

    PubMed

    Gaston, Kirk W; Limbach, Patrick A

    2014-01-01

    The analysis of ribonucleic acids (RNA) by mass spectrometry has been a valuable analytical approach for more than 25 years. In fact, mass spectrometry has become a method of choice for the analysis of modified nucleosides from RNA isolated out of biological samples. This review summarizes recent progress that has been made in both nucleoside and oligonucleotide mass spectral analysis. Applications of mass spectrometry in the identification, characterization and quantification of modified nucleosides are discussed. At the oligonucleotide level, advances in modern mass spectrometry approaches combined with the standard RNA modification mapping protocol enable the characterization of RNAs of varying lengths ranging from low molecular weight short interfering RNAs (siRNAs) to the extremely large 23 S rRNAs. New variations and improvements to this protocol are reviewed, including top-down strategies, as these developments now enable qualitative and quantitative measurements of RNA modification patterns in a variety of biological systems.

  17. The identification and characterization of non-coding and coding RNAs and their modified nucleosides by mass spectrometry

    PubMed Central

    Gaston, Kirk W; Limbach, Patrick A

    2014-01-01

    The analysis of ribonucleic acids (RNA) by mass spectrometry has been a valuable analytical approach for more than 25 years. In fact, mass spectrometry has become a method of choice for the analysis of modified nucleosides from RNA isolated out of biological samples. This review summarizes recent progress that has been made in both nucleoside and oligonucleotide mass spectral analysis. Applications of mass spectrometry in the identification, characterization and quantification of modified nucleosides are discussed. At the oligonucleotide level, advances in modern mass spectrometry approaches combined with the standard RNA modification mapping protocol enable the characterization of RNAs of varying lengths ranging from low molecular weight short interfering RNAs (siRNAs) to the extremely large 23 S rRNAs. New variations and improvements to this protocol are reviewed, including top-down strategies, as these developments now enable qualitative and quantitative measurements of RNA modification patterns in a variety of biological systems. PMID:25616408

  18. A Comprehensive Expression Profile of MicroRNAs and Other Classes of Non-Coding Small RNAs in Barley Under Phosphorous-Deficient and -Sufficient Conditions

    PubMed Central

    Hackenberg, Michael; Huang, Po-Jung; Huang, Chun-Yuan; Shi, Bu-Jun; Gustafson, Perry; Langridge, Peter

    2013-01-01

    Phosphorus (P) is essential for plant growth. MicroRNAs (miRNAs) play a key role in phosphate homeostasis. However, little is known about P effect on miRNA expression in barley (Hordeum vulgare L.). In this study, we used Illumina's next-generation sequencing technology to sequence small RNAs (sRNAs) in barley grown under P-deficient and P-sufficient conditions. We identified 221 conserved miRNAs and 12 novel miRNAs, of which 55 were only present in P-deficient treatment while 32 only existed in P-sufficient treatment. Total 47 miRNAs were significantly differentially expressed between the two P treatments (|log2| > 1). We also identified many other classes of sRNAs, including sense and antisense sRNAs, repeat-associated sRNAs, transfer RNA (tRNA)-derived sRNAs and chloroplast-derived sRNAs, and some of which were also significantly differentially expressed between the two P treatments. Of all the sRNAs identified, antisense sRNAs were the most abundant sRNA class in both P treatments. Surprisingly, about one-fourth of sRNAs were derived from the chloroplast genome, and a chloroplast-encoded tRNA-derived sRNA was the most abundant sRNA of all the sRNAs sequenced. Our data provide valuable clues for understanding the properties of sRNAs and new insights into the potential roles of miRNAs and other classes of sRNAs in the control of phosphate homeostasis. PMID:23266877

  19. Microarray profiling analysis of long non-coding RNAs expression in tendinopathy: identification for potential biomarkers and mechanisms.

    PubMed

    Zhang, Qiang; Ge, Heng'an; Jiang, Yuqing; Cheng, Biao; Zhou, Dong; Xu, Nanwei

    2015-12-01

    The role of lncRNAs in pathologies of tendinopathy has not been researched so far, this study aims to identify the role and potent mechanism of lncRNAs in tendinopathy with a bioinformatic analysis. The gene profile of GSE26051 based on the platform of Affymetrix Human Genome U133B Array condensed was downloaded from Gene Expression Omnibus. A total of 46 specimens (including 23 normal samples and 23 tendinopathy specimens) were available. Compared with the control samples, differentially expressed genes (DEGs) of tendinopathy was identified the by packages in R. The selected DEGs were further analysed using bioinformatics methods including co-expression and enrichment analysis to detect the potential role of lncRNAs. A total of 40 different expressed lncRNAs were identified. However, most of the identified lncRNAs have not been researched before. And this study only annotate one of the identified lncRNAs successfully, the LOC100507027 (myoregulin), with the potential role in regulating skeletal muscle tissue development and skeletal muscle organ development.

  20. Comprehensive Identification of Long Non-coding RNAs in Purified Cell Types from the Brain Reveals Functional LncRNA in OPC Fate Determination

    PubMed Central

    Dong, Xiaomin; Chen, Kenian; Cuevas-Diaz Duran, Raquel; You, Yanan; Sloan, Steven A.; Zhang, Ye; Zong, Shan; Cao, Qilin; Barres, Ben A.; Wu, Jia Qian

    2015-01-01

    Long non-coding RNAs (lncRNAs) (> 200 bp) play crucial roles in transcriptional regulation during numerous biological processes. However, it is challenging to comprehensively identify lncRNAs, because they are often expressed at low levels and with more cell-type specificity than are protein-coding genes. In the present study, we performed ab initio transcriptome reconstruction using eight purified cell populations from mouse cortex and detected more than 5000 lncRNAs. Predicting the functions of lncRNAs using cell-type specific data revealed their potential functional roles in Central Nervous System (CNS) development. We performed motif searches in ENCODE DNase I digital footprint data and Mouse ENCODE promoters to infer transcription factor (TF) occupancy. By integrating TF binding and cell-type specific transcriptomic data, we constructed a novel framework that is useful for systematically identifying lncRNAs that are potentially essential for brain cell fate determination. Based on this integrative analysis, we identified lncRNAs that are regulated during Oligodendrocyte Precursor Cell (OPC) differentiation from Neural Stem Cells (NSCs) and that are likely to be involved in oligodendrogenesis. The top candidate, lnc-OPC, shows highly specific expression in OPCs and remarkable sequence conservation among placental mammals. Interestingly, lnc-OPC is significantly up-regulated in glial progenitors from experimental autoimmune encephalomyelitis (EAE) mouse models compared to wild-type mice. OLIG2-binding sites in the upstream regulatory region of lnc-OPC were identified by ChIP (chromatin immunoprecipitation)-Sequencing and validated by luciferase assays. Loss-of-function experiments confirmed that lnc-OPC plays a functional role in OPC genesis. Overall, our results substantiated the role of lncRNA in OPC fate determination and provided an unprecedented data source for future functional investigations in CNS cell types. We present our datasets and analysis results

  1. RNA-Seq analysis of non-small cell lung cancer in female never-smokers reveals candidate cancer-associated long non-coding RNAs.

    PubMed

    Li, Jun; Bi, Lintao; Shi, Zhangzhen; Sun, Yanxia; Lin, Yumei; Shao, Hui; Zhu, Zhenxing

    2016-06-01

    We aimed to elucidate the potential mechanisms of long non-coding RNAs (lncRNAs) in the progression of non-small cell lung cancer (NSCLC). The microarray datasets of GSE37764, including 3 primary NSCLC tumors and 3 matched normal tissues isolated from 6 Korean female never-smokers, were downloaded from Gene Expression Omnibus database. The differentially expressed lncRNAs and mRNA in NSCLC samples were identified using NOISeq package. Co-expression network of differentially expressed lncRNAs and mRNA was established. Gene Ontology (GO) and pathway enrichment analysis were respectively performed. Finally, lncRNAs related to NSCLC were predicted by blasting the differentially expressed lncRNAs with all predicted lncRNAs related to NSCLC. A total of 182 and 539 differentially expressed lncRNAs and mRNA (109 up- and 73 down-regulated lncRNAs; 307 up- and 232 down-regulated mRNA) were respectively identified. Among them, 4 up-regulated lncRNAs, like lnc-geranylgeranyl diphosphate synthase 1 (GGPS1), lnc-zinc finger protein 793 (ZNF793) and lnc-serine/threonine kinase 4 (STK4), and 4 down-regulated lncRNAs including lnc-LOC284440 and lnc-peptidylprolyl isomerase E-like pseudogene (PPIEL), and lnc-zinc finger protein 461 (ZNF461) were predicted related to NSCLC. lncSSPS1, lnc-ZNF793 and lnc-STK4 were co-expressed with linker for activation of T cells (LAT) and Lck interacting transmembrane adaptor 1 (LIME1). Lnc-LOC284440, lnc-PPIEL and lnc-ZNF461 were co-expressed with Src-like-adaptor 2 (SLA2) and defensin beta 4A (DEFB4A). Our study indicates that immune response may be a crucial mechanism involved in NSCLC progression. Lnc-GGPS1, lnc-ZNF793, lnc-STK4, lnc-LOC284440, lnc-PPIEL, and lnc-ZNF461 may be involved in immune response for promoting NSCLC progression via co-expressing with LAT, LIME1, SLA2 and DEFB4A. Copyright © 2016 Elsevier GmbH. All rights reserved.

  2. Identification of long non-coding RNAs GAS5, linc0597 and lnc-DC in plasma as novel biomarkers for systemic lupus erythematosus.

    PubMed

    Wu, Guo-Cui; Li, Jun; Leng, Rui-Xue; Li, Xiang-Pei; Li, Xiao-Mei; Wang, De-Guang; Pan, Hai-Feng; Ye, Dong-Qing

    2017-04-04

    Despite increasing evidence that long non-coding RNAs (lncRNAs) widely take part in human diseases, the role of lncRNAs in systemic lupus erythematosus (SLE) is largely unknown. In this study, we performed a two-stage study to explore the plasma levels of five lncRNAs (GAS5, linc0949, linc0597, HOTAIRM1 and lnc-DC) and their potential as SLE biomarkers. Compared with healthy controls, plasma levels of GAS5 and lnc-DC were significantly decreased (P < 0.001 and P = 0.002, respectively) while linc0597 were overexpressed in SLE patients (P < 0.001). When SLE patients were divided into SLE without nephritis and lupus nephritis (LN), the levels of lnc-DC were significantly higher in LN compared with SLE without nephritis (P = 0.018), but no significant difference in levels of GAS5 and linc0597 were found between LN and SLE without nephritis; plasma linc0949 level showed no significant difference in all comparisons. Further evaluation on potential biomarkers showed that GAS5, linc0597 and lnc-DC may specifically identify patients with SLE, the combination of GAS5 and linc0597 provided better diagnostic accuracy; lnc-DC may discriminate LN from SLE without nephritis. In summary, GAS5, linc0597 and lnc-DC in plasma could be potential biomarkers for SLE.

  3. LincSNP 2.0: an updated database for linking disease-associated SNPs to human long non-coding RNAs and their TFBSs.

    PubMed

    Ning, Shangwei; Yue, Ming; Wang, Peng; Liu, Yue; Zhi, Hui; Zhang, Yan; Zhang, Jizhou; Gao, Yue; Guo, Maoni; Zhou, Dianshuang; Li, Xin; Li, Xia

    2017-01-04

    We describe LincSNP 2.0 (http://bioinfo.hrbmu.edu.cn/LincSNP), an updated database that is used specifically to store and annotate disease-associated single nucleotide polymorphisms (SNPs) in human long non-coding RNAs (lncRNAs) and their transcription factor binding sites (TFBSs). In LincSNP 2.0, we have updated the database with more data and several new features, including (i) expanding disease-associated SNPs in human lncRNAs; (ii) identifying disease-associated SNPs in lncRNA TFBSs; (iii) updating LD-SNPs from the 1000 Genomes Project; and (iv) collecting more experimentally supported SNP-lncRNA-disease associations. Furthermore, we developed three flexible online tools to retrieve and analyze the data. Linc-Mart is a convenient way for users to customize their own data. Linc-Browse is a tool for all data visualization. Linc-Score predicts the associations between lncRNA and disease. In addition, we provided users a newly designed, user-friendly interface to search and download all the data in LincSNP 2.0 and we also provided an interface to submit novel data into the database. LincSNP 2.0 is a continually updated database and will serve as an important resource for investigating the functions and mechanisms of lncRNAs in human diseases. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. LincSNP 2.0: an updated database for linking disease-associated SNPs to human long non-coding RNAs and their TFBSs

    PubMed Central

    Ning, Shangwei; Yue, Ming; Wang, Peng; Liu, Yue; Zhi, Hui; Zhang, Yan; Zhang, Jizhou; Gao, Yue; Guo, Maoni; Zhou, Dianshuang; Li, Xin; Li, Xia

    2017-01-01

    We describe LincSNP 2.0 (http://bioinfo.hrbmu.edu.cn/LincSNP), an updated database that is used specifically to store and annotate disease-associated single nucleotide polymorphisms (SNPs) in human long non-coding RNAs (lncRNAs) and their transcription factor binding sites (TFBSs). In LincSNP 2.0, we have updated the database with more data and several new features, including (i) expanding disease-associated SNPs in human lncRNAs; (ii) identifying disease-associated SNPs in lncRNA TFBSs; (iii) updating LD-SNPs from the 1000 Genomes Project; and (iv) collecting more experimentally supported SNP-lncRNA-disease associations. Furthermore, we developed three flexible online tools to retrieve and analyze the data. Linc-Mart is a convenient way for users to customize their own data. Linc-Browse is a tool for all data visualization. Linc-Score predicts the associations between lncRNA and disease. In addition, we provided users a newly designed, user-friendly interface to search and download all the data in LincSNP 2.0 and we also provided an interface to submit novel data into the database. LincSNP 2.0 is a continually updated database and will serve as an important resource for investigating the functions and mechanisms of lncRNAs in human diseases. PMID:27924020

  5. Sense overlapping transcripts in IS1341-type transposase genes are functional non-coding RNAs in archaea

    PubMed Central

    Gomes-Filho, José Vicente; Zaramela, Livia Soares; Italiani, Valéria Cristina da Silva; Baliga, Nitin S; Vêncio, Ricardo Z N; Koide, Tie

    2015-01-01

    The existence of sense overlapping transcripts that share regulatory and coding information in the same genomic sequence shows an additional level of prokaryotic gene expression complexity. Here we report the discovery of ncRNAs associated with IS1341-type transposase (tnpB) genes, at the 3'-end of such elements, with examples in archaea and bacteria. Focusing on the model haloarchaeon Halobacterium salinarum NRC-1, we show the existence of sense overlapping transcripts (sotRNAs) for all its IS1341-type transposases. Publicly available transcriptome compendium show condition-dependent differential regulation between sotRNAs and their cognate genes. These sotRNAs allowed us to find a UUCA tetraloop motif that is present in other archaea (ncRNA family HgcC) and in a H. salinarum intergenic ncRNA derived from a palindrome associated transposable elements (PATE). Overexpression of one sotRNA and the PATE-derived RNA harboring the tetraloop motif improved H. salinarum growth, indicating that these ncRNAs are functional. PMID:25806405

  6. DUSP11 - an RNA phosphatase that regulates host and viral non-coding RNAs in mammalian cells.

    PubMed

    Burke, James M; Sullivan, Christopher S

    2017-03-15

    Dual-specificity phosphatase 11 (DUSP11) is a conserved protein tyrosine phosphatase (PTP) in metazoans. The cellular substrates and physiological activities of DUSP11 remain largely unknown. In nematodes, DUSP11 is required for normal development and RNA interference against endogenous RNAs (endo-RNAi) via molecular mechanisms that are not well understood. However, mammals lack analogous endo-RNAi pathways and consequently, a role for DUSP11 in mammalian RNA silencing was unanticipated. Recent work from our lab demonstrated that DUSP11 activity alters the silencing potential of noncanonical viral miRNAs in mammalian cells. Our studies further uncovered direct cellular substrates of DUSP11 and suggest that DUSP11 is part of regulatory pathway that controls the abundance of select triphosphorylated noncoding RNAs. Here, we highlight recent findings and present new data that advance understanding of mammalian DUSP11 during gene silencing and discuss the emerging biological activities of DUSP11 in mammalian cells.

  7. Analysis of Microarray Data on Gene Expression and Methylation to Identify Long Non-coding RNAs in Non-small Cell Lung Cancer

    PubMed Central

    Feng, Nannan; Ching, Travers; Wang, Yu; Liu, Ben; Lin, Hongyan; Shi, Oumin; Zhang, Xiaohong; Zheng, Min; Zheng, Xin; Gao, Ming; Zheng, Zhi-jie; Yu, Herbert; Garmire, Lana; Qian, Biyun

    2016-01-01

    To identify what long non-coding RNAs (lncRNAs) are involved in non-small cell lung cancer (NSCLC), we analyzed microarray data on gene expression and methylation. Gene expression chip and HumanMethylation450BeadChip were used to interrogate genome-wide expression and methylation in tumor samples. Differential expression and methylation were analyzed through comparing tumors with adjacent non-tumor tissues. LncRNAs expressed differentially and correlated with coding genes and DNA methylation were validated in additional tumor samples using RT-qPCR and pyrosequencing. In vitro experiments were performed to evaluate lncRNA’s effects on tumor cells. We identified 8,500 lncRNAs expressed differentially between tumor and non-tumor tissues, of which 1,504 were correlated with mRNA expression. Two of the lncRNAs, LOC146880 and ENST00000439577, were positively correlated with expression of two cancer-related genes, KPNA2 and RCC2, respectively. High expression of LOC146880 and ENST00000439577 were also associated with poor survival. Analysis of lncRNA expression in relation to DNA methylation showed that LOC146880 expression was down-regulated by DNA methylation in its promoter. Lowering the expression of LOC146880 or ENST00000439577 in tumor cells could inhibit cell proliferation, invasion and migration. Analysis of microarray data on gene expression and methylation allows us to identify two lncRNAs, LOC146880 and ENST00000439577, which may promote the progression of NSCLC. PMID:27849024

  8. Non Coding RNAs and Viruses in the Framework of the Phylogeny of the Genes, Epigenesis and Heredity

    PubMed Central

    Frías-Lasserre, Daniel

    2012-01-01

    The origin of genes is one of the most enigmatic events in the origin of life. It has been suggested that noncoding (nc) RNA was probably a precursor in the formation of the first polypeptide, and also at the origin of the first manifestation of life and genes. ncRNAs are also becoming central for understanding gene expression and silencing. Indeed, before the discovery of ncRNAs, proteins were viewed as the major molecules in the regulation of gene expression and gene silencing; however, recent findings suggest that ncRNA also plays an important role in gene expression. Reverse transcription of RNA viruses and their integration into the genome of eukaryotes and also their relationship with the ncRNA suggest that their origin is basal in genome evolution, and also probably constitute the first mechanism of gene regulation. I am to review the different roles of ncRNAs in the framework of gene evolution, as well as the importance of ncRNAs and viruses in the epigenesis and in the non-Mendelian model of heredity and evolution. PMID:22312265

  9. Combined identification of long non-coding RNA CCAT1 and HOTAIR in serum as an effective screening for colorectal carcinoma.

    PubMed

    Zhao, Weimin; Song, Mu; Zhang, Jie; Kuerban, Mulati; Wang, Haijiang

    2015-01-01

    Long non-coding RNAs (lncRNAs) CCAT1 and HOTAIR have been shown to play an important regulatory role in cancer biology, and CCAT1 and HOTAIR are upregulated in several cancers, however, its value in the diagnosis of colorectal cancer (CRC) is unclear. Therefore, the aim of this study is to evaluate the clinical significance of plasma CCAT1 and HOTAIR as a biomarker in the screening of CRC. In our study, we found that the levels of HOTAIR (P < 0.05) and CCAT1 (P < 0.05) were significantly higher in plasma of CRC patients than that of the healthy control. Moreover, the levels of lincRNA-p21 (P < 0.05) were obviously decreased in plasma of CRC patients as compared to those of healthy control. There was highly correlated for CCAT1 (R = 0.752, mean differences = -0.06 ± 1.20), HOTAIR (R = 0.739, mean differences = -0.26 ± 0.76) and lincRNA-p21 (R = 0.848, mean differences = -0.41 ± 0.89) in plasma and serum. By receiver operating characteristic curve (ROC) analysis, plasma CCAT1 provided the higher diagnostic performance for detection of CRC (the area under the ROC curve (AUC), 0.836; P < 0.001; sensitivity, 75.7%; specificity, 85.3%). Moreover, CCAT1 combining with HOTAIR could provide a more effective diagnosis performance (AUC, 0.954, P < 0.001, sensitivity, 84.3%; specificity, 80.2%). Most importantly, this combination was effective to detect CRC at an early stage (85%). In conclusion, our results demonstrated that increased plasma HOTAIR and CCAT1 could be used as a predictive biomarker for CRC screening, and that combination of HOTAIR and CCAT1 had a higher positive diagnostic rate of CRC than HOTAIR or CCAT1 alone.

  10. Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells

    PubMed Central

    Li, Cheryl CY; Eaton, Sally A; Young, Paul E; Lee, Maggie; Shuttleworth, Rupert; Humphreys, David T; Grau, Georges E; Combes, Valery; Bebawy, Mary; Gong, Joyce; Brammah, Susan; Buckland, Michael E; Suter, Catherine M

    2013-01-01

    Interactions between glioma cells and their local environment are critical determinants of brain tumor growth, infiltration and neovascularisation. Communication with host cells and stroma via microvesicles represents one pathway by which tumors can modify their surroundings to achieve a tumor-permissive environment. Here we have taken an unbiased approach to identifying RNAs in glioma-derived microvesicles, and explored their potential to regulate gene expression in recipient cells. We find that glioma microvesicles are predominantly of exosomal origin and contain complex populations of coding and noncoding RNAs in proportions that are distinct from those in the cells from which they are derived. Microvesicles show a relative depletion in microRNA compared with their cells of origin, and are enriched in unusual or novel noncoding RNAs, most of which have no known function. Short-term exposure of brain microvascular endothelial cells to glioma microvesicles results in many gene expression changes in the endothelial cells, most of which cannot be explained by direct delivery of transcripts. Our data suggest that the scope of potential actions of tumor-derived microvesicles is much broader and more complex than previously supposed, and highlight a number of new classes of small RNA that remain to be characterized. PMID:23807490

  11. Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells.

    PubMed

    Li, Cheryl C Y; Eaton, Sally A; Young, Paul E; Lee, Maggie; Shuttleworth, Rupert; Humphreys, David T; Grau, Georges E; Combes, Valery; Bebawy, Mary; Gong, Joyce; Brammah, Susan; Buckland, Michael E; Suter, Catherine M

    2013-08-01

    Interactions between glioma cells and their local environment are critical determinants of brain tumor growth, infiltration and neovascularisation. Communication with host cells and stroma via microvesicles represents one pathway by which tumors can modify their surroundings to achieve a tumor-permissive environment. Here we have taken an unbiased approach to identifying RNAs in glioma-derived microvesicles, and explored their potential to regulate gene expression in recipient cells. We find that glioma microvesicles are predominantly of exosomal origin and contain complex populations of coding and noncoding RNAs in proportions that are distinct from those in the cells from which they are derived. Microvesicles show a relative depletion in microRNA compared with their cells of origin, and are enriched in unusual or novel noncoding RNAs, most of which have no known function. Short-term exposure of brain microvascular endothelial cells to glioma microvesicles results in many gene expression changes in the endothelial cells, most of which cannot be explained by direct delivery of transcripts. Our data suggest that the scope of potential actions of tumor-derived microvesicles is much broader and more complex than previously supposed, and highlight a number of new classes of small RNA that remain to be characterized.

  12. Identification and characterization of the gene expression profiles for protein coding and non-coding RNAs of pancreatic ductal adenocarcinomas

    PubMed Central

    Gutiérrez, María Laura; Corchete, Luis; Teodosio, Cristina; Sarasquete, María Eugenia; Abad, María del Mar; Iglesias, Manuel; Esteban, Carmen

    2015-01-01

    Significant advances have been achieved in recent years in the identification of the genetic and the molecular alterations of pancreatic ductal adenocarcinoma (PDAC). Despite this, at present the understanding of the precise mechanisms involved in the development and malignant transformation of PDAC remain relatively limited. Here, we evaluated for the first time, the molecular heterogeneity of PDAC tumors, through simultaneous assessment of the gene expression profile (GEP) for both coding and non-coding genes of tumor samples from 27 consecutive PDAC patients. Overall, we identified a common GEP for all PDAC tumors, characterized by an increased expression of genes involved in PDAC cell proliferation, local invasion and metastatic capacity, together with a significant alteration of the early steps of the cellular immune response. At the same time, we confirm and extend on previous observations about the genetic complexity of PDAC tumors as revealed by the demonstration of two clearly distinct and unique GEPs (e.g. epithelial-like vs. mesenchymal-like) reflecting the alteration of different signaling pathways involved in the oncogenesis and progression of these tumors. Our results also highlight the potential role of the immune system microenvironment in these tumors, with potential diagnostic and therapeutic implications. PMID:26053098

  13. Consensus Analysis of Whole Transcriptome Profiles from Two Breast Cancer Patient Cohorts Reveals Long Non-Coding RNAs Associated with Intrinsic Subtype and the Tumour Microenvironment.

    PubMed

    Bradford, James R; Cox, Angela; Bernard, Philip; Camp, Nicola J

    Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes and diseases such as cancer; however, their functions remain poorly characterised. Several studies have demonstrated that lncRNAs are typically disease and tumour subtype specific, particularly in breast cancer where lncRNA expression alone is sufficient to discriminate samples based on hormone status and molecular intrinsic subtype. However, little attempt has been made to assess the reproducibility of lncRNA signatures across more than one dataset. In this work, we derive consensus lncRNA signatures indicative of breast cancer subtype based on two clinical RNA-Seq datasets: the Utah Breast Cancer Study and The Cancer Genome Atlas, through integration of differential expression and hypothesis-free clustering analyses. The most consistent signature is associated with breast cancers of the basal-like subtype, leading us to generate a putative set of six lncRNA basal-like breast cancer markers, at least two of which may have a role in cis-regulation of known poor prognosis markers. Through in silico functional characterization of individual signatures and integration of expression data from pre-clinical cancer models, we discover that discordance between signatures derived from different clinical cohorts can arise from the strong influence of non-cancerous cells in tumour samples. As a consequence, we identify nine lncRNAs putatively associated with breast cancer associated fibroblasts, or the immune response. Overall, our study establishes the confounding effects of tumour purity on lncRNA signature derivation, and generates several novel hypotheses on the role of lncRNAs in basal-like breast cancers and the tumour microenvironment.

  14. ChIPBase v2.0: decoding transcriptional regulatory networks of non-coding RNAs and protein-coding genes from ChIP-seq data

    PubMed Central

    Zhou, Ke-Ren; Liu, Shun; Sun, Wen-Ju; Zheng, Ling-Ling; Zhou, Hui; Yang, Jian-Hua; Qu, Liang-Hu

    2017-01-01

    The abnormal transcriptional regulation of non-coding RNAs (ncRNAs) and protein-coding genes (PCGs) is contributed to various biological processes and linked with human diseases, but the underlying mechanisms remain elusive. In this study, we developed ChIPBase v2.0 (http://rna.sysu.edu.cn/chipbase/) to explore the transcriptional regulatory networks of ncRNAs and PCGs. ChIPBase v2.0 has been expanded with ∼10 200 curated ChIP-seq datasets, which represent about 20 times expansion when comparing to the previous released version. We identified thousands of binding motif matrices and their binding sites from ChIP-seq data of DNA-binding proteins and predicted millions of transcriptional regulatory relationships between transcription factors (TFs) and genes. We constructed ‘Regulator’ module to predict hundreds of TFs and histone modifications that were involved in or affected transcription of ncRNAs and PCGs. Moreover, we built a web-based tool, Co-Expression, to explore the co-expression patterns between DNA-binding proteins and various types of genes by integrating the gene expression profiles of ∼10 000 tumor samples and ∼9100 normal tissues and cell lines. ChIPBase also provides a ChIP-Function tool and a genome browser to predict functions of diverse genes and visualize various ChIP-seq data. This study will greatly expand our understanding of the transcriptional regulations of ncRNAs and PCGs. PMID:27924033

  15. ChIPBase v2.0: decoding transcriptional regulatory networks of non-coding RNAs and protein-coding genes from ChIP-seq data.

    PubMed

    Zhou, Ke-Ren; Liu, Shun; Sun, Wen-Ju; Zheng, Ling-Ling; Zhou, Hui; Yang, Jian-Hua; Qu, Liang-Hu

    2017-01-04

    The abnormal transcriptional regulation of non-coding RNAs (ncRNAs) and protein-coding genes (PCGs) is contributed to various biological processes and linked with human diseases, but the underlying mechanisms remain elusive. In this study, we developed ChIPBase v2.0 (http://rna.sysu.edu.cn/chipbase/) to explore the transcriptional regulatory networks of ncRNAs and PCGs. ChIPBase v2.0 has been expanded with ∼10 200 curated ChIP-seq datasets, which represent about 20 times expansion when comparing to the previous released version. We identified thousands of binding motif matrices and their binding sites from ChIP-seq data of DNA-binding proteins and predicted millions of transcriptional regulatory relationships between transcription factors (TFs) and genes. We constructed 'Regulator' module to predict hundreds of TFs and histone modifications that were involved in or affected transcription of ncRNAs and PCGs. Moreover, we built a web-based tool, Co-Expression, to explore the co-expression patterns between DNA-binding proteins and various types of genes by integrating the gene expression profiles of ∼10 000 tumor samples and ∼9100 normal tissues and cell lines. ChIPBase also provides a ChIP-Function tool and a genome browser to predict functions of diverse genes and visualize various ChIP-seq data. This study will greatly expand our understanding of the transcriptional regulations of ncRNAs and PCGs. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Consensus Analysis of Whole Transcriptome Profiles from Two Breast Cancer Patient Cohorts Reveals Long Non-Coding RNAs Associated with Intrinsic Subtype and the Tumour Microenvironment

    PubMed Central

    Cox, Angela; Bernard, Philip; Camp, Nicola J.

    2016-01-01

    Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes and diseases such as cancer; however, their functions remain poorly characterised. Several studies have demonstrated that lncRNAs are typically disease and tumour subtype specific, particularly in breast cancer where lncRNA expression alone is sufficient to discriminate samples based on hormone status and molecular intrinsic subtype. However, little attempt has been made to assess the reproducibility of lncRNA signatures across more than one dataset. In this work, we derive consensus lncRNA signatures indicative of breast cancer subtype based on two clinical RNA-Seq datasets: the Utah Breast Cancer Study and The Cancer Genome Atlas, through integration of differential expression and hypothesis-free clustering analyses. The most consistent signature is associated with breast cancers of the basal-like subtype, leading us to generate a putative set of six lncRNA basal-like breast cancer markers, at least two of which may have a role in cis-regulation of known poor prognosis markers. Through in silico functional characterization of individual signatures and integration of expression data from pre-clinical cancer models, we discover that discordance between signatures derived from different clinical cohorts can arise from the strong influence of non-cancerous cells in tumour samples. As a consequence, we identify nine lncRNAs putatively associated with breast cancer associated fibroblasts, or the immune response. Overall, our study establishes the confounding effects of tumour purity on lncRNA signature derivation, and generates several novel hypotheses on the role of lncRNAs in basal-like breast cancers and the tumour microenvironment. PMID:27685983

  17. Genetic polymorphisms of non-coding RNAs associated with increased head and neck cancer susceptibility: a systematic review and meta-analysis.

    PubMed

    Pan, Weiyi; Wu, Chenzhou; Su, Zhifei; Duan, Zexi; Li, Longjiang; Mi, Fanglin; Li, Chunjie

    2017-09-22

    Genetic polymorphisms, including single nucleotide polymorphisms (SNP) and nucleotide repeat expansions, can occur in regions that transcribe non-coding RNAs (ncRNA), such as, but not limited to, micro RNA and long non-coding RNA. An association between genetic polymorphisms of ncRNA and increasing head and neck cancer (HNC) risk has been identified by several studies. Therefore, the aim of this systematic review is to consolidate existing findings to clarify this association. Four electronic databases, such as MEDLINE, EMBASE, Chinese BioMedical Literature Database, and China National Knowledge Infrastructure, were utilised. Inclusion of studies and data extraction were accomplished in duplicate. A total of 42 eligible studies were included, involving 28,527 cases and 37,151 controls. Meta-analysis, sensitivity analysis and publication bias detection were performed. Among the eligible studies, 102 SNPs were investigated, and 21 of them were considered eligible for meta-analysis. Our analysis revealed that HOTAIR rs920778, uc003opf.1 rs11752942, and miR-196a2 rs11614913 were related to HNC susceptibility, while let-7 rs10877887, miR-124-1rs531564, and miR-608 rs4919510 were considered as protective factors. In conclusion, our results showed the extreme importance of an up-to-date comprehensive meta-analysis encompassing the most recent findings to obtain a relevant and reliable framework to understand the relationship between ncRNA SNPs and HNC susceptibility.

  18. In Silico identification and annotation of non-coding RNAs by RNA-seq and De Novo assembly of the transcriptome of Tomato Fruits

    PubMed Central

    Scarano, Daria; Rao, Rosa; Corrado, Giandomenico

    2017-01-01

    The complexity of the tomato (Solanum lycopersicum) transcriptome has not yet been fully elucidated. To gain insights into the diversity and features of coding and non-coding RNA molecules of tomato fruits, we generated strand-specific libraries from berries of two tomato cultivars grown in two open-field conditions with different soil type. Following high-throughput Illumina RNA-sequencing (RNA-seq), more than 90% of the reads (over one billion, derived from twelve dataset) were aligned to the tomato reference genome. We report a comprehensive analysis of the transcriptome, improved with 39,095 transcripts, which reveals previously unannotated novel transcripts, natural antisense transcripts, long non-coding RNAs and alternative splicing variants. In addition, we investigated the sequence variants between the cultivars under investigation to highlight their genetic difference. Our strand-specific analysis allowed us to expand the current tomato transcriptome annotation and it is the first to reveal the complexity of the poly-adenylated RNA world in tomato. Moreover, our work demonstrates the usefulness of strand specific RNA-seq approach for the transcriptome-based genome annotation and provides a resource valuable for further functional studies. PMID:28187155

  19. In Silico identification and annotation of non-coding RNAs by RNA-seq and De Novo assembly of the transcriptome of Tomato Fruits.

    PubMed

    Scarano, Daria; Rao, Rosa; Corrado, Giandomenico

    2017-01-01

    The complexity of the tomato (Solanum lycopersicum) transcriptome has not yet been fully elucidated. To gain insights into the diversity and features of coding and non-coding RNA molecules of tomato fruits, we generated strand-specific libraries from berries of two tomato cultivars grown in two open-field conditions with different soil type. Following high-throughput Illumina RNA-sequencing (RNA-seq), more than 90% of the reads (over one billion, derived from twelve dataset) were aligned to the tomato reference genome. We report a comprehensive analysis of the transcriptome, improved with 39,095 transcripts, which reveals previously unannotated novel transcripts, natural antisense transcripts, long non-coding RNAs and alternative splicing variants. In addition, we investigated the sequence variants between the cultivars under investigation to highlight their genetic difference. Our strand-specific analysis allowed us to expand the current tomato transcriptome annotation and it is the first to reveal the complexity of the poly-adenylated RNA world in tomato. Moreover, our work demonstrates the usefulness of strand specific RNA-seq approach for the transcriptome-based genome annotation and provides a resource valuable for further functional studies.

  20. Short non-coding RNAs as bacteria species identifiers detected by surface plasmon resonance enhanced common path interferometry

    NASA Astrophysics Data System (ADS)

    Greef, Charles; Petropavlovskikh, Viatcheslav; Nilsen, Oyvind; Khattatov, Boris; Plam, Mikhail; Gardner, Patrick; Hall, John

    2008-04-01

    Small non-coding RNA sequences have recently been discovered as unique identifiers of certain bacterial species, raising the possibility that they can be used as highly specific Biowarfare Agent detection markers in automated field deployable integrated detection systems. Because they are present in high abundance they could allow genomic based bacterial species identification without the need for pre-assay amplification. Further, a direct detection method would obviate the need for chemical labeling, enabling a rapid, efficient, high sensitivity mechanism for bacterial detection. Surface Plasmon Resonance enhanced Common Path Interferometry (SPR-CPI) is a potentially market disruptive, high sensitivity dual technology that allows real-time direct multiplex measurement of biomolecule interactions, including small molecules, nucleic acids, proteins, and microbes. SPR-CPI measures differences in phase shift of reflected S and P polarized light under Total Internal Reflection (TIR) conditions at a surface, caused by changes in refractive index induced by biomolecular interactions within the evanescent field at the TIR interface. The measurement is performed on a microarray of discrete 2-dimensional areas functionalized with biomolecule capture reagents, allowing simultaneous measurement of up to 100 separate analytes. The optical beam encompasses the entire microarray, allowing a solid state detector system with no scanning requirement. Output consists of simultaneous voltage measurements proportional to the phase differences resulting from the refractive index changes from each microarray feature, and is automatically processed and displayed graphically or delivered to a decision making algorithm, enabling a fully automatic detection system capable of rapid detection and quantification of small nucleic acids at extremely sensitive levels. Proof-of-concept experiments on model systems and cell culture samples have demonstrated utility of the system, and efforts are in

  1. Identification of an ortholog of the eukaryotic RNA polymerase III subunit RPC34 in Crenarchaeota and Thaumarchaeota suggests specialization of RNA polymerases for coding and non-coding RNAs in Archaea.

    PubMed

    Blombach, Fabian; Makarova, Kira S; Marrero, Jeannette; Siebers, Bettina; Koonin, Eugene V; van der Oost, John

    2009-10-14

    One of the hallmarks of eukaryotic information processing is the co-existence of 3 distinct, multi-subunit RNA polymerase complexes that are dedicated to the transcription of specific classes of coding or non-coding RNAs. Archaea encode only one RNA polymerase that resembles the eukaryotic RNA polymerase II with respect to the subunit composition. Here we identify archaeal orthologs of the eukaryotic RNA polymerase III subunit RPC34. Genome context analysis supports a function of this archaeal protein in the transcription of non-coding RNAs. These findings suggest that functional separation of RNA polymerases for protein-coding genes and non-coding RNAs might predate the origin of the Eukaryotes.

  2. Identification of an ortholog of the eukaryotic RNA polymerase III subunit RPC34 in Crenarchaeota and Thaumarchaeota suggests specialization of RNA polymerases for coding and non-coding RNAs in Archaea

    PubMed Central

    Blombach, Fabian; Makarova, Kira S; Marrero, Jeannette; Siebers, Bettina; Koonin, Eugene V; Oost, John van der

    2009-01-01

    One of the hallmarks of eukaryotic information processing is the co-existence of 3 distinct, multi-subunit RNA polymerase complexes that are dedicated to the transcription of specific classes of coding or non-coding RNAs. Archaea encode only one RNA polymerase that resembles the eukaryotic RNA polymerase II with respect to the subunit composition. Here we identify archaeal orthologs of the eukaryotic RNA polymerase III subunit RPC34. Genome context analysis supports a function of this archaeal protein in the transcription of non-coding RNAs. These findings suggest that functional separation of RNA polymerases for protein-coding genes and non-coding RNAs might predate the origin of the Eukaryotes. Reviewers: This article was reviewed by Andrei Osterman and Patrick Forterre (nominated by Purificación López-García) PMID:19828044

  3. Emerging Putative Associations between Non-Coding RNAs and Protein-Coding Genes in Neuropathic Pain: Added Value from Reusing Microarray Data

    PubMed Central

    Raju, Hemalatha B.; Tsinoremas, Nicholas F.; Capobianco, Enrico

    2016-01-01

    Regeneration of injured nerves is likely occurring in the peripheral nervous system, but not in the central nervous system. Although protein-coding gene expression has been assessed during nerve regeneration, little is currently known about the role of non-coding RNAs (ncRNAs). This leaves open questions about the potential effects of ncRNAs at transcriptome level. Due to the limited availability of human neuropathic pain (NP) data, we have identified the most comprehensive time-course gene expression profile referred to sciatic nerve (SN) injury and studied in a rat model using two neuronal tissues, namely dorsal root ganglion (DRG) and SN. We have developed a methodology to identify differentially expressed bioentities starting from microarray probes and repurposing them to annotate ncRNAs, while analyzing the expression profiles of protein-coding genes. The approach is designed to reuse microarray data and perform first profiling and then meta-analysis through three main steps. First, we used contextual analysis to identify what we considered putative or potential protein-coding targets for selected ncRNAs. Relevance was therefore assigned to differential expression of neighbor protein-coding genes, with neighborhood defined by a fixed genomic distance from long or antisense ncRNA loci, and of parental genes associated with pseudogenes. Second, connectivity among putative targets was used to build networks, in turn useful to conduct inference at interactomic scale. Last, network paths were annotated to assess relevance to NP. We found significant differential expression in long-intergenic ncRNAs (32 lincRNAs in SN and 8 in DRG), antisense RNA (31 asRNA in SN and 12 in DRG), and pseudogenes (456 in SN and 56 in DRG). In particular, contextual analysis centered on pseudogenes revealed some targets with known association to neurodegeneration and/or neurogenesis processes. While modules of the olfactory receptors were clearly identified in protein

  4. Non-coding MicroRNAs hsa-let-7g and hsa-miR-181b are Associated with Chemoresponse to S-1 in Colon Cancer.

    PubMed

    Nakajima, Go; Hayashi, Kazuhiko; Xi, Yaguang; Kudo, Kenji; Uchida, Kazumi; Takasaki, Ken; Yamamoto, Masakazu; Ju, Jingfang

    2006-10-01

    BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs (~22 nucleotides) that regulate gene expression at a post-transcriptional level via imperfect base pairing to the 3'-UTR of their target mRNAs. Previous studies from our group identified a number of deregulated miRNAs due to the loss of p53 tumor suppressor in colon cancer cell lines. To further investigate the in vivo biological significance of these miRNAs, the expressions of hsa-let-7g, hsa-miR-143, hsa-miR-145, hsa-miR-181b and hsa-miR-200c were investigated using formalin-fixed paraffin-embedded (FFPE) colon cancer specimens to evaluate the potential relationship with chemosensitivity and tumorigenesis. PATIENTS AND METHODS: Forty-six patients with recurrent or residual colon cancer lesions were treated with the 5-fluorouracil-based antimetabolite S-1. This includes twenty-one pairs of tumor and normal samples. Total RNAs were isolated and the expression level of each particular miRNA was quantified using real time qRT-PCR analysis. RESULTS: The expression levels of hsa-let-7g, hsa-miR-181b and hsa-miR-200c were over-expressed in tumor tissues compared to normal tissues. The expression levels of hsa-let-7g (p=0.03; Mann-Whitney test) and hsa-miR-181b (p=0.02; Mann-Whitney test) were strongly associated with clinical response to S-1. Although hsa-let-7g and hsa-miR-181b are strongly associated with patient's response to S-1 treatment, they are not significant prognostic factors for predicting survival. CONCLUSION: hsa-let-7g, hsa-miR-181b and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g and hsa-miR-181b may be potential indicators for chemoresponse to S-1 based chemotherapy.

  5. Co-expressed differentially expressed genes and long non-coding RNAs involved in the celecoxib treatment of gastric cancer: An RNA sequencing analysis

    PubMed Central

    Song, Bin; Du, Juan; Feng, Ye; Gao, Yong-Jian; Zhao, Ji-Sheng

    2016-01-01

    The aim of the present study was to investigate the mechanisms of long non-coding RNAs (lncRNAs) in a gastric cancer cell line treated with celecoxib. The human gastric carcinoma cell line NCI-N87 was treated with 15 µM celecoxib for 72 h (celecoxib group) and an equal volume of dimethylsulfoxide (control group), respectively. Libraries were constructed by NEBNext Ultra RNA Library Prep kit for Illumina. Paired-end RNA sequencing reads were aligned to a human hg19 reference genome using TopHat2. Differentially expressed genes (DEGs) and lncRNAs were identified using Cuffdiff. Enrichment analysis was performed using GO-function package and KEGG profile in Bioconductor. A protein-protein interaction network was constructed using STRING database and module analysis was performed using ClusterONE plugin of Cytoscape. ATP5G1, ATP5G3, COX8A, CYC1, NDUFS3, UQCRC1, UQCRC2 and UQCRFS1 were enriched in the oxidative phosphorylation pathway. CXCL1, CXCL3, CXCL5 and CXCL8 were enriched in the chemokine signaling and cytokine-cytokine receptor interaction pathways. ITGA3, ITGA6, ITGB4, ITGB5, ITGB6 and ITGB8 were enriched in the integrin-mediated signaling pathway. DEGs co-expressed with lnc-SCD-1:13, lnc-LRR1-1:2, lnc-PTMS-1:3, lnc-S100P-3:1, lnc-AP000974.1-1:1 and lnc-RAB3IL1-2:1 were enriched in the pathways associated with cancer, such as the basal cell carcinoma pathway in cancer. In conclusion, these DEGs and differentially expressed lncRNAs may be important in the celecoxib treatment of gastric cancer. PMID:27698747

  6. Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome

    PubMed Central

    Ravasi, Timothy; Suzuki, Harukazu; Pang, Ken C.; Katayama, Shintaro; Furuno, Masaaki; Okunishi, Rie; Fukuda, Shiro; Ru, Kelin; Frith, Martin C.; Gongora, M. Milena; Grimmond, Sean M.; Hume, David A.; Hayashizaki, Yoshihide; Mattick, John S.

    2006-01-01

    Recent large-scale analyses of mainly full-length cDNA libraries generated from a variety of mouse tissues indicated that almost half of all representative cloned sequences did not contain an apparent protein-coding sequence, and were putatively derived from non-protein-coding RNA (ncRNA) genes. However, many of these clones were singletons and the majority were unspliced, raising the possibility that they may be derived from genomic DNA or unprocessed pre-mRNA contamination during library construction, or alternatively represent nonspecific “transcriptional noise.” Here we show, using reverse transcriptase-dependent PCR, microarray, and Northern blot analyses, that many of these clones were derived from genuine transcripts of unknown function whose expression appears to be regulated. The ncRNA transcripts have larger exons and fewer introns than protein-coding transcripts. Analysis of the genomic landscape around these sequences indicates that some cDNA clones were produced not from terminal poly(A) tracts but internal priming sites within longer transcripts, only a minority of which is encompassed by known genes. A significant proportion of these transcripts exhibit tissue-specific expression patterns, as well as dynamic changes in their expression in macrophages following lipopolysaccharide stimulation. Taken together, the data provide strong support for the conclusion that ncRNAs are an important, regulated component of the mammalian transcriptome. PMID:16344565

  7. Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs

    PubMed Central

    Łabno, Anna; Warkocki, Zbigniew; Kuliński, Tomasz; Krawczyk, Paweł Szczepan; Bijata, Krystian; Tomecki, Rafał; Dziembowski, Andrzej

    2016-01-01

    The exosome-independent exoribonuclease DIS3L2 is mutated in Perlman syndrome. Here, we used extensive global transcriptomic and targeted biochemical analyses to identify novel DIS3L2 substrates in human cells. We show that DIS3L2 regulates pol II transcripts, comprising selected canonical and histone-coding mRNAs, and a novel FTL_short RNA from the ferritin mRNA 5′ UTR. Importantly, DIS3L2 contributes to surveillance of maturing snRNAs during their cytoplasmic processing. Among pol III transcripts, DIS3L2 particularly targets vault and Y RNAs and an Alu-like element BC200 RNA, but not Alu repeats, which are removed by exosome-associated DIS3. Using 3′ RACE-Seq, we demonstrate that all novel DIS3L2 substrates are uridylated in vivo by TUT4/TUT7 poly(U) polymerases. Uridylation-dependent DIS3L2-mediated decay can be recapitulated in vitro, thus reinforcing the tight cooperation between DIS3L2 and TUTases. Together these results indicate that catalytically inactive DIS3L2, characteristic of Perlman syndrome, can lead to deregulation of its target RNAs to disturb transcriptome homeostasis. PMID:27431325

  8. Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency.

    PubMed

    Rodie, M E; Mudaliar, M A V; Herzyk, P; McMillan, M; Boroujerdi, M; Chudleigh, S; Tobias, E S; Ahmed, S F

    2017-10-01

    It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC). To explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation. Median pre- and post-hCG testosterone for the overall group was 0.7 nmol/L (<0.5, 6) and 7.9 nmol/L (<0.5, 31.5), respectively. Of the 12 boys, 3 (25%) did not respond to hCG stimulation with a pre and post median serum testosterone of <0.5 nmol/L and <0.5 nmol/L, respectively. When corrected for gene expression changes in the non-responders to exclude hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR-37153 and piR-39248, non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5. On comparing fold-change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 (P = 0.01). The identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency. © 2017 The authors.

  9. The Bacteriophage Carrier State of Campylobacter jejuni Features Changes in Host Non-coding RNAs and the Acquisition of New Host-derived CRISPR Spacer Sequences

    PubMed Central

    Hooton, Steven P. T.; Brathwaite, Kelly J.; Connerton, Ian F.

    2016-01-01

    Incorporation of self-derived CRISPR DNA protospacers in Campylobacter jejuni PT14 occurs in the presence of bacteriophages encoding a CRISPR-like Cas4 protein. This phenomenon was evident in carrier state infections where both bacteriophages and host are maintained for seemingly indefinite periods as stable populations following serial passage. Carrier state cultures of C. jejuni PT14 have greater aerotolerance in nutrient limited conditions, and may have arisen as an evolutionary response to selective pressures imposed during periods in the extra-intestinal environment. A consequence of this is that bacteriophage and host remain associated and able to survive transition periods where the chances of replicative success are greatly diminished. The majority of the bacteriophage population do not commit to lytic infection, and conversely the bacterial population tolerates low-level bacteriophage replication. We recently examined the effects of Campylobacter bacteriophage/C. jejuni PT14 CRISPR spacer acquisition using deep sequencing strategies of DNA and RNA-Seq to analyze carrier state cultures. This approach identified de novo spacer acquisition in C. jejuni PT14 associated with Class III Campylobacter phages CP8/CP30A but spacer acquisition was oriented toward the capture of host DNA. In the absence of bacteriophage predation the CRISPR spacers in uninfected C. jejuni PT14 cultures remain unchanged. A distinct preference was observed for incorporation of self-derived protospacers into the third spacer position of the C. jejuni PT14 CRISPR array, with the first and second spacers remaining fixed. RNA-Seq also revealed the variation in the synthesis of non-coding RNAs with the potential to bind bacteriophage genes and/or transcript sequences. PMID:27047470

  10. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis

    PubMed Central

    Pirola, Carlos J; Gianotti, Tomas Fernández; Castaño, Gustavo O; Mallardi, Pablo; Martino, Julio San; Ledesma, María Mora Gonzalez Lopez; Flichman, Diego; Mirshahi, Faridodin; Sanyal, Arun J; Sookoian, Silvia

    2014-01-01

    Objectives We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome. Methods The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls. Results Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity. Conclusions miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk. PMID:24973316

  11. Genome-wide detection of predicted non-coding RNAs in Rhizobium etli expressed during free-living and host-associated growth using a high-resolution tiling array

    PubMed Central

    2010-01-01

    Background Non-coding RNAs (ncRNAs) play a crucial role in the intricate regulation of bacterial gene expression, allowing bacteria to quickly adapt to changing environments. In the past few years, a growing number of regulatory RNA elements have been predicted by computational methods, mostly in well-studied γ-proteobacteria but lately in several α-proteobacteria as well. Here, we have compared an extensive compilation of these non-coding RNA predictions to intergenic expression data of a whole-genome high-resolution tiling array in the soil-dwelling α-proteobacterium Rhizobium etli. Results Expression of 89 candidate ncRNAs was detected, both on the chromosome and on the six megaplasmids encompassing the R. etli genome. Of these, 11 correspond to functionally well characterized ncRNAs, 12 were previously identified in other α-proteobacteria but are as yet uncharacterized and 66 were computationally predicted earlier but had not been experimentally identified and were therefore classified as novel ncRNAs. The latter comprise 17 putative sRNAs and 49 putative cis-regulatory ncRNAs. A selection of these candidate ncRNAs was validated by RT-qPCR, Northern blotting and 5' RACE, confirming the existence of 4 ncRNAs. Interestingly, individual transcript levels of numerous ncRNAs varied during free-living growth and during interaction with the eukaryotic host plant, pointing to possible ncRNA-dependent regulation of these specialized processes. Conclusions Our data support the practical value of previous ncRNA prediction algorithms and significantly expand the list of candidate ncRNAs encoded in the intergenic regions of R. etli and, by extension, of α-proteobacteria. Moreover, we show high-resolution tiling arrays to be suitable tools for studying intergenic ncRNA transcription profiles across the genome. The differential expression levels of some of these ncRNAs may indicate a role in adaptation to changing environmental conditions. PMID:20089193

  12. Comprehensive Small RNA-Seq of Adeno-Associated Virus (AAV)-Infected Human Cells Detects Patterns of Novel, Non-Coding AAV RNAs in the Absence of Cellular miRNA Regulation.

    PubMed

    Stutika, Catrin; Mietzsch, Mario; Gogol-Döring, Andreas; Weger, Stefan; Sohn, Madlen; Chen, Wei; Heilbronn, Regine

    2016-01-01

    Most DNA viruses express small regulatory RNAs, which interfere with viral or cellular gene expression. For adeno-associated virus (AAV), a small ssDNA virus with a complex biphasic life cycle miRNAs or other small regulatory RNAs have not yet been described. This is the first comprehensive Illumina-based RNA-Seq analysis of small RNAs expressed by AAV alone or upon co-infection with helper adenovirus or HSV. Several hotspots of AAV-specific small RNAs were detected mostly close to or within the AAV-ITR and apparently transcribed from the newly identified anti-p5 promoter. An additional small RNA hotspot was located downstream of the p40 promoter, from where transcription of non-coding RNAs associated with the inhibition of adenovirus replication were recently described. Parallel detection of known Ad and HSV miRNAs indirectly validated the newly identified small AAV RNA species. The predominant small RNAs were analyzed on Northern blots and by human argonaute protein-mediated co-immunoprecipitation. None of the small AAV RNAs showed characteristics of bona fide miRNAs, but characteristics of alternative RNA processing indicative of differentially regulated AAV promoter-associated small RNAs. Furthermore, the AAV-induced regulation of cellular miRNA levels was analyzed at different time points post infection. In contrast to other virus groups AAV infection had virtually no effect on the expression of cellular miRNA, which underscores the long-established concept that wild-type AAV infection is apathogenic.

  13. Comprehensive Small RNA-Seq of Adeno-Associated Virus (AAV)-Infected Human Cells Detects Patterns of Novel, Non-Coding AAV RNAs in the Absence of Cellular miRNA Regulation

    PubMed Central

    Stutika, Catrin; Mietzsch, Mario; Gogol-Döring, Andreas; Weger, Stefan; Sohn, Madlen; Chen, Wei; Heilbronn, Regine

    2016-01-01

    Most DNA viruses express small regulatory RNAs, which interfere with viral or cellular gene expression. For adeno-associated virus (AAV), a small ssDNA virus with a complex biphasic life cycle miRNAs or other small regulatory RNAs have not yet been described. This is the first comprehensive Illumina-based RNA-Seq analysis of small RNAs expressed by AAV alone or upon co-infection with helper adenovirus or HSV. Several hotspots of AAV-specific small RNAs were detected mostly close to or within the AAV-ITR and apparently transcribed from the newly identified anti-p5 promoter. An additional small RNA hotspot was located downstream of the p40 promoter, from where transcription of non-coding RNAs associated with the inhibition of adenovirus replication were recently described. Parallel detection of known Ad and HSV miRNAs indirectly validated the newly identified small AAV RNA species. The predominant small RNAs were analyzed on Northern blots and by human argonaute protein-mediated co-immunoprecipitation. None of the small AAV RNAs showed characteristics of bona fide miRNAs, but characteristics of alternative RNA processing indicative of differentially regulated AAV promoter-associated small RNAs. Furthermore, the AAV-induced regulation of cellular miRNA levels was analyzed at different time points post infection. In contrast to other virus groups AAV infection had virtually no effect on the expression of cellular miRNA, which underscores the long-established concept that wild-type AAV infection is apathogenic. PMID:27611072

  14. Virtual screening of gene expression regulatory sites in non-coding regions of the infectious salmon anemia virus

    PubMed Central

    2014-01-01

    Background Members of the Orthomyxoviridae family, which contains an important fish pathogen called the infectious salmon anemia virus (ISAV), have a genome consisting of eight segments of single-stranded RNA that encode different viral proteins. Each of these segments is flanked by non-coding regions (NCRs). In other Orthomyxoviruses, sequences have been shown within these NCRs that regulate gene expression and virulence; however, only the sequences of these regions are known in ISAV, and a biological role has not yet been attributed to these regions. This study aims to determine possible functions of the NCRs of ISAV. Results The results suggested an association between the molecular architecture of NCR regions and their role in the viral life cycle. The available NCR sequences from ISAV isolates were compiled, alignments were performed to obtain a consensus sequence, and conserved regions were identified in this consensus sequence. To determine the molecular structure adopted by these NCRs, various bioinformatics tools, including RNAfold, RNAstructure, Sfold, and Mfold, were used. This hypothetical structure, together with a comparison with influenza, yielded reliable secondary structure models that lead to the identification of conserved nucleotide positions on an intergenus level. These models determined which nucleotide positions are involved in the recognition of the vRNA/cRNA by RNA-dependent RNA polymerase (RdRp) or mRNA by the ribosome. Conclusions The information obtained in this work allowed the proposal of previously unknown sites that are involved in the regulation of different stages of the viral cycle, leading to the identification of new viral targets that may assist future antiviral strategies. PMID:25069483

  15. Random small interfering RNA library screen identifies siRNAs that induce human erythroleukemia cell differentiation.

    PubMed

    Fan, Cuiqing; Xiong, Yuan; Zhu, Ning; Lu, Yabin; Zhang, Jiewen; Wang, Song; Liang, Zicai; Shen, Yan; Chen, Meihong

    2011-03-01

    Cancers are characterized by poor differentiation. Differentiation therapy is a strategy to alleviate malignant phenotypes by inducing cancer cell differentiation. Here we carried out a combinatorial high-throughput screen with a random siRNA library on human erythroleukemia K-562 cell differentiation. Two siRNAs screened from the library were validated to be able to induce erythroid differentiation to varying degrees, determined by CD235 and globin up-regulation, GATA-2 down-regulation, and cell growth inhibition. The screen we performed here is the first trial of screening cancer differentiation-inducing agents from a random siRNA library, demonstrating that a random siRNA library can be considered as a new resource in efforts to seek new therapeutic agents for cancers. As a random siRNA library has a broad coverage for the entire genome, including known/unknown genes and protein coding/non-coding sequences, screening using a random siRNA library can be expected to greatly augment the repertoire of therapeutic siRNAs for cancers.

  16. Organization of cytokeratin cytoskeleton and germ plasm in the vegetal cortex of Xenopus laevis oocytes depends on coding and non-coding RNAs: Three-dimensional and ultrastructural analysis

    SciTech Connect

    Kloc, Malgorzata . E-mail: mkloc@mdanderson.org; Bilinski, Szczepan; Dougherty, Matthew T.

    2007-05-01

    Recent studies discovered a novel structural role of RNA in maintaining the integrity of the mitotic spindle and cellular cytoskeleton. In Xenopus laevis, non-coding Xlsirts and coding VegT RNAs play a structural role in anchoring localized RNAs, maintaining the organization of the cytokeratin cytoskeleton and germinal granules in the oocyte vegetal cortex and in subsequent development of the germline in the embryo. We studied the ultrastructural effects of antisense oligonucleotide driven ablation of Xlsirts and VegT RNAs on the organization of the cytokeratin, germ plasm and other components of the vegetal cortex. We developed a novel method to immunolabel and visualize cytokeratin at the electron microscopy level, which allowed us to reconstruct the ultrastructural organization of the cytokeratin network relative to the components of the vegetal cortex in Xenopus oocytes. The removal of Xlsirts and VegT RNAs not only disrupts the cytokeratin cytoskeleton but also has a profound transcript-specific effect on the anchoring and distribution of germ plasm islands and their germinal granules and the arrangement of yolk platelets within the vegetal cortex. We suggest that the cytokeratin cytoskeleton plays a role in anchoring of germ plasm islands within the vegetal cortex and germinal granules within the germ plasm islands.

  17. Enhanced translation by Nucleolin via G-rich elements in coding and non-coding regions of target mRNAs.

    PubMed

    Abdelmohsen, Kotb; Tominaga, Kumiko; Lee, Eun Kyung; Srikantan, Subramanya; Kang, Min-Ju; Kim, Mihee M; Selimyan, Roza; Martindale, Jennifer L; Yang, Xiaoling; Carrier, France; Zhan, Ming; Becker, Kevin G; Gorospe, Myriam

    2011-10-01

    RNA-binding proteins (RBPs) regulate gene expression at many post-transcriptional levels, including mRNA stability and translation. The RBP nucleolin, with four RNA-recognition motifs, has been implicated in cell proliferation, carcinogenesis and viral infection. However, the subset of nucleolin target mRNAs and the influence of nucleolin on their expression had not been studied at a transcriptome-wide level. Here, we globally identified nucleolin target transcripts, many of which encoded cell growth- and cancer-related proteins, and used them to find a signature motif on nucleolin target mRNAs. Surprisingly, this motif was very rich in G residues and was not only found in the 3'-untranslated region (UTR), but also in the coding region (CR) and 5'-UTR. Nucleolin enhanced the translation of mRNAs bearing the G-rich motif, since silencing nucleolin did not change target mRNA stability, but decreased the size of polysomes forming on target transcripts and lowered the abundance of the encoded proteins. In summary, nucleolin binds G-rich sequences in the CR and UTRs of target mRNAs, many of which encode cancer proteins, and enhances their translation.

  18. Identification of important long non-coding RNAs and highly recurrent aberrant alternative splicing events in hepatocellular carcinoma through integrative analysis of multiple RNA-Seq datasets.

    PubMed

    Zhang, Lu; Liu, Xiaoqiao; Zhang, Xuegong; Chen, Ronghua

    2016-06-01

    Hepatocellular carcinoma (HCC) is an aggressive and deadly cancer. The molecular pathogenesis of the disease remains poorly understood. To better understand HCC biology and explore potential biomarkers and therapeutic targets, we investigated the whole transcriptome of HCC. Considering the genetic heterogeneity of HCC, four datasets from four studies consisting of 15 pairs of HCC and adjacent normal samples were analyzed. We observed that the number of lncRNAs expressed in each HCC sample was consistently greater than the adjacent normal sample. Moreover, 15 lncRNAs were identified expressed in five to seven HCC tissues but were not detected in any adjacent normal tissue. Differential expression analysis detected 35 up- and 80 down-regulated lncRNAs in HCC samples compared with adjacent normal samples. In addition, five differentially expressed lncRNAs were predicted to play a role in oxidation and reduction process. With regard to splicing alterations, we identified nine highly recurrent differential splicing events belonging to eight genes USO1, RPS24, CCDC50, THNSL2, NUMB, FN1 (two events), SLC39A14 and NR1I3. Of them, splicing alterations of SLC39A14 and NR1I3 were reported for the association with HCC for the first time. The splicing dysregulation in HCC may be influenced by three splicing factors ESRP2, CELF2 and SRSF5 which were significantly down-regulated in HCC samples. This study revealed uncharacterized aspects of HCC transcriptome and identified important lncRNAs and splicing isoforms with the potential to serve as biomarkers and therapeutic targets for the disease.

  19. Comprehensive cross production system assessment of the impact of in vitro microenvironment on the expression of messengers and long non-coding RNAs in the bovine blastocyst.

    PubMed

    Côté, Isabelle; Vigneault, Christian; Laflamme, Isabelle; Laquerre, Joanie; Fournier, Éric; Gilbert, Isabelle; Scantland, Sara; Gagné, Dominic; Blondin, Patrick; Robert, Claude

    2011-07-01

    In vitro production (IVP) of cattle embryos over the past two decades has revealed several negative impacts that have been attributed to the artificial microenvironment. Studies on embryos produced in vitro clearly point to aberrant gene expression levels. So far, the causal association between phenotype and measured gene expression has not led to substantial improvement of IVP systems. The aim of this study was to generate a unique dataset composed of microarray-derived relative transcript abundance values for blastocysts produced in ten in vitro systems differing primarily in culture medium formulation. Between-group comparisons determine the level of overall similarity among systems relative to in vivo reference embryos. The use of the dataset to contrast all in vitro treatments with the in vivo blastocysts pointed to a single common gene network. The 'boutique' array contained a panel of novel uncharacterized transcripts that were variably expressed depending on the medium in which the blastocysts were produced. These novel transcripts were differentially expressed in blastocysts even as carryover from conditions encountered 7 days earlier during oocyte maturation. All of the selected novel candidates thus expressed were from intergenic regions. The function of this long non-coding RNA remains unknown but clearly points to an additional level of complexity in early embryo development.

  20. Non-coding landscapes of colorectal cancer

    PubMed Central

    Ragusa, Marco; Barbagallo, Cristina; Statello, Luisa; Condorelli, Angelo Giuseppe; Battaglia, Rosalia; Tamburello, Lucia; Barbagallo, Davide; Di Pietro, Cinzia; Purrello, Michele

    2015-01-01

    For two decades Vogelstein’s model has been the paradigm for describing the sequence of molecular changes within protein-coding genes that would lead to overt colorectal cancer (CRC). This model is now too simplistic in the light of recent studies, which have shown that our genome is pervasively transcribed in RNAs other than mRNAs, denominated non-coding RNAs (ncRNAs). The discovery that mutations in genes encoding these RNAs [i.e., microRNAs (miRNAs), long non-coding RNAs, and circular RNAs] are causally involved in cancer phenotypes has profoundly modified our vision of tumour molecular genetics and pathobiology. By exploiting a wide range of different mechanisms, ncRNAs control fundamental cellular processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis: these data have also confirmed their role as oncogenes or tumor suppressors in cancer development and progression. The existence of a sophisticated RNA-based regulatory system, which dictates the correct functioning of protein-coding networks, has relevant biological and biomedical consequences. Different miRNAs involved in neoplastic and degenerative diseases exhibit potential predictive and prognostic properties. Furthermore, the key roles of ncRNAs make them very attractive targets for innovative therapeutic approaches. Several recent reports have shown that ncRNAs can be secreted by cells into the extracellular environment (i.e., blood and other body fluids): this suggests the existence of extracellular signalling mechanisms, which may be exploited by cells in physiology and pathology. In this review, we will summarize the most relevant issues on the involvement of cellular and extracellular ncRNAs in disease. We will then specifically describe their involvement in CRC pathobiology and their translational applications to CRC diagnosis, prognosis and therapy. PMID:26556998

  1. A Csr-type regulatory system, including small non-coding RNAs, regulates the global virulence regulator RovA of Yersinia pseudotuberculosis through RovM.

    PubMed

    Heroven, Ann Kathrin; Böhme, Katja; Rohde, Manfred; Dersch, Petra

    2008-06-01

    The MarR-type regulator RovA controls expression of virulence genes of Yersinia pseudotuberculosis in response to environmental signals. Using a genetic strategy to discover components that influence rovA expression, we identified new regulatory factors with homology to components of the carbon storage regulator system (Csr). We showed that overexpression of a CsrB- or a CsrC-type RNA activates rovA, whereas a CsrA-like protein represses RovA synthesis. We further demonstrate that influence of the Csr system on rovA is indirect and occurs through control of the LysR regulator RovM, which inhibits rovA transcription. The CsrA protein had also a major influence on the motility of Yersinia, which was independent of RovM. The CsrB and CsrC RNAs are differentially expressed in Yersinia. CsrC is highly induced in complex but not in minimal media, indicating that medium-dependent rovM expression is mediated through CsrC. CsrB synthesis is generally very low. However, overexpression of the response regulator UvrY was found to activate CsrB production, which in turn represses CsrC synthesis independent of the growth medium. In summary, the post-transcriptional Csr-type components were shown to be key regulators in the co-ordinated environmental control of physiological processes and virulence factors, which are crucial for the initiation of Yersinia infections.

  2. G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA.

    PubMed

    Bidet, Katell; Dadlani, Dhivya; Garcia-Blanco, Mariano A

    2014-07-01

    Viral RNA-host protein interactions are critical for replication of flaviviruses, a genus of positive-strand RNA viruses comprising major vector-borne human pathogens including dengue viruses (DENV). We examined three conserved host RNA-binding proteins (RBPs) G3BP1, G3BP2 and CAPRIN1 in dengue virus (DENV-2) infection and found them to be novel regulators of the interferon (IFN) response against DENV-2. The three RBPs were required for the accumulation of the protein products of several interferon stimulated genes (ISGs), and for efficient translation of PKR and IFITM2 mRNAs. This identifies G3BP1, G3BP2 and CAPRIN1 as novel regulators of the antiviral state. Their antiviral activity was antagonized by the abundant DENV-2 non-coding subgenomic flaviviral RNA (sfRNA), which bound to G3BP1, G3BP2 and CAPRIN1, inhibited their activity and lead to profound inhibition of ISG mRNA translation. This work describes a new and unexpected level of regulation for interferon stimulated gene expression and presents the first mechanism of action for an sfRNA as a molecular sponge of anti-viral effectors in human cells.

  3. G3BP1, G3BP2 and CAPRIN1 Are Required for Translation of Interferon Stimulated mRNAs and Are Targeted by a Dengue Virus Non-coding RNA

    PubMed Central

    Bidet, Katell; Dadlani, Dhivya; Garcia-Blanco, Mariano A.

    2014-01-01

    Viral RNA-host protein interactions are critical for replication of flaviviruses, a genus of positive-strand RNA viruses comprising major vector-borne human pathogens including dengue viruses (DENV). We examined three conserved host RNA-binding proteins (RBPs) G3BP1, G3BP2 and CAPRIN1 in dengue virus (DENV-2) infection and found them to be novel regulators of the interferon (IFN) response against DENV-2. The three RBPs were required for the accumulation of the protein products of several interferon stimulated genes (ISGs), and for efficient translation of PKR and IFITM2 mRNAs. This identifies G3BP1, G3BP2 and CAPRIN1 as novel regulators of the antiviral state. Their antiviral activity was antagonized by the abundant DENV-2 non-coding subgenomic flaviviral RNA (sfRNA), which bound to G3BP1, G3BP2 and CAPRIN1, inhibited their activity and lead to profound inhibition of ISG mRNA translation. This work describes a new and unexpected level of regulation for interferon stimulated gene expression and presents the first mechanism of action for an sfRNA as a molecular sponge of anti-viral effectors in human cells. PMID:24992036

  4. Genome-Wide and Species-Wide In Silico Screening for Intragenic MicroRNAs in Human, Mouse and Chicken

    PubMed Central

    Godnic, Irena; Zorc, Minja; Jevsinek Skok, Dasa; Calin, George Adrian; Horvat, Simon; Dovc, Peter; Kovac, Milena; Kunej, Tanja

    2013-01-01

    MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) involved in regulation of gene expression. Intragenic miRNAs, especially those exhibiting a high degree of evolutionary conservation, have been shown to be coordinately regulated and/or expressed with their host genes, either with synergistic or antagonistic correlation patterns. However, the degree of cross-species conservation of miRNA/host gene co-location is not known and co-expression information is incomplete and fragmented among several studies. Using the genomic resources (miRBase and Ensembl) we performed a genome-wide in silico screening (GWISS) for miRNA/host gene pairs in three well-annotated vertebrate species: human, mouse, and chicken. Approximately half of currently annotated miRNA genes resided within host genes: 53.0% (849/1,600) in human, 48.8% (418/855) in mouse, and 42.0% (210/499) in chicken, which we present in a central publicly available Catalog of intragenic miRNAs (http://www.integratomics-time.com/miR-host/catalog). The miRNA genes resided within either protein-coding or ncRNA genes, which include long intergenic ncRNAs (lincRNAs) and small nucleolar RNAs (snoRNAs). Twenty-seven miRNA genes were found to be located within the same host genes in all three species and the data integration from literature and databases showed that most (26/27) have been found to be co-expressed. Particularly interesting are miRNA genes located within genes encoding for miRNA silencing machinery (DGCR8, DICER1, and SND1 in human and Cnot3, Gdcr8, Eif4e, Tnrc6b, and Xpo5 in mouse). We furthermore discuss a potential for phenotype misattribution of miRNA host gene polymorphism or gene modification studies due to possible collateral effects on miRNAs hosted within them. In conclusion, the catalog of intragenic miRNAs and identified 27 miRNA/host gene pairs with cross-species conserved co-location, co-expression, and potential co-regulation, provide excellent candidates for further functional annotation of

  5. Small non-coding RNA and cancer.

    PubMed

    Romano, Giulia; Veneziano, Dario; Acunzo, Mario; Croce, Carlo M

    2017-05-01

    The ENCODE project has reported that at least 80% of the human genome is biologically active, yet only a small part of human DNA encodes for protein. The massive amount of RNA transcribed but not translated into protein can be classified as housekeeping RNA (such as rRNA, tRNA) and regulatory RNA (such as miRNA, piRNA, lncRNA). Small non-coding RNAs, in particular, have been the focus of many studies in the last 20 years and their fundamental role in many human diseases is currently well established. Inter alia, their role in cancer development and progression, as well as in drug resistance, is being increasingly investigated. In this review, focusing our attention on recent research results, we provide an overview of the four large classes of small non-coding RNAs, namely, miRNAs, piRNAs, snoRNA and the new class of tRNA-derived fragments, highlighting their fundamental role in cancer and their potential as diagnostic and prognostic biomarkers. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Screening candidate microRNAs (miRNAs) in different lambskin hair follicles in Hu sheep.

    PubMed

    Gao, Wen; Sun, Wei; Yin, Jinfeng; Lv, Xiaoyang; Bao, Jianjun; Yu, Jiarui; Wang, Lihong; Jin, Chengyan; Hu, Liang

    2017-01-01

    Hu sheep lambskin is a unique white lambskin from China that exhibits three types of flower patterns, including small waves, medium waves, and large waves, with small waves considered the best quality. However, our understanding of the molecular mechanism underlying flower pattern formation in Hu sheep lambskin is limited. The aim of the present study was to further explore the relevance between candidate microRNAs (miRNAs) and developmental characteristics of hair follicles and screen miRNAs for later functional validation. Herein, we employed Illumina Hiseq 2500 to identify differentially expressed miRNAs in hair follicles of different flower patterns with small, medium, and large waves to construct a comprehensive sequence database on the mechanism of hair follicle development. Paraffin sections of lambskin tissue were prepared to assess the structure of different hair follicles. Expression levels of candidate miRNAs in different flower patterns were analyzed by relative quantitation using real-time PCR, combined with histological observation and micro-observation technologies, and the correlation between expression levels of candidate miRNAs and histological properties of hair follicles was analyzed by using SPSS 17.0. A total of 522 differentially expressed miRNAs were identified, and RNA-seq analysis detected 7,266 target genes in different groups of flower patterns. Gene ontological analysis indicated these target genes were mainly involved in cell proliferation, differentiation, growth, apoptosis, and ion transport, and 14 miRNAs, including miR-143, miR-10a, and let-7 were screened as candidate miRNAs in Hu sheep hair follicle growth and development. In the same field of vision, variance analysis showed that the number of secondary follicles in small waves was significantly larger than that in large and medium waves (P<0.01); the diameter of the primary and secondary follicles in large waves was respectively larger than those in medium and small waves (P<0

  7. Definition and annotation of (myco)bacterial non-coding RNA.

    PubMed

    Lamichhane, Gyanu; Arnvig, Kristine B; McDonough, Kathleen A

    2013-01-01

    RNA in bacteria may be broadly classified into coding and non-coding types. The prior, also known as messenger RNA, encode proteins as their final product. The non-coding RNA include all RNAs that are not translated into a protein. Examples of extensively studied and therefore prominent non-coding RNAs include rRNA, tRNA, tmRNA, whose designations reflect the functions performed by these RNAs. Discoveries of non-coding RNAs in mycobacteria have been reported in the recent years. At this early stage of this discipline of mycobacterial research, there is an opportunity for the scientific community to establish a consistent, systematic and objective approach to annotation of these RNAs. We are providing recommendations for this systematic annotation that we hope will be adopted by the mycobacterial research community. These may also serve as templates for annotation of non-coding RNAs in other bacteria.

  8. Screening of long non-coding RNA and TUG1 inhibits proliferation with TGF-β induction in patients with COPD

    PubMed Central

    Tang, Wenxiang; Shen, Zhenyu; Guo, Jiang; Sun, Shenghua

    2016-01-01

    Objective To evaluate differentially expressed long noncoding RNAs (lncRNAs) and the potential role of lncRNA TUG1 in patients with chronic obstructive pulmonary disease (COPD). Methods Total RNA was extracted from both COPD and non-COPD lung tissues, and microarray analysis was performed with 25,628 lncRNA probes and 20,106 mRNA probes. In addition, five up-regulated and five down-regulated lncRNAs were selected for identification using quantitative real-time polymerase chain reaction. COPD cell model was established by transforming growth factor β (TGF-β) treatment. Cell Counting Kit-8 assay was used to detect BEAS-2B and HFL1 cell proliferation after TUG-siRNA transfection with TGF-β treatment. In addition, the expression levels of α-SMA and fibronectin proteins were determined using Western blot in BEAS-2B and HFL1 cells after TUG-siRNA transfection with TGF-β treatment. Results There were 8,376 (32.7%) differentially expressed lncRNAs and 5,094 (25.3%) differentially expressed mRNAs in COPD lung tissues compared with non-COPD lung tissues. Five of the analyzed lncRNAs (BC038205, BC130595, TUG1, MEG3, and LOC646329) were markedly increased, while five lncRNAs (LOC729178, PLAC2, LOC339529, LINC00229, and SNHG5) were significantly decreased in COPD lung tissues compared with non-COPD lung tissues (n=20) (***P<0.001). Knockdown of lncRNA TUG1 promotes BEAS-2B and HFL1 cell proliferation after TGF-β treatment through inhibiting the expression levels of α-SMA and fibronectin. Conclusion Abundant, differentially expressed lncRNAs and mRNAs were identified by microarray analysis and these might play a partial or key role in the diagnosis of patients with COPD. LncRNA TUG1 may become a very important class of biomarker and may act as a potential diagnostic and therapeutic target for patients with COPD. PMID:27932875

  9. Disease-Causing 7.4 kb Cis-Regulatory Deletion Disrupting Conserved Non-Coding Sequences and Their Interaction with the FOXL2 Promotor: Implications for Mutation Screening

    PubMed Central

    Dostie, Josée; Lemire, Edmond; Bouchard, Philippe; Field, Michael; Jones, Kristie; Lorenz, Birgit; Menten, Björn; Buysse, Karen; Pattyn, Filip; Friedli, Marc; Ucla, Catherine; Rossier, Colette; Wyss, Carine; Speleman, Frank; De Paepe, Anne; Dekker, Job; Antonarakis, Stylianos E.; De Baere, Elfride

    2009-01-01

    To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs. Apart from three larger distant deletions, a de novo deletion as small as 7.4 kb was found at 283 kb 5′ to FOXL2. The deletion appeared to be triggered by an H-DNA-induced double-stranded break (DSB). In addition, it disrupts a novel long non-coding RNA (ncRNA) PISRT1 and 8 CNCs. The regulatory potential of the deleted CNCs was substantiated by in vitro luciferase assays. Interestingly, Chromosome Conformation Capture (3C) of a 625 kb region surrounding FOXL2 in expressing cellular systems revealed physical interactions of three upstream fragments and the FOXL2 core promoter. Importantly, one of these contains the 7.4 kb deleted fragment. Overall, this study revealed the smallest distant deletion causing monogenic disease and impacts upon the concept of mutation screening in human disease and developmental disorders in particular. PMID:19543368

  10. High-throughput screens identify microRNAs essential for HER2 positive breast cancer cell growth.

    PubMed

    Leivonen, Suvi-Katri; Sahlberg, Kristine Kleivi; Mäkelä, Rami; Due, Eldri Undlien; Kallioniemi, Olli; Børresen-Dale, Anne-Lise; Perälä, Merja

    2014-02-01

    MicroRNAs (miRNAs) are non-coding RNAs regulating gene expression post-transcriptionally. We have characterized the role of miRNAs in regulating the human epidermal growth factor receptor 2 (HER2)-pathway in breast cancer. We performed miRNA gain-of-function assays by screening two HER2 amplified cell lines (KPL-4 and JIMT-1) with a miRNA mimic library consisting of 810 human miRNAs. The levels of HER2, phospho-AKT, phospho-ERK1/2, cell proliferation (Ki67) and apoptosis (cPARP) were analyzed with reverse-phase protein arrays. Rank product analyses identified 38 miRNAs (q < 0.05) as inhibitors of HER2 signaling and cell growth, the most effective being miR-491-5p, miR-634, miR-637 and miR-342-5p. We also characterized miRNAs directly targeting HER2 and identified seven novel miRNAs (miR-552, miR-541, miR-193a-5p, miR-453, miR-134, miR-498, and miR-331-3p) as direct regulators of the HER2 3'UTR. We demonstrated the clinical relevance of the miRNAs and identified miR-342-5p and miR-744* as significantly down-regulated in HER2-positive breast tumors as compared to HER2-negative tumors from two cohorts of breast cancer patients (101 and 1302 cases). miR-342-5p specifically inhibited HER2-positive cell growth, as it had no effect on the growth of HER2-negative control cells in vitro. Furthermore, higher expression of miR-342-5p was associated with better survival in both breast cancer patient cohorts. In conclusion, we have identified miRNAs which are efficient negative regulators of the HER2 pathway that may play a role in vivo during breast cancer progression. These results give mechanistic insights in HER2 regulation which may open potential new strategies towards prevention and therapeutic inhibition of HER2-positive breast cancer.

  11. The development of non-coding RNA ontology.

    PubMed

    Huang, Jingshan; Eilbeck, Karen; Smith, Barry; Blake, Judith A; Dou, Dejing; Huang, Weili; Natale, Darren A; Ruttenberg, Alan; Huan, Jun; Zimmermann, Michael T; Jiang, Guoqian; Lin, Yu; Wu, Bin; Strachan, Harrison J; de Silva, Nisansa; Kasukurthi, Mohan Vamsi; Jha, Vikash Kumar; He, Yongqun; Zhang, Shaojie; Wang, Xiaowei; Liu, Zixing; Borchert, Glen M; Tan, Ming

    2016-01-01

    Identification of non-coding RNAs (ncRNAs) has been significantly improved over the past decade. On the other hand, semantic annotation of ncRNA data is facing critical challenges due to the lack of a comprehensive ontology to serve as common data elements and data exchange standards in the field. We developed the Non-Coding RNA Ontology (NCRO) to handle this situation. By providing a formally defined ncRNA controlled vocabulary, the NCRO aims to fill a specific and highly needed niche in semantic annotation of large amounts of ncRNA biological and clinical data.

  12. The development of non-coding RNA ontology

    PubMed Central

    Eilbeck, Karen; Smith, Barry; Blake, Judith A.; Dou, Dejing; Huang, Weili; Natale, Darren A.; Ruttenberg, Alan; Huan, Jun; Zimmermann, Michael T.; Jiang, Guoqian; Lin, Yu; Wu, Bin; Strachan, Harrison J.; de Silva, Nisansa; Kasukurthi, Mohan Vamsi; Jha, Vikash Kumar; He, Yongqun; Zhang, Shaojie; Wang, Xiaowei; Liu, Zixing; Borchert, Glen M.; Tan, Ming

    2016-01-01

    Identification of non-coding RNAs (ncRNAs) has been significantly improved over the past decade. On the other hand, semantic annotation of ncRNA data is facing critical challenges due to the lack of a comprehensive ontology to serve as common data elements and data exchange standards in the field. We developed the Non-Coding RNA Ontology (NCRO) to handle this situation. By providing a formally defined ncRNA controlled vocabulary, the NCRO aims to fill a specific and highly needed niche in semantic annotation of large amounts of ncRNA biological and clinical data. PMID:27990175

  13. A comprehensive review of web-based non-coding RNA resources for cancer research.

    PubMed

    Zheng, Yun; Liu, Li; Shukla, Girish C

    2017-08-18

    Non-coding RNAs include many kinds of RNAs that did not encode proteins. Recent evidences reveal that ncRNAs play critical roles in initiation and progression of cancers. But it is not easy for cancer biologists and medical doctors to easily know the potential roles of ncRNAs in cancer and retrieve the information of ncRNAs under their investigations. To make the available web-based resources more accessible and understandable, we made a comprehensive review for 49 web-based resources of three types of ncRNAs, i.e., microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). We also listed some preferred resources for 6 different types of analyses related to ncRNAs. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. NONCODE v2.0: decoding the non-coding.

    PubMed

    He, Shunmin; Liu, Changning; Skogerbø, Geir; Zhao, Haitao; Wang, Jie; Liu, Tao; Bai, Baoyan; Zhao, Yi; Chen, Runsheng

    2008-01-01

    The NONCODE database is an integrated knowledge database designed for the analysis of non-coding RNAs (ncRNAs). Since NONCODE was first released 3 years ago, the number of known ncRNAs has grown rapidly, and there is growing recognition that ncRNAs play important regulatory roles in most organisms. In the updated version of NONCODE (NONCODE v2.0), the number of collected ncRNAs has reached 206 226, including a wide range of microRNAs, Piwi-interacting RNAs and mRNA-like ncRNAs. The improvements brought to the database include not only new and updated ncRNA data sets, but also an incorporation of BLAST alignment search service and access through our custom UCSC Genome Browser. NONCODE can be found under http://www.noncode.org or http://noncode.bioinfo.org.cn.

  15. Precise long non-coding RNA modulation in visual maintenance and impairment

    PubMed Central

    Wan, Peixing; Su, Wenru; Zhuo, Yehong

    2017-01-01

    Long non-coding RNAs (lncRNAs) are remarkably powerful, flexible and pervasive cellular regulators. With the help of cheaper RNA-seq, high-throughput screening of lncRNAs has become widely applied and has identified large numbers of specific lncRNAs in various physiological or pathological processes. Vision is known to be a complex and vital perception that comprises 80% of the sensory information we receive. A consensus has been reached that normal visual maintenance and impairment are primarily driven by gene regulation. Recently, it has become understood that lncRNAs are key regulators in most biological processes, including cell proliferation, apoptosis, differentiation, immune responses, oxidative stress and inflammation. Our review is intended to provide insight towards a comprehensive view of the precise modulation of lncRNAs in visual maintenance and impairment. We also highlight the challenges and future directions in conducting lncRNA studies, particularly in patients whose lncRNAs may hold expanded promise for diagnostic, prognostic and therapeutic applications. PMID:28003323

  16. Putting Non-coding RNA on Display with CRISPR.

    PubMed

    Perez-Pinera, Pablo; Jones, Matthew F; Lal, Ashish; Lu, Timothy K

    2015-07-16

    In a recent issue of Nature Methods, Shechner et al. (2015) reported the development of CRISPR Display (CRISP-Disp), which is a sophisticated, flexible, modular, and multiplexable platform for targeting different types of non-coding RNAs (ncRNAs) to genomic loci. CRISP-Disp will facilitate synthetic-biology applications and enable the elucidation of ncRNA functions. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Identification and analysis of mouse non-coding RNA using transcriptome data.

    PubMed

    Zhao, Yuhui; Liu, Wanfei; Zeng, Jingyao; Liu, Shoucheng; Tan, Xinyu; Aljohi, Hasanawad; Hu, Songnian

    2016-06-01

    Transcripts are expressed spatially and temporally and they are very complicated, precise and specific; however, most studies are focused on protein-coding related genes. Recently, massively parallel cDNA sequencing (RNA-seq) has emerged to be a new and promising tool for transcriptome research, and numbers of non-coding RNAs, especially lincRNAs, have been widely identified and well characterized as important regulators of diverse biological processes. In this study, we used ultra-deep RNA-seq data from 15 mouse tissues to study the diversity and dynamic of non-coding RNAs in mouse. Using our own criteria, we identified totally 16,249 non-coding genes (21,569 non-coding RNAs) in mouse. We annotated these non-coding RNAs by diverse properties and found non-coding RNAs are generally shorter, have fewer exons, express in lower level and are more strikingly tissue-specific compared with protein-coding genes. Moreover, these non-coding RNAs show significant enrichment with transcriptional initiation and elongation signals including histone modifications (H3K4me3, H3K27me3 and H3K36me3), RNAPII binding sites and CAGE tags. The gene set enrichment analysis (GSEA) result revealed several sets of lincRNAs associated with diverse biological processes such as immune effector process, muscle development and sexual reproduction. Taken together, this study provides a more comprehensive annotation of mouse non-coding RNAs and gives an opportunity for future functional and evolutionary study of mouse non-coding RNAs.

  18. Small non-coding RNA deregulation in endometrial carcinogenesis