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Sample records for screening non-coding rnas

  1. Gene regulation by non-coding RNAs.

    PubMed

    Patil, Veena S; Zhou, Rui; Rana, Tariq M

    2014-01-01

    The past two decades have seen an explosion in research on non-coding RNAs and their physiological and pathological functions. Several classes of small (20-30 nucleotides) and long (>200 nucleotides) non-coding RNAs have been firmly established as key regulators of gene expression in myriad processes ranging from embryonic development to innate immunity. In this review, we focus on our current understanding of the molecular mechanisms underlying the biogenesis and function of small interfering RNAs (siRNAs), microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs). In addition, we briefly review the relevance of small and long non-coding RNAs to human physiology and pathology and their potential to be exploited as therapeutic agents.

  2. Non-Coding RNAs in Cardiac Aging.

    PubMed

    Wang, Hui; Bei, Yihua; Shi, Jing; Xiao, Junjie; Kong, Xiangqing

    2015-01-01

    Aging has a remarkable impact on the function of the heart, and is independently associated with increased risk for cardiovascular diseases. Cardiac aging is an intrinsic physiological process that results in impaired cardiac function, along with lots of cellular and molecular changes. Non-coding RNAs include small transcripts, such as microRNAs and a wide range of long non-coding RNAs (lncRNAs). Emerging evidence has revealed that non-coding RNAs acted as powerful and dynamic modifiers of cardiac aging. This review aims to provide a general overview of non-coding RNAs implicated in cardiac aging, and the underlying mechanisms involved in maintaining homeo-stasis and retarding aging.

  3. Screening non-coding RNAs in transcriptomes from neglected species using PORTRAIT: case study of the pathogenic fungus Paracoccidioides brasiliensis

    PubMed Central

    Arrial, Roberto T; Togawa, Roberto C; Brigido, Marcelo de M

    2009-01-01

    Background Transcriptome sequences provide a complement to structural genomic information and provide snapshots of an organism's transcriptional profile. Such sequences also represent an alternative method for characterizing neglected species that are not expected to undergo whole-genome sequencing. One difficulty for transcriptome sequencing of these organisms is the low quality of reads and incomplete coverage of transcripts, both of which compromise further bioinformatics analyses. Another complicating factor is the lack of known protein homologs, which frustrates searches against established protein databases. This lack of homologs may be caused by divergence from well-characterized and over-represented model organisms. Another explanation is that non-coding RNAs (ncRNAs) may be caught during sequencing. NcRNAs are RNA sequences that, unlike messenger RNAs, do not code for protein products and instead perform unique functions by folding into higher order structural conformations. There is ncRNA screening software available that is specific for transcriptome sequences, but their analyses are optimized for those transcriptomes that are well represented in protein databases, and also assume that input ESTs are full-length and high quality. Results We propose an algorithm called PORTRAIT, which is suitable for ncRNA analysis of transcriptomes from poorly characterized species. Sequences are translated by software that is resistant to sequencing errors, and the predicted putative proteins, along with their source transcripts, are evaluated for coding potential by a support vector machine (SVM). Either of two SVM models may be employed: if a putative protein is found, a protein-dependent SVM model is used; if it is not found, a protein-independent SVM model is used instead. Only ab initio features are extracted, so that no homology information is needed. We illustrate the use of PORTRAIT by predicting ncRNAs from the transcriptome of the pathogenic fungus

  4. 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.

  5. Non-Coding RNAs and Lipid Metabolism

    PubMed Central

    Smolle, Elisabeth; Haybaeck, Johannes

    2014-01-01

    A high percentage of the mammalian genome consists of non-coding RNAs (ncRNAs). Among ncRNAs two main subgroups have been identified: long ncRNAs (lncRNAs) and micro RNAs (miRNAs). ncRNAs have been demonstrated to play a role in a vast variety of diseases, since they regulate gene transcription and are involved in post-transcriptional regulation. They have the potential to function as molecular signals or as guides for transcription factors and to regulate epigenetic modifiers. In this literature review we have summarized data on miRNAs and lncRNAs and their involvement in dyslipidaemia, atherosclerosis, insulin resistance and adipogenesis. Outlining certain ncRNAs as disease biomarkers and/or therapeutic targets, and testing them in vivo, will be the next steps in future research. PMID:25093715

  6. Detection of small non-coding RNAs.

    PubMed

    Dalmay, Tamas

    2010-01-01

    Gene expression is regulated at several levels in plants, and one of the most recently discovered regulatory layers involve short RNAs. Short RNAs are produced through several pathways and target either mRNAs or genomic DNA. Different classes of short RNAs have slightly different sizes and detection of their accumulation is an important step in validating and studying non-coding short RNAs. Northern blotting is routinely used to detect short RNAs because it gives information about both the amount and size of the analysed short RNAs. Choice of the right RNA extraction protocol is crucial when short RNAs are being studied, because several routinely used commercial RNA extraction kits do not yield any short RNAs. This chapter describes optimised RNA extraction methods, which give good yields of short RNAs, and separation, transfer and hybridisation protocols to study the accumulation of short RNAs.

  7. Employment opportunities for non-coding RNAs.

    PubMed

    Morey, Céline; Avner, Philip

    2004-06-01

    Analysis of the genomes of several higher eukaryotic organisms, including mouse and human, has reached the striking conclusion that the mammalian transcriptome is constituted in large part of non-protein-coding transcripts. Conversely, the number of protein-coding genes was initially at least overestimated. A growing number of studies report the involvement of non-coding transcripts in a large variety of regulatory processes. This review examines the different types of non-coding RNAs (ncRNAs) and discusses their putative mode of action with particular reference to large ncRNAs and their role in epigenetic regulation.

  8. Non-coding RNAs and gastric cancer.

    PubMed

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

    2014-05-14

    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. 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

  10. Dysregulation of non-coding RNAs in gastric cancer.

    PubMed

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

    2015-10-21

    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.

  11. Non-coding RNAs in cardiac regeneration

    PubMed Central

    Zhou, Yanli; Xiao, Junjie; Li, Xinli

    2015-01-01

    Developing new therapeutic strategies which could enhance cardiomyocyte regenerative capacity is of significant clinical importance. Though promising, methods to promote cardiac regeneration have had limited success due to the weak regenerative capacity of the adult mammalian heart. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs) and long non-coding RNAs (lncRNAs), are functional RNA molecules without a protein coding function that have been reported to engage in cardiac regeneration and repair. In light of current regenerative strategies, the regulatory effects of ncRNAs can be categorized as follows: cardiac proliferation, cardiac differentiation, cardiac survival and cardiac reprogramming. miR-590, miR-199a, miR-17-92 cluster, miR302-367 cluster and miR-222 have been reported to promote cardiomyocyte proliferation while miR-1 and miR-133 suppress that. miR-499 and miR-1 promote the differentiation of cardiac progenitors into cardiomyocyte while miR-133 and H19 inhibit that. miR-21, miR-24, miR-221, miR-199a and miR-155 improve cardiac survival while miR-34a, miR-1 and miR-320 exhibit opposite effects. miR-1, miR-133, miR-208 and miR-499 are capable of reprogramming fibroblasts to cardiomyocyte-like cells and miR-284, miR-302, miR-93, miR-106b and lncRNA-ST8SIA3 are able to enhace cardiac reprogramming. Exploring non-coding RNA-based methods to enhance cardiac regeneration would be instrumental for devising new effective therapies against cardiovascular diseases. PMID:26462179

  12. Regulatory non-coding RNAs: revolutionizing the RNA world.

    PubMed

    Huang, Biao; Zhang, Rongxin

    2014-06-01

    The majority of the genomic DNA sequence in mammalian and other higher organisms can be transcribed into abundant functional RNA transcripts, especially regulatory non-coding RNAs (ncRNAs) that are expressed in a developmentally and species-specific regulated manner. Here, we review various regulatory non-coding RNAs, including regulatory small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs), and summarize two and eight kinds of distinct modes of action for sncRNAs and lncRNAs respectively, by which functional ncRNAs mediate the regulation of intracellular events.

  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 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. PMID:26659490

  15. Non coding RNAs in aortic aneurysmal disease

    PubMed Central

    Duggirala, Aparna; Delogu, Francesca; Angelini, Timothy G.; Smith, Tanya; Caputo, Massimo; Rajakaruna, Cha; Emanueli, Costanza

    2015-01-01

    An aneurysm is a local dilatation of a vessel wall which is >50% its original diameter. Within the spectrum of cardiovascular diseases, aortic aneurysms are among the most challenging to treat. Most patients present acutely after aneurysm rupture or dissection from a previous asymptomatic condition and are managed by open surgical or endovascular repair. In addition, patients may harbor concurrent disease contraindicating surgical intervention. Collectively, these factors have driven the search for alternative methods of identifying, monitoring and treating aortic aneurisms using less invasive approaches. Non-coding RNA (ncRNAs) are emerging as new fundamental regulators of gene expression. The small microRNAs have opened the field of ncRNAs capturing the attention of basic and clinical scientists for their potential to become new therapeutic targets and clinical biomarkers for aortic aneurysm. More recently, long ncRNAs (lncRNAs) have started to be actively investigated, leading to first exciting reports, which further suggest their important and yet largely unexplored contribution to vascular physiology and disease. This review introduces the different ncRNA types and focus at ncRNA roles in aorta aneurysms. We discuss the potential of therapeutic interventions targeting ncRNAs and we describe the research models allowing for mechanistic studies and clinical translation attempts for controlling aneurysm progression. Furthermore, we discuss the potential role of microRNAs and lncRNAs as clinical biomarkers. PMID:25883602

  16. Non-coding RNAs in lung cancer.

    PubMed

    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.

  17. 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.

  18. Functional roles of non-coding Y RNAs

    PubMed Central

    Kowalski, Madzia P.; Krude, Torsten

    2015-01-01

    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. PMID:26159929

  19. 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

  20. Towards structural classification of long non-coding RNAs.

    PubMed

    Sanbonmatsu, Karissa Y

    2016-01-01

    While long non-coding RNAs play key roles in disease and development, few structural studies have been performed to date for this emerging class of RNAs. Previous structural studies are reviewed, and a pipeline is presented to determine secondary structures of long non-coding RNAs. Similar to riboswitches, experimentally determined secondary structures of long non-coding RNAs for one species, may be used to improve sequence/structure alignments for other species. As riboswitches have been classified according to their secondary structure, a similar scheme could be used to classify long non-coding RNAs. This article is part of a Special Issue titled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa.

  1. Non-coding RNAs regulate tumor cell plasticity.

    PubMed

    Liu, Bodu; Sun, Lijuan; Song, Erwei

    2013-10-01

    Tumor metastasis is one of the most serious challenges for human cancers as the majority of deaths caused by cancer are associated with metastasis, rather than the primary tumor. Recent studies have demonstrated that tumor cell plasticity plays a critical role in tumor metastasis by giving rise to various cell types which is necessary for tumor to invade adjacent tissues and form distant metastasis. These include differentiation of cancer stem cells (CSCs), or epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET). A growing body of evidence has demonstrated that the biology of tumor cell plasticity is tightly linked to functions of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Therefore, understanding the mechanisms how non-coding RNAs regulate tumor cell plasticity is essential for discovery of new diagnostic markers and therapeutic targets to overcome metastasis.

  2. Non-coding RNAs in DNA damage response

    PubMed Central

    Liu, Yunhua; Lu, Xiongbin

    2012-01-01

    Genome-wide studies have revealed that human and other mammalian genomes are pervasively transcribed and produce thousands of regulatory non-protein-coding RNAs (ncRNAs), including miRNAs, siRNAs, piRNAs and long non-coding RNAs (lncRNAs). Emerging evidences suggest that these ncRNAs also play a pivotal role in genome integrity and stability via the regulation of DNA damage response (DDR). In this review, we discuss the recent finding on the interplay of ncRNAs with the canonical DDR signaling pathway, with a particular emphasis on miRNAs and lncRNAs. While the expression of ncRNAs is regulated in the DDR, the DDR is also subjected to regulation by those DNA damage-responsive ncRNAs. In addition, the roles of those Dicer- and Drosha-dependent small RNAs produced in the vicinity of double-strand breaks sites are also described. PMID:23226613

  3. Regulatory Roles of Non-Coding RNAs in Colorectal Cancer.

    PubMed

    Wang, Jun; Song, Yong-Xi; Ma, Bin; Wang, Jia-Jun; Sun, Jing-Xu; Chen, Xiao-Wan; Zhao, Jun-Hua; Yang, Yu-Chong; Wang, Zhen-Ning

    2015-08-21

    Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various diseases including cancer. The present review is a comprehensive examination of the aberrant regulation of ncRNAs in colorectal cancer (CRC) and a summary of the current findings on ncRNAs, including long ncRNAs, microRNAs, small interfering RNAs, small nucleolar RNAs, small nuclear RNAs, Piwi-interacting RNAs, and circular RNAs. These ncRNAs might become novel biomarkers and targets as well as potential therapeutic tools for the treatment of CRC in the near future and this review may provide important clues for further research on CRC and for the selection of effective therapeutic targets.

  4. Regulatory Roles of Non-Coding RNAs in Colorectal Cancer

    PubMed Central

    Wang, Jun; Song, Yong-Xi; Ma, Bin; Wang, Jia-Jun; Sun, Jing-Xu; Chen, Xiao-Wan; Zhao, Jun-Hua; Yang, Yu-Chong; Wang, Zhen-Ning

    2015-01-01

    Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various diseases including cancer. The present review is a comprehensive examination of the aberrant regulation of ncRNAs in colorectal cancer (CRC) and a summary of the current findings on ncRNAs, including long ncRNAs, microRNAs, small interfering RNAs, small nucleolar RNAs, small nuclear RNAs, Piwi-interacting RNAs, and circular RNAs. These ncRNAs might become novel biomarkers and targets as well as potential therapeutic tools for the treatment of CRC in the near future and this review may provide important clues for further research on CRC and for the selection of effective therapeutic targets. PMID:26307974

  5. Non-coding RNAs in the pathogenesis of COPD.

    PubMed

    De Smet, Elise G; Mestdagh, Pieter; Vandesompele, Jo; Brusselle, Guy G; Bracke, Ken R

    2015-08-01

    A large part of the human genome is transcribed in non-coding RNAs, transcripts that do not code for protein, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). MiRNAs are short single-stranded RNA molecules that negatively regulate gene expression at the post-transcriptional level. They play an important regulatory role in many biological processes. Consequently, altered expression of these non-coding RNAs has been shown to lead to inflammation and disease. In contrast, lncRNAs, can both enhance or repress the expression of protein-coding genes. COPD is typically caused by tobacco smoking and leads to a progressive decline in lung function and a premature death. Exaggerated pulmonary inflammation is a hallmark feature in this disease, leading to obstructive bronchiolitis and emphysema. In this review, we discuss the miRNA expression patterns in lungs of patients with COPD and in mouse models and we highlight various miRNAs involved in COPD pathogenesis. In addition, we briefly discuss a specific lncRNA that is upregulated upon cigarette smoke exposure, providing a short introduction to this more recently discovered group of non-coding RNAs.

  6. 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. PMID:27550823

  7. 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.

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

    PubMed

    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

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

    PubMed

    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.

  10. Long non-coding RNAs and hepatocellular carcinoma.

    PubMed

    Yu, Fu-Jun; Zheng, Jian-Jian; Dong, Pei-Hong; Fan, Xiao-Ming

    2015-01-01

    Recent advances in next-generation sequencing technology in transcriptome analysis have helped identify numerous non-coding RNAs. The long non-coding RNA (lncRNA) is commonly defined as an RNA molecule with a length of 200 bp-100 kbp that lacks protein-coding potential. LncRNAs play a critical role in the regulation of gene expression, including chromatin modification, transcription and post-transcriptional processing. It has been confirmed that dysregulation of lncRNAs is associated with a number of human diseases, particularly tumors. In this study, we focused on the most extensively investigated lncRNAs in hepatocellular carcinoma (HCC). The biological functions and molecular mechanisms of the majority of lncRNAs have yet to be investigated. The improved knowledge on lncRNAs in HCC may help identify lncRNAs that may be used as novel prognostic markers and therapeutic targets.

  11. Non-coding RNAs: Classification, Biology and Functioning.

    PubMed

    Hombach, Sonja; Kretz, Markus

    2016-01-01

    One of the long-standing principles of molecular biology is that DNA acts as a template for transcription of messenger RNAs, which serve as blueprints for protein translation. A rapidly growing number of exceptions to this rule have been reported over the past decades: they include long known classes of RNAs involved in translation such as transfer RNAs and ribosomal RNAs, small nuclear RNAs involved in splicing events, and small nucleolar RNAs mainly involved in the modification of other small RNAs, such as ribosomal RNAs and transfer RNAs. More recently, several classes of short regulatory non-coding RNAs, including piwi-associated RNAs, endogenous short-interfering RNAs and microRNAs have been discovered in mammals, which act as key regulators of gene expression in many different cellular pathways and systems. Additionally, the human genome encodes several thousand long non-protein coding RNAs >200 nucleotides in length, some of which play crucial roles in a variety of biological processes such as epigenetic control of chromatin, promoter-specific gene regulation, mRNA stability, X-chromosome inactivation and imprinting. In this chapter, we will introduce several classes of short and long non-coding RNAs, describe their diverse roles in mammalian gene regulation and give examples for known modes of action. PMID:27573892

  12. Uncovering RNA Editing Sites in Long Non-Coding RNAs.

    PubMed

    Picardi, Ernesto; D'Erchia, Anna Maria; Gallo, Angela; Montalvo, Antonio; Pesole, Graziano

    2014-01-01

    RNA editing is an important co/post-transcriptional molecular process able to modify RNAs by nucleotide insertions/deletions or substitutions. In human, the most common RNA editing event involves the deamination of adenosine (A) into inosine (I) through the adenosine deaminase acting on RNA proteins. Although A-to-I editing can occur in both coding and non-coding RNAs, recent findings, based on RNA-seq experiments, have clearly demonstrated that a large fraction of RNA editing events alter non-coding RNAs sequences including untranslated regions of mRNAs, introns, long non-coding RNAs (lncRNAs), and low molecular weight RNAs (tRNA, miRNAs, and others). An accurate detection of A-to-I events occurring in non-coding RNAs is of utmost importance to clarify yet unknown functional roles of RNA editing in the context of gene expression regulation and maintenance of cell homeostasis. In the last few years, massive transcriptome sequencing has been employed to identify putative RNA editing changes at genome scale. Despite several efforts, the computational prediction of A-to-I sites in complete eukaryotic genomes is yet a challenging task. We have recently developed a software package, called REDItools, in order to simplify the detection of RNA editing events from deep sequencing data. In the present work, we show the potential of our tools in recovering A-to-I candidates from RNA-Seq experiments as well as guidelines to improve the RNA editing detection in non-coding RNAs, with specific attention to the lncRNAs.

  13. Emerging roles of non-coding RNAs in epigenetic regulation.

    PubMed

    Chen, Juan; Xue, Yuanchao

    2016-03-01

    Recent deep sequencing surveys of mammalian genomes have unexpectedly revealed pervasive and complex transcription and identified tens of thousands of RNA transcripts that do not code for proteins. These non-coding RNAs (ncRNAs) highlight the central role of RNA in gene regulation. ncRNAs are arbitrarily divided into two main groups: The first includes small RNAs, such as miRNAs, piRNAs, and endogenous siRNAs, that usually range from 20 to 30 nt, while the second group includes long non-coding RNAs (lncRNAs), which are typically more than 200 nt in length. These ncRNAs were initially thought to merely regulate gene expression at the post-transcriptional level, but recent studies have indicated that ncRNAs, especially lncRNAs, are extensively associated with diverse chromatin remodeling complexes and target them to specific genomic loci to alter DNA methylation or histone status. These findings suggest an emerging theme of ncRNAs in epigenetic regulation. In this review, we discuss the wide spectrum of ncRNAs in the regulation of DNA methylation and chromatin state, as well as the key questions that needs to be investigated and acknowledging the elegant design of these intriguing macromolecules.

  14. Identification of maize long non-coding RNAs responsive to drought stress.

    PubMed

    Zhang, Wei; Han, Zhaoxue; Guo, Qingli; Liu, Yu; Zheng, Yuxian; Wu, Fangli; Jin, Weibo

    2014-01-01

    Long non-coding RNAs (lncRNAs) represent a class of riboregulators that either directly act in long form or are processed to shorter miRNAs and siRNAs. Emerging evidence shows that lncRNAs participate in stress responsive regulation. In this study, to identify the putative maize lncRNAs responsive to drought stress, 8449 drought responsive transcripts were first uploaded to the Coding Potential Calculator website for classification as protein coding or non-coding RNAs, and 1724 RNAs were identified as potential non-coding RNAs. A Perl script was written to screen these 1724 ncRNAs and 664 transcripts were ultimately identified as drought-responsive lncRNAs. Of these 664 transcripts, 126 drought-responsive lncRNAs were highly similar to known maize lncRNAs; the remaining 538 transcripts were considered as novel lncRNAs. Among the 664 lncRNAs identified as drought responsive, 567 were upregulated and 97 were downregulated in drought-stressed leaves of maize. 8 lncRNAs were identified as miRNA precursor lncRNAs, 62 were classified as both shRNA and siRNA precursors, and 279 were classified as siRNA precursors. The remaining 315 lncRNAs were classified as other lncRNAs that are likely to function as longer molecules. Among these 315 lncRNAs, 10 are identified as antisense lncRNAs and 7 could pair with 17 CDS sequences with near-perfect matches. Finally, RT-qPCR results confirmed that all selected lncRNAs could respond to drought stress. These findings extend the current view on lncRNAs as ubiquitous regulators under stress conditions.

  15. Long non-coding RNAs era in liver cancer.

    PubMed

    Guerrieri, Francesca

    2015-08-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies leading to high mortality rates in the general population and the sixth most common cancer worldwide. HCC is characterized by deregulation of multiple genes and signalling pathways. These genetic effects can involve both protein coding genes as well as non-coding RNA genes. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt, constituting a subpopulation of ncRNAs. Their biological effects are not well understood compared to small non-coding RNA (microRNAs), but they have been recently recognized to exert a crucial role in the regulation of gene expression and modulation of signalling pathways. Notably, several studies indicated that lncRNAs contribute to the pathogenesis and progression of HCC. Investigating the molecular mechanisms underlying lncRNAs expression opens potential applications in diagnosis and treatment of liver disease. This editorial provides three examples (MALAT-1 metastasis associated lung adenocarcinoma transcript, HULC highly upregulated in liver cancer and HOTAIR HOX transcript antisense intergenic RNA) of well-known lncRNAs upregulated in HCC, whose mechanisms of action are known, and for which therapeutic applications are delineated. Targeting of lncRNAs using several approaches (siRNA-mediated silencing or changing their secondary structure) offers new possibility to treat HCC.

  16. Long non-coding RNAs in pluripotent stem cell biology.

    PubMed

    Lammens, Tim; D'hont, Inge; D'Herde, Katharina; Benoit, Yves; Diez-Fraile, Araceli

    2013-12-01

    Pluripotent stem cells are defined by their unlimited self-renewal capacities and potential to differentiate into any cell lineage. Many crucial determinants for the induction and maintenance of this pluripotent state have been identified. Long non-coding RNAs have recently emerged as key regulators of pluripotent stem cells and have enhanced our understanding of their potential functions in tissue regeneration. This review provides an overview of recent important insights into the roles of long non-coding RNAs as regulators and markers of pluripotency.

  17. 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

  18. 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.

  19. Long non-coding RNAs: emerging players in osteosarcoma.

    PubMed

    Li, Zheng; Yu, Xin; Shen, Jianxiong

    2016-03-01

    Osteosarcoma is the most common kind of primary bone tumors with high morbidity in infants and adolescents. While the molecular mechanism of osteosarcoma has gained considerable attention, the mechanisms underlying its initiation and progression remain unclear. Recent studies have discovered that long non-coding RNAs (lncRNAs) play an important role in multiply biological processes including cell development, differentiation, proliferation, invasion, and migration. Deregulated expression of lncRNAs has been found in cancers including osteosarcoma. This review summarized the deregulation and functional role of lncRNAs in osteosarcoma and their potential application for diagnosis and treatment of osteosarcoma.

  20. Viroids, infectious long non-coding RNAs with autonomous replication.

    PubMed

    Gago-Zachert, Selma

    2016-01-01

    Transcriptome deep-sequencing studies performed during the last years confirmed that the vast majority of the RNAs transcribed in higher organisms correspond to several types of non-coding RNAs including long non-coding RNAs (lncRNAs). The study of lncRNAs and the identification of their functions, is still an emerging field in plants but the characterization of some of them indicate that they play an important role in crucial regulatory processes like flowering regulation, and responses to abiotic stress and plant hormones. A second group of lncRNAs present in plants is formed by viroids, exogenous infectious subviral plant pathogens well known since many years. Viroids are composed of circular RNA genomes without protein-coding capacity and subvert enzymatic activities of their hosts to complete its own biological cycle. Different aspects of viroid biology and viroid-host interactions have been elucidated in the last years and some of them are the main topic of this review together with the analysis of the state-of-the-art about the growing field of endogenous lncRNAs in plants.

  1. 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

  2. Long non-coding RNAs in stem cell pluripotency.

    PubMed

    Ng, Shi-Yan; Stanton, Lawrence W

    2013-01-01

    Pluripotency refers to the self-renewal of undifferentiated embryonic stem cells (ESCs), and is maintained by a tightly regulated gene regulatory network involving an intricate interplay between transcription factors and their genomic targets, as well as epigenetic processes that influence gene expression. Long non-coding RNAs (lncRNAs) are newly discovered members of gene regulatory networks that govern a variety of cell functions. Defined as RNA transcripts larger than 200 nucleotides, lncRNAs have little or no protein-coding capacity and have been shown to act via various mechanisms, and are important in a variety of biological functions. Recent reports have described the discovery of pluripotent lncRNAs involved in the maintenance and induction of stem cell pluripotency. Here, we discuss how lncRNAs may integrate into the pluripotency network, as well as prominent questions in this emerging field.

  3. Non-coding RNAs and disease: the classical ncRNAs make a comeback.

    PubMed

    de Almeida, Rogerio Alves; Fraczek, Marcin G; Parker, Steven; Delneri, Daniela; O'Keefe, Raymond T

    2016-08-15

    Many human diseases have been attributed to mutation in the protein coding regions of the human genome. The protein coding portion of the human genome, however, is very small compared with the non-coding portion of the genome. As such, there are a disproportionate number of diseases attributed to the coding compared with the non-coding portion of the genome. It is now clear that the non-coding portion of the genome produces many functional non-coding RNAs and these RNAs are slowly being linked to human diseases. Here we discuss examples where mutation in classical non-coding RNAs have been attributed to human disease and identify the future potential for the non-coding portion of the genome in disease biology. PMID:27528754

  4. 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.

  5. 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

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

    PubMed

    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

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

    PubMed

    Huang, Ya-Kai; Yu, Jian-Chun

    2015-09-14

    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.

  8. 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

  9. Regulatory non-coding RNAs in pluripotent stem cells.

    PubMed

    Rosa, Alessandro; Brivanlou, Ali H

    2013-01-01

    The most part of our genome encodes for RNA transcripts are never translated into proteins. These include families of RNA molecules with a regulatory function, which can be arbitrarily subdivided in short (less than 200 nucleotides) and long non-coding RNAs (ncRNAs). MicroRNAs, which act post-transcriptionally to repress the function of target mRNAs, belong to the first group. Included in the second group are multi-exonic and polyadenylated long ncRNAs (lncRNAs), localized either in the nucleus, where they can associate with chromatin remodeling complexes to regulate transcription, or in the cytoplasm, acting as post-transcriptional regulators. Pluripotent stem cells, such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), represent useful systems for modeling normal development and human diseases, as well as promising tools for regenerative medicine. To fully explore their potential, however, a deep understanding of the molecular basis of stemness is crucial. In recent years, increasing evidence of the importance of regulation by ncRNAs in pluripotent cells is accumulating. In this review, we will discuss recent findings pointing to multiple roles played by regulatory ncRNAs in ESC and iPSCs, where they act in concert with signaling pathways, transcriptional regulatory circuitries and epigenetic factors to modulate the balance between pluripotency and differentiation.

  10. Non-coding RNAs Functioning in Colorectal Cancer Stem Cells.

    PubMed

    Fanale, Daniele; Barraco, Nadia; Listì, Angela; Bazan, Viviana; Russo, Antonio

    2016-01-01

    In recent years, the hypothesis of the presence of tumor-initiating cancer stem cells (CSCs) has received a considerable support. This model suggested the existence of CSCs which, thanks to their self-renewal properties, are able to drive the expansion and the maintenance of malignant cell populations with invasive and metastatic potential in cancer. Increasing evidence showed the ability of such cells to acquire self-renewal, multipotency, angiogenic potential, immune evasion, symmetrical and asymmetrical divisions which, along with the presence of several DNA repair mechanisms, further enhance their oncogenic potential making them highly resistant to common anticancer treatments. The main signaling pathways involved in the homeostasis of colorectal (CRC) stem cells are the Wnt, Notch, Sonic Hedgehog, and Bone Morfogenic Protein (BMP) pathways, which are mostly responsible for all the features that have been widely referred to stem cells. The same pathways have been identified in colorectal cancer stem cells (CRCSCs), conferring a more aggressive phenotype compared to non-stem CRC cells. Recently, several evidences suggested that non-coding RNAs (ncRNAs) may play a crucial role in the regulation of different biological mechanisms in CRC, by modulating the expression of critical stem cell transcription factors that have been found active in CSCs. In this chapter, we will discuss the involvement of ncRNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in stemness acquisition and maintenance by CRCSCs, through the regulation of pathways modulating the CSC phenotype and growth, carcinogenesis, differentiation, and epithelial to mesenchymal transition (EMT). PMID:27573896

  11. Non-coding RNAs Functioning in Colorectal Cancer Stem Cells.

    PubMed

    Fanale, Daniele; Barraco, Nadia; Listì, Angela; Bazan, Viviana; Russo, Antonio

    2016-01-01

    In recent years, the hypothesis of the presence of tumor-initiating cancer stem cells (CSCs) has received a considerable support. This model suggested the existence of CSCs which, thanks to their self-renewal properties, are able to drive the expansion and the maintenance of malignant cell populations with invasive and metastatic potential in cancer. Increasing evidence showed the ability of such cells to acquire self-renewal, multipotency, angiogenic potential, immune evasion, symmetrical and asymmetrical divisions which, along with the presence of several DNA repair mechanisms, further enhance their oncogenic potential making them highly resistant to common anticancer treatments. The main signaling pathways involved in the homeostasis of colorectal (CRC) stem cells are the Wnt, Notch, Sonic Hedgehog, and Bone Morfogenic Protein (BMP) pathways, which are mostly responsible for all the features that have been widely referred to stem cells. The same pathways have been identified in colorectal cancer stem cells (CRCSCs), conferring a more aggressive phenotype compared to non-stem CRC cells. Recently, several evidences suggested that non-coding RNAs (ncRNAs) may play a crucial role in the regulation of different biological mechanisms in CRC, by modulating the expression of critical stem cell transcription factors that have been found active in CSCs. In this chapter, we will discuss the involvement of ncRNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in stemness acquisition and maintenance by CRCSCs, through the regulation of pathways modulating the CSC phenotype and growth, carcinogenesis, differentiation, and epithelial to mesenchymal transition (EMT).

  12. Experimental approaches to identify non-coding RNAs

    PubMed Central

    Hüttenhofer, Alexander; Vogel, Jörg

    2006-01-01

    Cellular RNAs that do not function as messenger RNAs (mRNAs), transfer RNAs (tRNAs) or ribosomal RNAs (rRNAs) comprise a diverse class of molecules that are commonly referred to as non-protein-coding RNAs (ncRNAs). These molecules have been known for quite a while, but their importance was not fully appreciated until recent genome-wide searches discovered thousands of these molecules and their genes in a variety of model organisms. Some of these screens were based on biocomputational prediction of ncRNA candidates within entire genomes of model organisms. Alternatively, direct biochemical isolation of expressed ncRNAs from cells, tissues or entire organisms has been shown to be a powerful approach to identify ncRNAs both at the level of individual molecules and at a global scale. In this review, we will survey several such wet-lab strategies, i.e. direct sequencing of ncRNAs, shotgun cloning of small-sized ncRNAs (cDNA libraries), microarray analysis and genomic SELEX to identify novel ncRNAs, and discuss the advantages and limits of these approaches. PMID:16436800

  13. Non-coding RNAs in schistosomes: an unexplored world.

    PubMed

    Oliveira, Katia C; Carvalho, Mariana L P; Maracaja-Coutinho, Vinicius; Kitajima, João P; Verjovski-Almeida, Sergio

    2011-06-01

    Non-coding RNAs (ncRNAs) were recently given much higher attention due to technical advances in sequencing which expanded the characterization of transcriptomes in different organisms. ncRNAs have different lengths (22 nt to >1,000 nt) and mechanisms of action that essentially comprise a sophisticated gene expression regulation network. Recent publication of schistosome genomes and transcriptomes has increased the description and characterization of a large number of parasite genes. Here we review the number of predicted genes and the coverage of genomic bases in face of the public ESTs dataset available, including a critical appraisal of the evidence and characterization of ncRNAs in schistosomes. We show expression data for ncRNAs in Schistosoma mansoni. We analyze three different microarray experiment datasets: (1) adult worms' large-scale expression measurements; (2) differentially expressed S. mansoni genes regulated by a human cytokine (TNF-α) in a parasite culture; and (3) a stage-specific expression of ncRNAs. All these data point to ncRNAs involved in different biological processes and physiological responses that suggest functionality of these new players in the parasite's biology. Exploring this world is a challenge for the scientists under a new molecular perspective of host-parasite interactions and parasite development.

  14. Non-coding RNAs, the cutting edge of histone messages

    PubMed Central

    Köhn, Marcel; Hüttelmaier, Stefan

    2016-01-01

    ABSTRACT In metazoan the 3′-end processing of histone mRNAs is a conserved process involving the concerted action of many protein factors and the non-coding U7 snRNA. Recently, we identified that the processing of histone pre-mRNAs is promoted by an additional ncRNA, the Y3-derived Y3** RNA. U7 modulates the association of the U7 snRNP whereas Y3** promotes recruitment of CPSF (cleavage and polyadenylation specific factor) proteins to nascent histone transcripts at histone locus bodies (HLBs) in mammals. This enhances the 3′-end cleavage of nascent histone pre-mRNAs and modulates HLB assembly. Here we discuss new insights in the role of ncRNAs in the spatiotemporal control of histone synthesis. We propose that ncRNAs scaffold the formation of functional protein-RNA complexes and their sequential deposition on nascent histone pre-mRNAs at HLBs. These findings add to the multiple roles of ncRNAs in controlling gene expression and may provide new avenues for targeting histone synthesis in cancer. PMID:26909464

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

    PubMed

    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/).

  16. 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

    2016-02-01

    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.

  17. Associating schizophrenia, long non-coding RNAs and neurostructural dynamics.

    PubMed

    Merelo, Veronica; Durand, Dante; Lescallette, Adam R; Vrana, Kent E; Hong, L Elliot; Faghihi, Mohammad Ali; Bellon, Alfredo

    2015-01-01

    Several lines of evidence indicate that schizophrenia has a strong genetic component. But the exact nature and functional role of this genetic component in the pathophysiology of this mental illness remains a mystery. Long non-coding RNAs (lncRNAs) are a recently discovered family of molecules that regulate gene transcription through a variety of means. Consequently, lncRNAs could help us bring together apparent unrelated findings in schizophrenia; namely, genomic deficiencies on one side and neuroimaging, as well as postmortem results on the other. In fact, the most consistent finding in schizophrenia is decreased brain size together with enlarged ventricles. This anomaly appears to originate from shorter and less ramified dendrites and axons. But a decrease in neuronal arborizations cannot explain the complex pathophysiology of this psychotic disorder; however, dynamic changes in neuronal structure present throughout life could. It is well recognized that the structure of developing neurons is extremely plastic. This structural plasticity was thought to stop with brain development. However, breakthrough discoveries have shown that neuronal structure retains some degree of plasticity throughout life. What the neuroscientific field is still trying to understand is how these dynamic changes are regulated and lncRNAs represent promising candidates to fill this knowledge gap. Here, we present evidence that associates specific lncRNAs with schizophrenia. We then discuss the potential role of lncRNAs in neurostructural dynamics. Finally, we explain how dynamic neurostructural modifications present throughout life could, in theory, reconcile apparent unrelated findings in schizophrenia. PMID:26483630

  18. 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

  19. Associating schizophrenia, long non-coding RNAs and neurostructural dynamics

    PubMed Central

    Merelo, Veronica; Durand, Dante; Lescallette, Adam R.; Vrana, Kent E.; Hong, L. Elliot; Faghihi, Mohammad Ali; Bellon, Alfredo

    2015-01-01

    Several lines of evidence indicate that schizophrenia has a strong genetic component. But the exact nature and functional role of this genetic component in the pathophysiology of this mental illness remains a mystery. Long non-coding RNAs (lncRNAs) are a recently discovered family of molecules that regulate gene transcription through a variety of means. Consequently, lncRNAs could help us bring together apparent unrelated findings in schizophrenia; namely, genomic deficiencies on one side and neuroimaging, as well as postmortem results on the other. In fact, the most consistent finding in schizophrenia is decreased brain size together with enlarged ventricles. This anomaly appears to originate from shorter and less ramified dendrites and axons. But a decrease in neuronal arborizations cannot explain the complex pathophysiology of this psychotic disorder; however, dynamic changes in neuronal structure present throughout life could. It is well recognized that the structure of developing neurons is extremely plastic. This structural plasticity was thought to stop with brain development. However, breakthrough discoveries have shown that neuronal structure retains some degree of plasticity throughout life. What the neuroscientific field is still trying to understand is how these dynamic changes are regulated and lncRNAs represent promising candidates to fill this knowledge gap. Here, we present evidence that associates specific lncRNAs with schizophrenia. We then discuss the potential role of lncRNAs in neurostructural dynamics. Finally, we explain how dynamic neurostructural modifications present throughout life could, in theory, reconcile apparent unrelated findings in schizophrenia. PMID:26483630

  20. Non-coding RNAs and complex distributed genetic networks

    NASA Astrophysics Data System (ADS)

    Zhdanov, Vladimir

    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.

  1. Long Non-Coding RNAs in Endometrial Carcinoma.

    PubMed

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

    2015-11-04

    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.

  2. 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

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

    PubMed Central

    Kumari, Pooja; Sampath, Karuna

    2015-01-01

    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. PMID:26498036

  4. 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.

  5. 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

  6. Environmental Health and Long Non-coding RNAs.

    PubMed

    Karlsson, Oskar; Baccarelli, Andrea A

    2016-09-01

    An individual's risk of developing a common disease typically depends on an interaction of genetic and environmental factors. Epigenetic research is uncovering novel ways through which environmental factors such as diet, air pollution, and chemical exposure can affect our genes. DNA methylation and histone modifications are the most commonly studied epigenetic mechanisms. The role of long non-coding RNAs (lncRNAs) in epigenetic processes has been more recently highlighted. LncRNAs are defined as transcribed RNA molecules greater than 200 nucleotides in length with little or no protein-coding capability. While few functional lncRNAs have been well characterized to date, they have been demonstrated to control gene regulation at every level, including transcriptional gene silencing via regulation of the chromatin structure and DNA methylation. This review aims to provide a general overview of lncRNA function with a focus on their role as key regulators of health and disease and as biomarkers of environmental exposure. PMID:27234044

  7. Non-coding RNAs in epithelial immunity to Cryptosporidium infection

    PubMed Central

    Zhou, Rui; Feng, Yaoyu; Chen, Xian-Ming

    2015-01-01

    SUMMARY Cryptosporidium spp. is a protozoan parasite that infects the gastrointestinal epithelium and causes diarrhoeal disease worldwide. It is one of the most common pathogens responsible for moderate to severe diarrhoea in children younger than 2 years. Because of the ‘minimally invasive’ nature of Cryptosporidium infection, mucosal epithelial cells are critical to the host’s anti-Cryptosporidium immunity. Gastrointestinal epithelial cells not only provide the first and most rapid defence against Cryptosporidium infection, they also mobilize immune effector cells to the infection site to activate adaptive immunity. Recent advances in genomic research have revealed the existence of a large number of non-protein-coding RNA transcripts, so called non-coding RNAs (ncRNAs), in mammalian cells. Some ncRNAs may be key regulators for diverse biological functions, including innate immune responses. Specifically, ncRNAs may modulate epithelial immune responses at every step of the innate immune network following Cryptosporidium infection, including production of antimicrobial molecules, expression of cytokines/chemokines, release of epithelial cell-derived exosomes, and feedback regulation of immune homoeostasis. This review briefly summarizes the current science on ncRNA regulation of innate immunity to Cryptosporidium, with a focus on microRNA-associated epithelial immune responses. PMID:24828969

  8. Long non-coding RNAs as emerging regulators of differentiation, development, and disease.

    PubMed

    Dey, Bijan K; Mueller, Adam C; Dutta, Anindya

    2014-01-01

    A significant portion of the mammalian genome encodes numerous transcripts that are not translated into proteins, termed long non-coding RNAs. Initial studies identifying long non-coding RNAs inferred these RNA sequences were a consequence of transcriptional noise or promiscuous RNA polymerase II activity. However, the last decade has seen a revolution in the understanding of regulation and function of long non-coding RNAs. Now it has become apparent that long non-coding RNAs play critical roles in a wide variety of biological processes. In this review, we describe the current understanding of long non-coding RNA-mediated regulation of cellular processes: differentiation, development, and disease.

  9. Neighboring Gene Regulation by Antisense Long Non-Coding RNAs

    PubMed Central

    Villegas, Victoria E.; Zaphiropoulos, Peter G.

    2015-01-01

    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. PMID:25654223

  10. [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.

  11. Chromatin, Non-Coding RNAs, and the Expression of HIV

    PubMed Central

    Groen, Jessica N.; Morris, Kevin V.

    2013-01-01

    HIV is a chronic viral infection affecting an estimated 34 million people worldwide. Current therapies employ the use of a cocktail of antiretroviral medications to reduce the spread and effects of HIV, however complete eradication from an individual currently remains unattainable. Viral latency and regulation of gene expression is a key consideration when developing effective treatments. While our understanding of these processes remains incomplete new developments suggest that non-coding RNA (ncRNA) mediated regulation may provide an avenue to controlling both viral expression and latency. Here we discuss the importance of known regulatory mechanisms and suggest directions for further study, in particular the use ncRNAs in controlling HIV expression. PMID:23812489

  12. The cross talk between long, non-coding RNAs and microRNAs in gastric cancer.

    PubMed

    Deng, Kaiyuan; Wang, Hao; Guo, Xiaoqiang; Xia, Jiazeng

    2016-02-01

    Gastric cancer is one of the most common malignant diseases and remains the second leading cause of cancer-related mortality worldwide. Although great effort has been made during the past decades to facilitate the early detection and treatment of gastric cancer, the prognosis is not yet satisfactory and the underlying molecular mechanisms of gastric cancer pathogenesis are not fully understood. Meanwhile, non-coding RNAs have been established as key players in regulating various biological and pathological processes, such as cell-cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Furthermore, numerous studies have also revealed a complicated interplay among different species of non-coding RNAs; therefore, the cross-regulation between long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) has begun to emerge. This lncRNA-miRNA cross talk, which has attracted increasing attention in recent years, is involved in a great number of human diseases including gastric cancer. In this review, we summarize the latest research progress of the interactions between lncRNAs and miRNAs, highlighting their influences on the development and progression of gastric cancer to provide novel approaches for cancer diagnosis and treatment.

  13. Genome-wide identification of non-coding RNAs interacted with microRNAs in soybean

    PubMed Central

    Ye, Chu-Yu; Xu, Hao; Shen, Enhui; Liu, Yang; Wang, Yu; Shen, Yifei; Qiu, Jie; Zhu, Qian-Hao; Fan, Longjiang

    2014-01-01

    A wide range of RNA species interacting with microRNAs (miRNAs) form a complex gene regulation network and play vital roles in diverse biological processes. In this study, we performed a genome-wide identification of endogenous target mimics (eTMs) for miRNAs and phased-siRNA-producing loci (PHAS) in soybean with a focus on those involved in lipid metabolism. The results showed that a large number of eTMs and PHAS genes could be found in soybean. Additionally, we found that lipid metabolism related genes were potentially regulated by 28 miRNAs, and nine of them were potentially further regulated by a number of eTMs with expression evidence. Thirty-three miRNAs were found to trigger production of phasiRNAs from 49 PHAS genes, which were able to target lipid metabolism related genes. Degradome data supported miRNA- and/or phasiRNA-mediated cleavage of genes involved in lipid metabolism. Most eTMs for miRNAs involved in lipid metabolism and phasiRNAs targeting lipid metabolism related genes showed a tissue-specific expression pattern. Our bioinformatical evidences suggested that lipid metabolism in soybean is potentially regulated by a complex non-coding network, including miRNAs, eTMs, and phasiRNAs, and the results extended our knowledge on functions of non-coding RNAs. PMID:25566308

  14. 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.

  15. Genetic variation in the non-coding genome: Involvement of micro-RNAs and long non-coding RNAs in disease.

    PubMed

    Hrdlickova, Barbara; de Almeida, Rodrigo Coutinho; Borek, Zuzanna; Withoff, Sebo

    2014-10-01

    It has been found that the majority of disease-associated genetic variants identified by genome-wide association studies are located outside of protein-coding regions, where they seem to affect regions that control transcription (promoters, enhancers) and non-coding RNAs that also can influence gene expression. In this review, we focus on two classes of non-coding RNAs that are currently a major focus of interest: micro-RNAs and long non-coding RNAs. We describe their biogenesis, suggested mechanism of action, and discuss how these non-coding RNAs might be affected by disease-associated genetic alterations. The discovery of these alterations has already contributed to a better understanding of the etiopathology of human diseases and yielded insight into the function of these non-coding RNAs. We also provide an overview of available databases, bioinformatics tools, and high-throughput techniques that can be used to study the mechanism of action of individual non-coding RNAs. This article is part of a Special Issue entitled: From Genome to Function.

  16. Small and Long Non-Coding RNAs: Novel Targets in Perspective Cancer Therapy.

    PubMed

    Han Li, Chi; Chen, Yangchao

    2015-10-01

    Non-coding RNA refers to a large group of endogenous RNA molecules that have no protein coding capacity, while having specialized cellular and molecular functions. They possess wide range of functions such as the regulation of gene transcription and translation, post-transcriptional modification, epigenetic landscape establishment, protein scaffolding and cofactors recruitments. They are further divided into small non-coding RNAs with size < 200nt (e.g. miRNA, piRNA) and long non-coding RNAs with size >= 200nt (e.g. lincRNA, NAT). Increasing evidences suggest that both non-coding RNAs groups play important roles in cancer development, progression and pathology. Clinically, non-coding RNAs aberrations show high diagnostic and prognostic values. With improved understanding of the nature and roles of non-coding RNAs, it is believed that we can develop therapeutic treatment against cancer via the modulation of these RNA molecules. Advances in nucleic acid drug technology and computational simulation prompt the development of agents to intervene the malignant effects of non-coding RNAs. In this review, we will discuss the role of non-coding RNAs in cancer, and evaluate the potential of non-coding RNA-based cancer therapies.

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

    PubMed

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

    2012-11-01

    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.

  18. From snoRNA to miRNA: Dual function regulatory non-coding RNAs

    PubMed Central

    Scott, Michelle S.; Ono, Motoharu

    2011-01-01

    Small nucleolar RNAs (snoRNAs) are an ancient class of small non-coding RNAs present in all eukaryotes and a subset of archaea that carry out a fundamental role in the modification and processing of ribosomal RNA. In recent years, however, a large proportion of snoRNAs have been found to be further processed into smaller molecules, some of which display different functionality. In parallel, several studies have uncovered extensive similarities between snoRNAs and other types of small non-coding RNAs, and in particular microRNAs. Here, we explore the extent of the relationship between these types of non-coding RNA and the possible underlying evolutionary forces that shaped this subset of the current non-coding RNA landscape. PMID:21664409

  19. Non-coding RNAs in hepatitis C-induced hepatocellular carcinoma: dysregulation and implications for early detection, diagnosis and therapy.

    PubMed

    Hou, Weihong; Bonkovsky, Herbert L

    2013-11-28

    Hepatitis C virus (HCV) infection is one of main causes of hepatocellular carcinoma (HCC) and the prevalence of HCV-associated HCC is on the rise worldwide. It is particularly important and helpful to identify potential markers for screening and early diagnosis of HCC among high-risk individuals with chronic hepatitis C, and to identify target molecules for the prevention and treatment of HCV-associated-HCC. Small non-coding RNAs, mainly microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) with size greater than 200 nucleotides, are likely to play important roles in a variety of biological processes, including development and progression of HCC. For the most part their underlying mechanisms of action remain largely unknown. In recent years, with the advance of high-resolution of microarray and application of next generation sequencing techniques, a significant number of non-coding RNAs (ncRNAs) associated with HCC, particularly caused by HCV infection, have been found to be differentially expressed and to be involved in pathogenesis of HCV-associated HCC. In this review, we focus on recent studies of ncRNAs, especially miRNAs and lncRNAs related to HCV-induced HCC. We summarize those ncRNAs aberrantly expressed in HCV-associated HCC and highlight the potential uses of ncRNAs in early detection, diagnosis and therapy of HCV-associated HCC. We also discuss the limitations of recent studies, and suggest future directions for research in the field. miRNAs, lncRNAs and their target genes may represent new candidate molecules for the prevention, diagnosis and treatment of HCC in patients with HCV infection. Studies of the potential uses of miRNAs and lncRNAs as diagnostic tools or therapies are still in their infancy.

  20. Biogenesis and function of non-coding RNAs in muscle differentiation and in Duchenne muscular dystrophy.

    PubMed

    Twayana, Shyam; Legnini, Ivano; Cesana, Marcella; Cacchiarelli, Davide; Morlando, Mariangela; Bozzoni, Irene

    2013-08-01

    It is now becoming largely accepted that the non-coding portion of the genome, rather than its coding counterpart, is likely to account for the greater complexity of higher eukaryotes. Moreover, non-coding RNAs have been demonstrated to participate in regulatory circuitries that are crucial for development and differentiation. Whereas the biogenesis and function of small non-coding RNAs, particularly miRNAs (microRNAs), has been extensively clarified in many eukaryotic systems, very little is known about the long non-coding counterpart of the transcriptome. In the present review, we revise the current knowledge of how small non-coding RNAs and lncRNAs (long non-coding RNAs) impinge on circuitries controlling proper muscle differentiation and homoeostasis and how their biogenesis is regulated. Moreover, we provide new insights into an additional mechanism of post-transcriptional regulation mediated by lncRNAs, which, acting as miRNA 'sponges', have an impact on the distribution of miRNA molecules on their targets with features similar to those described for ceRNAs (competing endogenous RNAs).

  1. 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.

  2. Roles of Long Non-Coding RNAs on Tumorigenesis and Glioma Development.

    PubMed

    Park, Ju Young; Lee, Jeong Eun; Park, Jong Bae; Yoo, Heon; Lee, Seung-Hoon; Kim, Jong Heon

    2014-04-01

    More than 98% of eukaryotic tanscriptomes are composed of non-coding RNAs with no functional protein-coding capacity. Those transcripts also include tens of thousands of long non-coding RNAs (lncRNAs) which are emerging as key elements of cellular homeostasis, essentially tumorigenesis steps. However, we are only beginning to understand the nature and extent of the involvement of lncRNAs on tumorigeneis. Here, we highlight recent progresses that have identified a myriad of molecular functions on tumorigenesis for several lncRNAs including metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), prostate cancer associated non-coding RNA 1 (PRNCR1), prostate cancer gene expression marker 1 (PCGEM1), H19, and homeobox transcript antisense intergenic RNA (HOTAIR), and several new lncRNAs for glioma development. Potential therapeutic approaches for the lncRNAs in various human diseases are also discussed.

  3. Genomic variations in non-coding RNAs: Structure, function and regulation.

    PubMed

    Bhartiya, Deeksha; Scaria, Vinod

    2016-03-01

    The last decade has seen tremendous improvements in the understanding of human variations and their association with human traits and diseases. The availability of high-resolution map of the human transcriptome and the discovery of a large number of non-protein coding RNA genes has created a paradigm shift in the understanding of functional variations in non-coding RNAs. Several groups in recent years have reported functional variations and trait or disease associated variations mapping to non-coding RNAs including microRNAs, small nucleolar RNAs and long non-coding RNAs. The understanding of the functional consequences of variations in non-coding RNAs has been largely restricted by the limitations in understanding the functionalities of the non-coding RNAs. In this short review, we outline the current state-of-the-art of the field with emphasis on providing a conceptual outline as on how variations could modulate changes in the sequence, structure, and thereby the functionality of non-coding RNAs.

  4. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  6. Non-coding RNAs in Exosomes: New Players in Cancer Biology.

    PubMed

    Silva, Miguel; Melo, Sonia A

    2015-10-01

    Exosomes are lipid bilayer extracellular vesicles (EVs) of 50-150nm in size, which contain nucleic acids (mRNA, ncRNAs and DNA), proteins and lipids. They are secreted by all cells and circulate in all body fluids. Exosomes are key mediators of several processes in cancer that mediate tumor progression and metastasis. These nano-vesicles, when secreted from cancer cells, are enriched in non-coding RNAs (e.g. microRNAs) complexed with the RNA-Induced Silencing Complex (RISC), that mediate an efficient and rapid silencing of mRNAs at the recipient cell, reprogramming their transcriptome. MicroRNAs in circulation encapsulated in exosomes are protected from degradation by a lipid bilayer and might serve as potential non-invasive diagnostic and screening tools to detect early stage cancer, to facilitate treatment options and possible help in curative surgical therapy decisions. Additionally, engineered exosomes can be used as therapy vehicles for targeted delivery of RNAi molecules, escaping the immune system detection.

  7. Non-coding RNAs in Exosomes: New Players in Cancer Biology

    PubMed Central

    Silva, Miguel; Melo, Sonia A.

    2015-01-01

    Exosomes are lipid bilayer extracellular vesicles (EVs) of 50-150nm in size, which contain nucleic acids (mRNA, ncRNAs and DNA), proteins and lipids. They are secreted by all cells and circulate in all body fluids. Exosomes are key mediators of several processes in cancer that mediate tumor progression and metastasis. These nano-vesicles, when secreted from cancer cells, are enriched in non-coding RNAs (e.g. microRNAs) complexed with the RNA-Induced Silencing Complex (RISC), that mediate an efficient and rapid silencing of mRNAs at the recipient cell, reprogramming their transcriptome. MicroRNAs in circulation encapsulated in exosomes are protected from degradation by a lipid bilayer and might serve as potential non-invasive diagnostic and screening tools to detect early stage cancer, to facilitate treatment options and possible help in curative surgical therapy decisions. Additionally, engineered exosomes can be used as therapy vehicles for targeted delivery of RNAi molecules, escaping the immune system detection. PMID:27047249

  8. The Clinical Relevance of Long Non-Coding RNAs in Cancer

    PubMed Central

    Silva, Andreia; Bullock, Marc; Calin, George

    2015-01-01

    Non-coding RNAs have long been associated with cancer development and progression, and since their earliest discovery, their clinical potential in identifying and characterizing the disease has been pursued. Long non-coding (lncRNAs), a diverse class of RNA transcripts >200 nucleotides in length with limited protein coding potential, has been only modestly studied relative to other categories of non-coding RNAs. However, recent data suggests they too may be important players in cancer. In this article, we consider the value of lncRNAs in the clinical setting, and in particular their potential roles as diagnostic and prognostic markers in cancer. Furthermore, we summarize the most significant studies linking lncRNA expression in human biological samples to cancer outcomes. The diagnostic sensitivity, specificity and validity of these non-coding RNA transcripts is compared in the various biological compartments in which they have been detected including tumor tissue, whole body fluids and exosomes. PMID:26516918

  9. The Clinical Relevance of Long Non-Coding RNAs in Cancer.

    PubMed

    Silva, Andreia; Bullock, Marc; Calin, George

    2015-10-27

    Non-coding RNAs have long been associated with cancer development and progression, and since their earliest discovery, their clinical potential in identifying and characterizing the disease has been pursued. Long non-coding (lncRNAs), a diverse class of RNA transcripts >200 nucleotides in length with limited protein coding potential, has been only modestly studied relative to other categories of non-coding RNAs. However, recent data suggests they too may be important players in cancer. In this article, we consider the value of lncRNAs in the clinical setting, and in particular their potential roles as diagnostic and prognostic markers in cancer. Furthermore, we summarize the most significant studies linking lncRNA expression in human biological samples to cancer outcomes. The diagnostic sensitivity, specificity and validity of these non-coding RNA transcripts is compared in the various biological compartments in which they have been detected including tumor tissue, whole body fluids and exosomes.

  10. 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.

  11. Standing your ground to exoribonucleases: Function of Flavivirus long non-coding RNAs.

    PubMed

    Charley, Phillida A; Wilusz, Jeffrey

    2016-01-01

    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 subgenomic flavivirus 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.

  12. Non-coding RNAs as Emerging Regulators of Neural Injury Responses and Regeneration.

    PubMed

    Zhou, Songlin; Ding, Fei; Gu, Xiaosong

    2016-06-01

    Non-coding RNAs (ncRNAs) are a large cluster of RNAs that do not encode proteins, but have multiple functions in diverse cellular processes. Mounting evidence indicates the involvement of ncRNAs in the physiology and pathophysiology of the central and peripheral nervous systems. It has been shown that numerous ncRNAs, especially microRNAs and long non-coding RNAs, are differentially expressed after insults such as acquired brain injury, spinal cord injury, and peripheral nerve injury. These ncRNAs affect neuronal survival, neurite regrowth, and glial phenotype primarily by targeting specific mRNAs, resulting in translation repression or degradation of the mRNAs. An increasing number of studies have investigated the regulatory roles of microRNAs and long non-coding RNAs in neural injury and regeneration, and thus a new research field is emerging. In this review, we highlight current progress in the field in an attempt to provide further insight into post-transcriptional changes occurring after neural injury, and to facilitate the potential use of ncRNAs for improving neural regeneration. We also suggest potential directions for future studies.

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

    PubMed

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

    2016-01-21

    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.

  14. 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

  15. Integrating non-coding RNAs in JAK-STAT regulatory networks.

    PubMed

    Witte, Steven; Muljo, Stefan A

    2014-01-01

    Being a well-characterized pathway, JAK-STAT signaling serves as a valuable paradigm for studying the architecture of gene regulatory networks. The discovery of untranslated or non-coding RNAs, namely microRNAs and long non-coding RNAs, provides an opportunity to elucidate their roles in such networks. In principle, these regulatory RNAs can act as downstream effectors of the JAK-STAT pathway and/or affect signaling by regulating the expression of JAK-STAT components. Examples of interactions between signaling pathways and non-coding RNAs have already emerged in basic cell biology and human diseases such as cancer, and can potentially guide the identification of novel biomarkers or drug targets for medicine.

  16. The emerging role of long non-coding RNAs in HIV infection.

    PubMed

    Lazar, Daniel C; Morris, Kevin V; Saayman, Sheena M

    2016-01-01

    The discovery of long non-coding RNAs (lncRNAs) and the elucidation of the mechanisms by which they affect different disease states are providing researchers with a better understanding of a wide array of disease pathways. Moreover, lncRNAs are presenting themselves as both unique diagnostic biomarkers as well as novel targets against which to develop new therapeutics. Here we will explore the intricate network of non-coding RNAs associated with infection by the human immunodeficiency virus (HIV). Non-coding RNAs derived from both the human host as well as those from HIV itself are emerging as important regulatory elements. We discuss here the various mechanisms through which both small and long non-coding RNAs impact viral replication, pathogenesis and disease progression. Given the lack of an effective vaccine or cure for HIV and the scale of the current pandemic, a deeper understanding of the complex interplay between non-coding RNAs and HIV will support the development of innovative strategies for the treatment of HIV/acquired immunodeficiency disease (AIDS).

  17. In silico prediction of long intergenic non-coding RNAs in sheep.

    PubMed

    Bakhtiarizadeh, Mohammad Reza; Hosseinpour, Batool; Arefnezhad, Babak; Shamabadi, Narges; Salami, Seyed Alireza

    2016-04-01

    Long non-coding RNAs (lncRNAs) are transcribed RNA molecules >200 nucleotides in length that do not encode proteins and serve as key regulators of diverse biological processes. Recently, thousands of long intergenic non-coding RNAs (lincRNAs), a type of lncRNAs, have been identified in mammalians using massive parallel large sequencing technologies. The availability of the genome sequence of sheep (Ovis aries) has allowed us genomic prediction of non-coding RNAs. This is the first study to identify lincRNAs using RNA-seq data of eight different tissues of sheep, including brain, heart, kidney, liver, lung, ovary, skin, and white adipose. A computational pipeline was employed to characterize 325 putative lincRNAs with high confidence from eight important tissues of sheep using different criteria such as GC content, exon number, gene length, co-expression analysis, stability, and tissue-specific scores. Sixty-four putative lincRNAs displayed tissues-specific expression. The highest number of tissues-specific lincRNAs was found in skin and brain. All novel lincRNAs that aligned to the human and mouse lincRNAs had conserved synteny. These closest protein-coding genes were enriched in 11 significant GO terms such as limb development, appendage development, striated muscle tissue development, and multicellular organismal development. The findings reported here have important implications for the study of sheep genome.

  18. Distinct Expression of Long Non-Coding RNAs in an Alzheimer's Disease Model.

    PubMed

    Lee, Doo Young; Moon, Jangsup; Lee, Soon-Tae; Jung, Keun-Hwa; Park, Dong-Kyu; Yoo, Jung-Seok; Sunwoo, Jun-Sang; Byun, Jung-Ick; Shin, Jung-Won; Jeon, Daejong; Jung, Ki-Young; Kim, Manho; Lee, Sang Kun; Chu, Kon

    2015-01-01

    With the recent advancement in transcriptome-wide profiling approach, numerous non-coding transcripts previously unknown have been identified. Among the non-coding transcripts, long non-coding RNAs (lncRNAs) have received increasing attention for their capacity to modulate transcriptional regulation. Although alterations in the expressions of non-coding RNAs have been studied in Alzheimer's disease (AD), most research focused on the involvement of microRNAs, and comprehensive expression profiling of lncRNAs in AD has been lacking. In this study, microarray analysis was performed to procure the expression profile of lncRNAs dysregulated in a triple transgenic model of AD (3xTg-AD). A total of 4,622 lncRNAs were analyzed: 205 lncRNAs were significantly dysregulated in 3xTg-AD compared with control mice, and 230 lncRNAs were significantly dysregulated within 3xTg-AD in an age-dependent manner (≥2.0-fold, p < 0.05). Among these, 27 and 15 lncRNAs, respectively, had adjacent protein-coding genes whose expressions were also significantly dysregulated. A majority of these lncRNAs and their adjacent genes shared the same direction of dysregulation. For these pairs of lncRNAs and adjacent genes, significant Gene Ontology terms were DNA-dependent regulation of transcription, transcription regulator activity, and embryonic organ morphogenesis. One of the most highly upregulated lncRNAs had a 395 bp core sequence that overlapped with multiple chromosomal regions. This is the first study that comprehensively identified dysregulated lncRNAs in 3xTg-AD mice and will likely facilitate the development of therapeutics targeting lncRNAs in AD.

  19. Non-coding RNAs: Therapeutic Strategies and Delivery Systems.

    PubMed

    Ling, Hui

    2016-01-01

    The vast majority of the human genome is transcribed into RNA molecules that do not code for proteins, which could be small ones approximately 20 nucleotide in length, known as microRNAs, or transcripts longer than 200 bp, defined as long noncoding RNAs. The prevalent deregulation of microRNAs in human cancers prompted immediate interest on the therapeutic value of microRNAs as drugs and drug targets. Many features of microRNAs such as well-defined mechanisms, and straightforward oligonucleotide design further make them attractive candidates for therapeutic development. The intensive efforts of exploring microRNA therapeutics are reflected by the large body of preclinical studies using oligonucleotide-based mimicking and blocking, culminated by the recent entry of microRNA therapeutics in clinical trial for several human diseases including cancer. Meanwhile, microRNA therapeutics faces the challenge of effective and safe delivery of nucleic acid therapeutics into the target site. Various chemical modifications of nucleic acids and delivery systems have been developed to increase targeting specificity and efficacy, and reduce the associated side effects including activation of immune response. Recently, long noncoding RNAs become attractive targets for therapeutic intervention because of their association with complex and delicate phenotypes, and their unconventional pharmaceutical activities such as capacity of increasing output of proteins. Here I discuss the general therapeutic strategies targeting noncoding RNAs, review delivery systems developed to maximize noncoding RNA therapeutic efficacy, and offer perspectives on the future development of noncoding RNA targeting agents for colorectal cancer. PMID:27573903

  20. 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

  1. The functional role of long non-coding RNAs and epigenetics.

    PubMed

    Cao, Jinneng

    2014-01-01

    Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. The post-transcriptional regulation is influenced by these lncRNAs by interfering with the microRNA pathways, involving in diverse cellular processes. The regulation of gene expression by lncRNAs at the epigenetic level, transcriptional and post-transcriptional level have been well known and widely studied. Recent recognition that lncRNAs make effects in many biological and pathological processes such as stem cell pluripotency, neurogenesis, oncogenesis and etc. This review will focus on the functional roles of lncRNAs in epigenetics and related research progress will be summarized.

  2. 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

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

    PubMed

    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 AND 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

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

    PubMed

    Shortridge, Matthew D; Varani, Gabriele

    2015-02-01

    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.

  5. 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.

  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. Identification and characterisation of non-coding small RNAs in the pathogenic filamentous fungus Trichophyton rubrum

    PubMed Central

    2013-01-01

    Background Accumulating evidence demonstrates that non-coding RNAs (ncRNAs) are indispensable components of many organisms and play important roles in cellular events, regulation, and development. Results Here, we analysed the small non-coding RNA (ncRNA) transcriptome of Trichophyton rubrum by constructing and sequencing a cDNA library from conidia and mycelia. We identified 352 ncRNAs and their corresponding genomic loci. These ncRNA candidates included 198 entirely novel ncRNAs and 154 known ncRNAs classified as snRNAs, snoRNAs and other known ncRNAs. Further bioinformatic analysis detected 96 snoRNAs, including 56 snoRNAs that had been annotated in other organisms and 40 novel snoRNAs. All snoRNAs belonged to two major classes—C/D box snoRNAs and H/ACA snoRNAs—and their potential target sites in rRNAs and snRNAs were predicted. To analyse the evolutionary conservation of the ncRNAs in T. rubrum, we aligned all 352 ncRNAs to the genomes of six dermatophytes and to the NCBI non-redundant nucleotide database (NT). The results showed that most of the identified snRNAs were conserved in dermatophytes. Of the 352 ncRNAs, 102 also had genomic loci in other dermatophytes, and 27 were dermatophyte-specific. Conclusions Our systematic analysis may provide important clues to the function and evolution of ncRNAs in T. rubrum. These results also provide important information to complement the current annotation of the T. rubrum genome, which primarily comprises protein-coding genes. PMID:24377353

  8. Bistability in self-activating genes regulated by non-coding RNAs

    NASA Astrophysics Data System (ADS)

    Miro-Bueno, Jesus

    2015-01-01

    Non-coding RNA molecules are able to regulate gene expression and play an essential role in cells. On the other hand, bistability is an important behaviour of genetic networks. Here, we propose and study an ODE model in order to show how non-coding RNA can produce bistability in a simple way. The model comprises a single gene with positive feedback that is repressed by non-coding RNA molecules. We show how the values of all the reaction rates involved in the model are able to control the transitions between the high and low states. This new model can be interesting to clarify the role of non-coding RNA molecules in genetic networks. As well, these results can be interesting in synthetic biology for developing new genetic memories and biomolecular devices based on non-coding RNAs.

  9. Functional diversity of long non-coding RNAs in immune regulation

    PubMed Central

    Geng, Hua; Tan, Xiao-Di

    2016-01-01

    Precise and dynamic regulation of gene expression is a key feature of immunity. In recent years, rapid advances in transcriptome profiling analysis have led to recognize long non-coding RNAs (lncRNAs) as an additional layer of gene regulation context. In the immune system, lncRNAs are found to be widely expressed in immune cells including monocytes, macrophages, dendritic cells (DCs), neutrophils, T cells and B cells during their development, differentiation and activation. However, the functional importance of immune-related lncRNAs is just emerging to be characterized. In this review, we discuss the up-to-date knowledge of lncRNAs in immune regulation. PMID:27617274

  10. Insights into multiple sclerosis provided by non-coding RNAs: meeting summary from the symposium 'non-coding RNAs in autoimmune disorders of the central nervous system' on 5 April 2013 in Warsaw, Poland.

    PubMed

    Mycko, Marcin P; Weiner, Howard L; Selmaj, Krzysztof W

    2014-10-01

    More than 80% of the human genome is biochemically active, whereas less than 3% of the genome encodes proteins. The emerging field of non-coding ribonucleic acids (RNAs) that are products of the genome, but do not program proteins, has revolutionized our understanding of cell biology. This was followed by a growing interest in the role of non-coding RNAs in the pathogenesis of human diseases, including multiple sclerosis (MS). In April 2013, a symposium in Warsaw, Poland, was the first meeting entirely dedicated to advances in the understanding of the roles of various subclasses of non-coding RNAs and showcased their involvement in autoimmune demyelination and MS. New mechanisms of action of small non-coding RNAs, as well as the advent of long non-coding RNAs were discussed, including the potential role of non-coding RNAs as MS biomarkers and their use for therapeutic intervention in MS.

  11. Involvement of Non-coding RNAs in the Signaling Pathways of Colorectal Cancer.

    PubMed

    Yang, Yinxue; Du, Yong; Liu, Xiaoming; Cho, William C

    2016-01-01

    Colorectal cancer (CRC) is one of the most common diagnosed cancers worldwide. The metastasis and development of resistance to anti-cancer treatment are major challenges in the treatment of CRC. Understanding mechanisms underpinning the pathogenesis is therefore critical in developing novel agents for CRC treatments. A large number of evidence has demonstrated that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs have functional roles in both the physiological and pathological processes by regulating the expression of their target genes. These molecules are engaged in the pathobiology of neoplastic diseases and are targets for the diagnosis, prognosis and therapy of a variety of cancers, including CRC. In this regard, ncRNAs have emerged as one of the hallmarks of CRC pathogenesis and they also play key roles in metastasis, drug resistance and the stemness of CRC stem cell by regulating various signaling networks. Therefore, a better understanding the ncRNAs involved in the signaling pathways of CRC may lead to the development of novel strategy for diagnosis, prognosis and treatment of CRC. In this chapter, we summarize the latest findings on ncRNAs, with a focus on miRNAs and lncRNAs involving in signaling networks and in the regulation of pathogenic signaling pathways in CRC.

  12. Non-coding RNAs in cerebral endothelial pathophysiology: emerging roles in stroke.

    PubMed

    Yin, Ke-Jie; Hamblin, Milton; Chen, Y Eugene

    2014-11-01

    Cerebral vascular endothelial cells form the major element of the blood-brain barrier (BBB) and constitute the primary interface between circulating blood and brain parenchyma. The structural and functional changes in cerebral endothelium during cerebral ischemia are well known to result in BBB disruption, vascular inflammation, edema, and angiogenesis. These complex pathological processes directly contribute to brain infarction, neurological deficits, and post-stroke neurovascular remodeling. Ischemic endothelial dysfunction appears to be tightly controlled by multiple gene signaling networks. Non-coding RNAs (ncRNAs) are functional RNA molecules that are generally not translated into proteins but can actively regulate the expression and function of many thousands of protein-coding genes by different mechanisms. Various classes of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), small nucleolar RNAs (snoRNAs) and piwi-interacting RNAs (piRNAs), are highly expressed in the cerebrovascular endothelium where they serve as critical mediators to maintain normal cerebral vascular functions. Dysregulation of ncRNA activities has been closely linked to the pathophysiology of cerebral vascular endothelium and neurologic functional disorders in the brain's response to ischemic stimuli. In this review, we summarize recent advancements of these ncRNA mediators in the brain vasculature, highlighting the specific roles of endothelial miRNAs in stroke.

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

    PubMed

    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.

  14. Biogenesis and Mechanism of Action of Small Non-Coding RNAs: Insights from the Point of View of Structural Biology

    PubMed Central

    Costa, Marina C.; Leitão, Ana Lúcia; Enguita, Francisco J.

    2012-01-01

    Non-coding RNAs are dominant in the genomic output of the higher organisms being not simply occasional transcripts with idiosyncratic functions, but constituting an extensive regulatory network. Among all the species of non-coding RNAs, small non-coding RNAs (miRNAs, siRNAs and piRNAs) have been shown to be in the core of the regulatory machinery of all the genomic output in eukaryotic cells. Small non-coding RNAs are produced by several pathways containing specialized enzymes that process RNA transcripts. The mechanism of action of these molecules is also ensured by a group of effector proteins that are commonly engaged within high molecular weight protein-RNA complexes. In the last decade, the contribution of structural biology has been essential to the dissection of the molecular mechanisms involved in the biosynthesis and function of small non-coding RNAs. PMID:22949860

  15. 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.

  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. 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

  18. Small non-coding RNAs and aptamers in diagnostics and therapeutics.

    PubMed

    Leonard, Marissa; Zhang, Yijuan; Zhang, Xiaoting

    2015-01-01

    Small non-coding RNAs (sncRNAs) such as small interfering RNAs (siRNAs), microRNAs (miRNAs) and RNA aptamers have recently emerged as highly versatile and valuable tools in disease diagnostics and therapeutics, largely due to their key regulatory functions in many human diseases including cancer, viral infections, genetic disorders, etc. Recent technological advancements as described in the previous chapters have greatly aided the discovery of sncRNAs and their applications for disease detection and therapy. Here, we describe the advantages of using sncRNAs as diagnostic and therapeutic tools, followed by some of the most recent examples of their use and a vision for the future perspectives.

  19. 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

  20. Long Non-Coding RNAs as Master Regulators in Cardiovascular Diseases

    PubMed Central

    Archer, Krystal; Broskova, Zuzana; Bayoumi, Ahmed S.; Teoh, Jian-peng; Davila, Alec; Tang, Yaoliang; Su, Huabo; Kim, Il-man

    2015-01-01

    Cardiovascular disease is the leading cause of death in the United States, accounting for nearly one in every seven deaths. Over the last decade, various targeted therapeutics have been introduced, but there has been no corresponding improvement in patient survival. Since the mortality rate of cardiovascular disease has not been significantly decreased, efforts have been made to understand the link between heart disease and novel therapeutic targets such as non-coding RNAs. Among multiple non-coding RNAs, long non-coding RNA (lncRNA) has emerged as a novel therapeutic in cardiovascular medicine. LncRNAs are endogenous RNAs that contain over 200 nucleotides and regulate gene expression. Recent studies suggest critical roles of lncRNAs in modulating the initiation and progression of cardiovascular diseases. For example, aberrant lncRNA expression has been associated with the pathogenesis of ischemic heart failure. In this article, we present a synopsis of recent discoveries that link the roles and molecular interactions of lncRNAs to cardiovascular diseases. Moreover, we describe the prevalence of circulating lncRNAs and assess their potential utilities as biomarkers for diagnosis and prognosis of heart disease. PMID:26445043

  1. Long Non-Coding RNAs as Master Regulators in Cardiovascular Diseases.

    PubMed

    Archer, Krystal; Broskova, Zuzana; Bayoumi, Ahmed S; Teoh, Jian-peng; Davila, Alec; Tang, Yaoliang; Su, Huabo; Kim, Il-man

    2015-10-05

    Cardiovascular disease is the leading cause of death in the United States, accounting for nearly one in every seven deaths. Over the last decade, various targeted therapeutics have been introduced, but there has been no corresponding improvement in patient survival. Since the mortality rate of cardiovascular disease has not been significantly decreased, efforts have been made to understand the link between heart disease and novel therapeutic targets such as non-coding RNAs. Among multiple non-coding RNAs, long non-coding RNA (lncRNA) has emerged as a novel therapeutic in cardiovascular medicine. LncRNAs are endogenous RNAs that contain over 200 nucleotides and regulate gene expression. Recent studies suggest critical roles of lncRNAs in modulating the initiation and progression of cardiovascular diseases. For example, aberrant lncRNA expression has been associated with the pathogenesis of ischemic heart failure. In this article, we present a synopsis of recent discoveries that link the roles and molecular interactions of lncRNAs to cardiovascular diseases. Moreover, we describe the prevalence of circulating lncRNAs and assess their potential utilities as biomarkers for diagnosis and prognosis of heart disease.

  2. 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.

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

    PubMed

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

    2016-04-15

    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.

  4. 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.

  5. The emerging role of pseudogene expressed non-coding RNAs in cellular functions

    PubMed Central

    Groen, Jessica N.; Capraro, David; Morris, Kevin V.

    2014-01-01

    A paradigm shift is sweeping modern day molecular biology following the realisation that large amounts of “junk” DNA”, thought initially to be evolutionary remnants, may actually be functional. Several recent studies support a functional role for pseudogene-expressed non-coding RNAs in regulating their protein-coding counterparts. Several hundreds of pseudogenes have been reported as transcribed into RNA in a large variety of tissues and tumours. Most studies have focused on pseudogenes expressed in the sense direction, but some reports suggest that pseudogenes can also be transcribed as antisense RNAs (asRNAs). A few examples of key regulatory genes, such as PTEN and OCT4, have in fact been reported to be under the regulation of pseudogene-expressed asRNAs. Here, we review what are known about pseudogene expressed non-coding RNA mediated gene regulation and their roles in the control of epigenetic states. PMID:24842102

  6. Elements and machinery of non-coding RNAs: toward their taxonomy

    PubMed Central

    Hirose, Tetsuro; Mishima, Yuichiro; Tomari, Yukihide

    2014-01-01

    Although recent transcriptome analyses have uncovered numerous non-coding RNAs (ncRNAs), their functions remain largely unknown. ncRNAs assemble with proteins and operate as ribonucleoprotein (RNP) machineries, formation of which is thought to be determined by specific fundamental elements embedded in the primary RNA transcripts. Knowledge about the relationships between RNA elements, RNP machinery, and molecular and physiological functions is critical for understanding the diverse roles of ncRNAs and may eventually allow their systematic classification or “taxonomy.” In this review, we catalog and discuss representative small and long non-coding RNA classes, focusing on their currently known (and unknown) RNA elements and RNP machineries. PMID:24731943

  7. Long non-coding RNAs: new players in cell differentiation and development.

    PubMed

    Fatica, Alessandro; Bozzoni, Irene

    2014-01-01

    Genomes of multicellular organisms are characterized by the pervasive expression of different types of non-coding RNAs (ncRNAs). Long ncRNAs (lncRNAs) belong to a novel heterogeneous class of ncRNAs that includes thousands of different species. lncRNAs have crucial roles in gene expression control during both developmental and differentiation processes, and the number of lncRNA species increases in genomes of developmentally complex organisms, which highlights the importance of RNA-based levels of control in the evolution of multicellular organisms. In this Review, we describe the function of lncRNAs in developmental processes, such as in dosage compensation, genomic imprinting, cell differentiation and organogenesis, with a particular emphasis on mammalian development.

  8. Long non-coding RNAs and cancer: a new frontier of translational research?

    PubMed Central

    Spizzo, R; Almeida, MI; Colombatti, A; Calin, GA

    2012-01-01

    Tiling array and novel sequencing technologies have made available the transcription profile of the entire human genome. However, the extent of transcription and the function of genetic elements that occur outside of protein-coding genes, particularly those involved in disease, are still a matter of debate. In this review, we focus on long non-coding RNAs (lncRNAs) that are involved in cancer. We define lncRNAs and present a cancer-oriented list of lncRNAs, list some tools (for example, public databases) that classify lncRNAs or that scan genome spans of interest to find whether known lncRNAs reside there, and describe some of the functions of lncRNAs and the possible genetic mechanisms that underlie lncRNA expression changes in cancer, as well as current and potential future applications of lncRNA research in the treatment of cancer. PMID:22266873

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

    PubMed

    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.

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

    PubMed

    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. 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

  13. Small non-coding RNAs, mammalian cells, and viruses: regulatory interactions?

    PubMed

    Yeung, Man Lung; Benkirane, Monsef; Jeang, Kuan-Teh

    2007-01-01

    Recent findings suggest that mammalian cells can use small non-coding RNAs (ncRNA) to regulate physiological viral infections. Here, we comment on several lines of evidence that support this concept. We discuss how viruses may in turn protect, suppress, evade, modulate, or adapt to the host cell's ncRNA regulatory schema. PMID:17937800

  14. 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

  15. 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.

  16. 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.

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

    PubMed

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

    2015-09-01

    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

  19. 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.

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

    PubMed

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

    2014-11-01

    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. PMID:25450361

  1. Processing of snoRNAs as a new source of regulatory non-coding RNAs snoRNA fragments form a new class of functional RNAs

    PubMed Central

    Falaleeva, Marina; Stamm, Stefan

    2013-01-01

    Recent experimental evidence suggests that most of the genome is transcribed into non-coding RNAs. The initially made transcripts undergo further processing generating shorter, metabolically stable RNAs with diverse functions. Small nucleolar RNAs (snoRNAs) are non-coding RNAs acting in modification of rRNAs, tRNAs and snRNAs that were considered stable. We review evidence that snoRNAs undergo further processing. High-throughput sequencing and RNase protection experiments showed widespread expression of snoRNA fragments, called sdRNAs for snoRNA derived RNAs. Some sdRNAs resemble miRNAs, associate with argonaute proteins and influence translation. Other sdRNAs are longer, form complexes with hnRNPs and influence gene expression. C/D box snoRNA fragmentation patterns are conserved across multiple cell types, suggesting a processing event, rather than degradation. The loss of expression from genetic loci that generate canonical snoRNAs and processed snoRNAs results in diseases, such as the Prader-Willi Syndrome, indicating possible physiological roles for processed snoRNAs. We propose that processed snoRNAs acquire new roles in gene expression and represent a new class of regulatory RNAs distinct from canonical snoRNAs. PMID:23180440

  2. Emerging roles of RNA processing factors in regulating long non-coding RNAs

    PubMed Central

    Zhang, Huiming; Zhu, Jian-Kang

    2014-01-01

    Long non-coding RNAs (lncRNAs) can be important regulators of various biological processes such as RNA-directed DNA methylation (RdDM). In the RdDM pathway, recruitment of the DNA methylation complex is mediated through complementary pairing between scaffold RNAs and Argonaute-associated siRNAs. Scaffold RNAs are chromatin-associated lncRNAs transcribed by RNA polymerase Pol V or Pol II, while siRNAs originate from Pol IV- or Pol II-dependent production of lncRNAs. In contrast to the vast literature on co-transcriptional and post-transcriptional processing of mRNAs, information is limited for lncRNA regulation that enables their production and function. Recently Arabidopsis RRP6L1, a plant paralog of the conserved nuclear RNA surveillance protein Rrp6, was shown to mediate RdDM through retention of lncRNAs in the chromatin, thereby revealing that accumulation of functional lncRNAs requires more than simply RNA polymerases. By focusing on the canonical RdDM pathway, here we summarize recent evidence that indicate co-transcriptional and/or post-transcriptional regulation of lncRNAs, and highlight the emerging theme of lncRNA regulation by RNA processing factors. PMID:25144332

  3. Non-coding RNAs as modulators of the cardiac fibroblast phenotype.

    PubMed

    Piccoli, Maria-Teresa; Bär, Christian; Thum, Thomas

    2016-03-01

    Cardiac fibroblasts represent one of the most frequent cell type in the heart of rodents and humans and alterations of their phenotype have a great impact on cardiac function. Due to aging, ischemic injuries, valvular dysfunctions, hypertension and aortic stenosis, multiple signals trigger the accumulation of extracellular matrix in the cardiac interstitium and perivascular space, leading to structural and functional detrimental changes in the heart. Cardiac fibroblasts are the principal orchestrators of matrix formation and degradation and indirectly regulate cardiac hypertrophy and inflammation. Understanding the molecular bases of their action could provide tools for the treatment of cardiac remodeling. This review summarizes recent evidences on non-coding RNAs, including microRNAs and long non-coding RNAs that modulate the phenotype of cardiac fibroblasts and may serve in the future as targets for novel therapeutic strategies against cardiac fibrosis.

  4. Missing links in cardiology: long non-coding RNAs enter the arena.

    PubMed

    Peters, Tim; Schroen, Blanche

    2014-06-01

    Heart failure as a consequence of ischemic, hypertensive, infectious, or hereditary heart disease is a major challenge in cardiology and topic of intense research. Recently, new players appeared in this field and promise deeper insights into cardiac development, function, and disease. Long non-coding RNAs are a novel class of transcripts that can regulate gene expression and may have many more functions inside the cell. Here, we present examples on long non-coding RNA (lncRNA) function in cardiac development and give suggestions on how lncRNAs may be involved in cardiomyocyte dysfunction, myocardial fibrosis, and inflammation, three hallmarks of the failing heart. Above that, we point out opportunities as well as challenges that should be considered in the endeavor to investigate cardiac lncRNAs. PMID:24619481

  5. Detecting and Comparing Non-Coding RNAs in the High-Throughput Era

    PubMed Central

    Bussotti, Giovanni; Notredame, Cedric; Enright, Anton J.

    2013-01-01

    In recent years there has been a growing interest in the field of non-coding RNA. This surge is a direct consequence of the discovery of a huge number of new non-coding genes and of the finding that many of these transcripts are involved in key cellular functions. In this context, accurately detecting and comparing RNA sequences has become important. Aligning nucleotide sequences is a key requisite when searching for homologous genes. Accurate alignments reveal evolutionary relationships, conserved regions and more generally any biologically relevant pattern. Comparing RNA molecules is, however, a challenging task. The nucleotide alphabet is simpler and therefore less informative than that of amino-acids. Moreover for many non-coding RNAs, evolution is likely to be mostly constrained at the structural level and not at the sequence level. This results in very poor sequence conservation impeding comparison of these molecules. These difficulties define a context where new methods are urgently needed in order to exploit experimental results to their full potential. This review focuses on the comparative genomics of non-coding RNAs in the context of new sequencing technologies and especially dealing with two extremely important and timely research aspects: the development of new methods to align RNAs and the analysis of high-throughput data. PMID:23887659

  6. Non-coding RNAs revealed during identification of genes involved in chicken immune responses.

    PubMed

    Ahanda, Marie-Laure Endale; Ruby, Thomas; Wittzell, Håkan; Bed'Hom, Bertrand; Chaussé, Anne-Marie; Morin, Veronique; Oudin, Anne; Chevalier, Catherine; Young, John R; Zoorob, Rima

    2009-01-01

    Recent large-scale cDNA cloning studies have shown that a significant proportion of the transcripts expressed from vertebrate genomes do not appear to encode protein. Moreover, it was reported in mammals (human and mice) that these non-coding transcripts are expressed and regulated by mechanisms similar to those involved in the control of protein-coding genes. We have produced a collection of cDNA sequences from immunologically active tissues with the aim of discovering chicken genes involved in immune mechanisms, and we decided to explore the non-coding component of these immune-related libraries. After finding known non-coding RNAs (miRNA, snRNA, snoRNA), we identified new putative mRNA-like non-coding RNAs. We characterised their expression profiles in immune-related samples. Some of them showed changes in expression following viral infections. As they exhibit patterns of expression that parallel the behaviour of protein-coding RNAs in immune tissues, our study suggests that they could play an active role in the immune response.

  7. Population genomic analysis of gibberellin-responsive long non-coding RNAs in Populus.

    PubMed

    Tian, Jiaxing; Song, Yuepeng; Du, Qingzhang; Yang, Xiaohui; Ci, Dong; Chen, Jinhui; Xie, Jianbo; Li, Bailian; Zhang, Deqiang

    2016-04-01

    Long non-coding RNAs (lncRNAs) participate in a wide range of biological processes, but lncRNAs in plants remain largely unknown; in particular, we lack a systematic identification of plant lncRNAs involved in hormone responses. Moreover, allelic variation in lncRNAs remains poorly characterized at a large scale. Here, we conducted high-throughput RNA-sequencing of leaves from control and gibberellin (GA)-treated Populus tomentosa and identified 7655 reliably expressed lncRNAs. Among the 7655 lncRNAs, the levels of 410 lncRNAs changed in response to GA. Seven GA-responsive lncRNAs were predicted to be putative targets of 18 miRNAs, and one GA-responsive lncRNA (TCONS_00264314) was predicted to be a target mimic of ptc-miR6459b. Computational analysis predicted 939 potential cis-regulated target genes and 965 potential trans-regulated target genes for GA-responsive lncRNAs. Functional annotation of these potential target genes showed that they participate in many different biological processes, including auxin signal transduction and synthesis of cellulose and pectin, indicating that GA-responsive lncRNAs may influence growth and wood properties. Finally, single nucleotide polymorphism (SNP)-based association analysis showed that 112 SNPs from 52 GA-responsive lncRNAs and 1014 SNPs from 296 potential target genes were significantly associated with growth and wood properties. Epistasis analysis also provided evidence for interactions between lncRNAs and their potential target genes. Our study provides a comprehensive view of P. tomentosa lncRNAs and offers insights into the potential functions and regulatory interactions of GA-responsive lncRNAs, thus forming the foundation for future functional analysis of GA-responsive lncRNAs in P. tomentosa.

  8. Population genomic analysis of gibberellin-responsive long non-coding RNAs in Populus.

    PubMed

    Tian, Jiaxing; Song, Yuepeng; Du, Qingzhang; Yang, Xiaohui; Ci, Dong; Chen, Jinhui; Xie, Jianbo; Li, Bailian; Zhang, Deqiang

    2016-04-01

    Long non-coding RNAs (lncRNAs) participate in a wide range of biological processes, but lncRNAs in plants remain largely unknown; in particular, we lack a systematic identification of plant lncRNAs involved in hormone responses. Moreover, allelic variation in lncRNAs remains poorly characterized at a large scale. Here, we conducted high-throughput RNA-sequencing of leaves from control and gibberellin (GA)-treated Populus tomentosa and identified 7655 reliably expressed lncRNAs. Among the 7655 lncRNAs, the levels of 410 lncRNAs changed in response to GA. Seven GA-responsive lncRNAs were predicted to be putative targets of 18 miRNAs, and one GA-responsive lncRNA (TCONS_00264314) was predicted to be a target mimic of ptc-miR6459b. Computational analysis predicted 939 potential cis-regulated target genes and 965 potential trans-regulated target genes for GA-responsive lncRNAs. Functional annotation of these potential target genes showed that they participate in many different biological processes, including auxin signal transduction and synthesis of cellulose and pectin, indicating that GA-responsive lncRNAs may influence growth and wood properties. Finally, single nucleotide polymorphism (SNP)-based association analysis showed that 112 SNPs from 52 GA-responsive lncRNAs and 1014 SNPs from 296 potential target genes were significantly associated with growth and wood properties. Epistasis analysis also provided evidence for interactions between lncRNAs and their potential target genes. Our study provides a comprehensive view of P. tomentosa lncRNAs and offers insights into the potential functions and regulatory interactions of GA-responsive lncRNAs, thus forming the foundation for future functional analysis of GA-responsive lncRNAs in P. tomentosa. PMID:26912799

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

    PubMed

    Shen, Xiaokun; Xie, Bojian; Ma, Zhaosheng; Yu, Wenjie; Wang, Wenmin; Xu, Dong; Yan, Xinqiang; Chen, Beibei; Yu, Longyao; Li, Jicheng; Chen, Xiaobing; Ding, Kan; Cao, Feilin

    2015-08-28

    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.

  10. Comparative analysis of non-coding RNAs in the antibiotic-producing Streptomyces bacteria

    PubMed Central

    2013-01-01

    Background Non-coding RNAs (ncRNAs) are key regulatory elements that control a wide range of cellular processes in all bacteria in which they have been studied. Taking advantage of recent technological innovations, we set out to fully explore the ncRNA potential of the multicellular, antibiotic-producing Streptomyces bacteria. Results Using a comparative RNA sequencing analysis of three divergent model streptomycetes (S. coelicolor, S. avermitilis and S. venezuelae), we discovered hundreds of novel cis-antisense RNAs and intergenic small RNAs (sRNAs). We identified a ubiquitous antisense RNA species that arose from the overlapping transcription of convergently-oriented genes; we termed these RNA species ‘cutoRNAs’, for convergent untranslated overlapping RNAs. Conservation between different classes of ncRNAs varied greatly, with sRNAs being more conserved than antisense RNAs. Many species-specific ncRNAs, including many distinct cutoRNA pairs, were located within antibiotic biosynthetic clusters, including the actinorhodin, undecylprodigiosin, and coelimycin clusters of S. coelicolor, the chloramphenicol cluster of S. venezuelae, and the avermectin cluster of S. avermitilis. Conclusions These findings indicate that ncRNAs, including a novel class of antisense RNA, may exert a previously unrecognized level of regulatory control over antibiotic production in these bacteria. Collectively, this work has dramatically expanded the ncRNA repertoire of three Streptomyces species and has established a critical foundation from which to investigate ncRNA function in this medically and industrially important bacterial genus. PMID:23947565

  11. 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. PMID:25399417

  12. 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

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

    PubMed

    St Laurent, Georges; 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

    2016-04-20

    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 vlinc RNAs genes likely function in cisto activate nearby genes. This effect while most pronounced in closely spaced vlinc RNA-gene pairs can be detected over relatively large genomic distances. Furthermore, we identified 101 vlinc RNA 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.

  14. Deciphering the function of non-coding RNAs in prostate cancer.

    PubMed

    Ramalho-Carvalho, João; Fromm, Bastian; Henrique, Rui; Jerónimo, Carmen

    2016-06-01

    The advent of next-generation sequencing methods is fuelling the discovery of multiple non-coding RNA transcripts with direct implication in cell biology and homeostasis. This new layer of biological regulation seems to be of particular importance in human pathogenesis, including cancer. The aberrant expression of ncRNAs is a feature of prostate cancer, as they promote tumor-suppressive or oncogenic activities, controlling multicellular events leading to carcinogenesis and tumor progression. From the small RNAs involved in the RNAi pathway to the long non-coding RNAs controlling chromatin remodeling, alternative splicing, and DNA repair, the non-coding transcriptome represents the significant majority of transcriptional output. As such, ncRNAs appear as exciting new diagnostic, prognostic, and therapeutic tools. However, additional work is required to characterize the RNA species, their functions, and their applicability to clinical practice in oncology. In this review, we summarize the most important features of ncRNA biology, emphasizing its relevance in prostate carcinogenesis and its potential for clinical applications. PMID:27221068

  15. 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.

  16. 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

  17. Profiles of Small Non-Coding RNAs in Schistosoma japonicum during Development

    PubMed Central

    Cai, Pengfei; Hou, Nan; Piao, Xianyu; Liu, Shuai; Liu, Haiying; Yang, Fan; Wang, Jianwei; Jin, Qi; Wang, Heng; Chen, Qijun

    2011-01-01

    Background The gene regulation mechanism along the life cycle of the genus Schistosoma is complex. Small non-coding RNAs (sncRNAs) are essential post transcriptional gene regulation elements that affect gene expression and mRNA stability. Preliminary studies indicated that sncRNAs in schistosomal parasites are generated through different pathways, which are developmentally regulated. However, the data of sncRNAs of schistosomal parasites are still fragmental and a complete expression profile of sncRNAs during the parasite development requires a deep investigation. Methodology/Principal Findings We employed high-throughput genome-wide transcriptome analytic techniques to explore the dynamic expression of microRNAs (miRNAs) and endogenous siRNAs (endo-siRNAs) of Schistosoma japonicum covering the free-living cercarial stage and all stages in the definitive host. This led us to analyze over 70 million clean reads represented both high and low abundance of the small RNA population. Patterns of differential expression of miRNAs and endo-siRNAs were observed. MiRNAs was twice more than endo-siRNAs in cercariae, but gradually decreased along with the development of the parasite. Both small RNA types were presented in equal aboudance in lung-stage schistosomula, while endo-siRNAs accumulated to 6 times more than miRNAs in adult female worms and hepatic eggs. Further, miRNAs were found mainly derived from genes located in the intergenic regions, while endo-siRNAs were mainly generated from transposable elements (TEs). The expression pattern of TE-siRNAs, as well as the pseudogene-derived siRNAs clustered in mRNAs of cytoskeletal proteins, stress proteins, enzymes related to energy metabolism also revealed distinction throughout different developmental stages. Natural antisense transcripts (NATs)-related siRNAs accounted for minor proportion of the endo-siRNAs which were dominantly expressed in cercariae. Conclusions/Significance Our results represented a comprehensive

  18. 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

  19. 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

  20. 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.

  1. Long non-coding RNAs: the epigenetic regulators involved in the pathogenesis of reproductive disorder.

    PubMed

    Shen, Chen; Zhong, Nanbert

    2015-02-01

    Long non-coding RNAs (lncRNAs) are long single-stranded RNAs without translation potential. LncRNAs function in regulating epigenetic and cellular processes through various mechanisms. Nowadays, rapidly growing evidence has shown that abnormally expressed lncRNAs were involved in various inflammation-related states or diseases. Abnormal inflammation responses contribute to reproductive pathology and play vital roles in developing most disorders of the female reproductive system. In this review, we discussed the history of ncRNAs including lncRNAs, methodologies for lncRNA identification, mechanisms of lncRNA expression and regulation and mainly discussed the expression and function of lncRNAs in the female reproductive system with special focus on the inflammation and infection pathway. By analyzing the present available studies of lncRNA transcripts within the reproductive system and the current understanding of the biology of lncRNAs, we have suggested the important diagnostic and therapeutic roles of lncRNAs in the etiology of reproductive disorders.

  2. 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

  3. Exploration of Deregulated Long Non-Coding RNAs in Association with Hepatocarcinogenesis and Survival.

    PubMed

    Shen, Jing; Siegel, Abby B; Remotti, Helen; Wang, Qiao; Shen, Yueyue; Santella, Regina M

    2015-09-10

    Long non-coding RNAs (lncRNAs) are larger than 200 nucleotides in length and pervasively expressed across the genome. An increasing number of studies indicate that lncRNA transcripts play integral regulatory roles in cellular growth, division, differentiation and apoptosis. Deregulated lncRNAs have been observed in a variety of human cancers, including hepatocellular carcinoma (HCC). We determined the expression profiles of 90 lncRNAs for 65 paired HCC tumor and adjacent non-tumor tissues, and 55 lncRNAs were expressed in over 90% of samples. Eight lncRNAs were significantly down-regulated in HCC tumor compared to non-tumor tissues (p < 0.05), but no lncRNA achieved statistical significance after Bonferroni correction for multiple comparisons. Within tumor tissues, carrying more aberrant lncRNAs (6-7) was associated with a borderline significant reduction Cancers 2015, 7 1848 in survival (HR = 8.5, 95% CI: 1.0-72.5). The predictive accuracy depicted by the AUC was 0.93 for HCC survival when using seven deregulated lncRNAs (likelihood ratio test p = 0.001), which was similar to that combining the seven lncRNAs with tumor size and treatment (AUC = 0.96, sensitivity = 87%, specificity = 87%). These data suggest the potential association of deregulated lncRNAs with hepatocarcinogenesis and HCC survival.

  4. Identification of differentially expressed non-coding RNAs in embryonic stem cell neural differentiation

    PubMed Central

    Skreka, Konstantinia; Schafferer, Simon; Nat, Irina-Roxanna; Zywicki, Marek; Salti, Ahmad; Apostolova, Galina; Griehl, Matthias; Rederstorff, Mathieu; Dechant, Georg; Hüttenhofer, Alexander

    2012-01-01

    Protein-coding genes, guiding differentiation of ES cells into neural cells, have extensively been studied in the past. However, for the class of ncRNAs only the involvement of some specific microRNAs (miRNAs) has been described. Thus, to characterize the entire small non-coding RNA (ncRNA) transcriptome, involved in the differentiation of mouse ES cells into neural cells, we have generated three specialized ribonucleo-protein particle (RNP)-derived cDNA libraries, i.e. from pluripotent ES cells, neural progenitors and differentiated neural cells, respectively. By high-throughput sequencing and transcriptional profiling we identified several novel miRNAs to be involved in ES cell differentiation, as well as seven small nucleolar RNAs. In addition, expression of 7SL, 7SK and vault-2 RNAs was significantly up-regulated during ES cell differentiation. About half of ncRNA sequences from the three cDNA libraries mapped to intergenic or intragenic regions, designated as interRNAs and intraRNAs, respectively. Thereby, novel ncRNA candidates exhibited a predominant size of 18–30 nt, thus resembling miRNA species, but, with few exceptions, lacking canonical miRNA features. Additionally, these novel intraRNAs and interRNAs were not only found to be differentially expressed in stem-cell derivatives, but also in primary cultures of hippocampal neurons and astrocytes, strengthening their potential function in neural ES cell differentiation. PMID:22492625

  5. Identification of differentially expressed non-coding RNAs in embryonic stem cell neural differentiation.

    PubMed

    Skreka, Konstantinia; Schafferer, Simon; Nat, Irina-Roxanna; Zywicki, Marek; Salti, Ahmad; Apostolova, Galina; Griehl, Matthias; Rederstorff, Mathieu; Dechant, Georg; Hüttenhofer, Alexander

    2012-07-01

    Protein-coding genes, guiding differentiation of ES cells into neural cells, have extensively been studied in the past. However, for the class of ncRNAs only the involvement of some specific microRNAs (miRNAs) has been described. Thus, to characterize the entire small non-coding RNA (ncRNA) transcriptome, involved in the differentiation of mouse ES cells into neural cells, we have generated three specialized ribonucleo-protein particle (RNP)-derived cDNA libraries, i.e. from pluripotent ES cells, neural progenitors and differentiated neural cells, respectively. By high-throughput sequencing and transcriptional profiling we identified several novel miRNAs to be involved in ES cell differentiation, as well as seven small nucleolar RNAs. In addition, expression of 7SL, 7SK and vault-2 RNAs was significantly up-regulated during ES cell differentiation. About half of ncRNA sequences from the three cDNA libraries mapped to intergenic or intragenic regions, designated as interRNAs and intraRNAs, respectively. Thereby, novel ncRNA candidates exhibited a predominant size of 18-30 nt, thus resembling miRNA species, but, with few exceptions, lacking canonical miRNA features. Additionally, these novel intraRNAs and interRNAs were not only found to be differentially expressed in stem-cell derivatives, but also in primary cultures of hippocampal neurons and astrocytes, strengthening their potential function in neural ES cell differentiation. PMID:22492625

  6. 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

    2016-01-01

    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

  7. Novel modulators of senescence, aging, and longevity: Small non-coding RNAs enter the stage.

    PubMed

    Grillari, Johannes; Grillari-Voglauer, Regina

    2010-04-01

    During the last decade evidence has accumulated that the aging process is driven by limited allocation of energy to somatic maintenance resulting in accumulation of stochastic damage. This damage, affecting molecules, cells, and tissues, is counteracted by genetically programmed repair, the efficiency of which thus importantly determines the life and 'health span' of organisms. Therefore, understanding the regulation of gene expression during cellular and organismal aging as well as upon exposure to various damaging events is important to understand the biology of aging and to positively influence the health span. The recent identification of small non-coding RNAs (ncRNAs), has added an additional layer of complexity to the regulation of gene expression with the classes of endogenous small inhibitory RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), QDE1-interacting RNAs (qiRNAs) and microRNAs (miRNAs). Some of these ncRNAs have not yet been identified in mammalian cells and are dependent on RNA-dependent RNA polymerases. The first mammalian enzyme with such activity has only now emerged and surprisingly consists of the catalytic subunit of telomerase (hTERT) together with RMPR, an alternative RNA component. The so far most studied small non-coding RNAs, miRNAs, however, are now increasingly found to operate in the complex network of cellular aging. Recent findings show that (i) miRNAs are regulated during cellular senescence in vitro, (ii) they contribute to tissue regeneration by regulation of stem cell function, and (iii) at least one miRNA modulates the life span of the model organism C. elegans. Additionally, (iv) they act as inhibitors of proteins mediating the insulin/IGF1 and target of rapamycin (TOR) signalling, both of which are conserved modulators of organism life span. Here we will give an overview on the current status of these topics. Since little is so far known on the functions of small ncRNAs in the context of aging and longevity, the entry of the

  8. Regulatory networks of non-coding RNAs in brown/beige adipogenesis

    PubMed Central

    Xu, Shaohai; Chen, Peng; Sun, Lei

    2015-01-01

    BAT (brown adipose tissue) is specialized to burn fatty acids for heat generation and energy expenditure to defend against cold and obesity. Accumulating studies have demonstrated that manipulation of BAT activity through various strategies can regulate metabolic homoeostasis and lead to a healthy phenotype. Two classes of ncRNA (non-coding RNA), miRNA and lncRNA (long non-coding RNA), play crucial roles in gene regulation during tissue development and remodelling. In the present review, we summarize recent findings on regulatory role of distinct ncRNAs in brown/beige adipocytes, and discuss how these ncRNA regulatory networks contribute to brown/beige fat development, differentiation and function. We suggest that targeting ncRNAs could be an attractive approach to enhance BAT activity for protecting the body against obesity and its pathological consequences. PMID:26283634

  9. 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. PMID:25885578

  10. 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.

  11. 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

  12. 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

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

    PubMed

    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

  14. Non-coding RNAs and a layered architecture of genetic networks

    NASA Astrophysics Data System (ADS)

    Zhdanov, Vladimir P.

    2010-12-01

    In eukaryotic cells, protein-coding sequences constitute a relatively small part of the genome. The rest of the genome is transcribed to non-coding RNAs (ncRNAs). Such RNAs form the cornerstone of a regulatory network that operates in parallel with the protein network. Their biological functions are based primarily on the ability to pair with and deactivate target messenger RNAs (mRNAs). To clarify the likely role of ncRNAs in complex genetic networks, we present and comprehensively analyze a kinetic model of one of the key counterparts of the network architectures. Specifically, the genes transcribed to ncRNAs are considered to interplay with a hierarchical two-layer set of genes transcribed to mRNAs. The genes forming the bottom layer are regulated from the top and negatively self-regulated. If the former regulation is positive, the dependence of the RNA populations on the governing parameters is found to be often non-monotonous. Specifically, the model predicts bistability. If the regulation is negative, the dependence of the RNA populations on the governing parameters is monotonous. In particular, the population of the mRNAs, corresponding to the genes forming the bottom layer, is nearly constant.

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

    PubMed

    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.

  16. 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

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

    PubMed

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

    2016-01-01

    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. PMID:27629831

  18. Stochastic bursts in the kinetics of gene expression with regulation by long non-coding RNAs

    NASA Astrophysics Data System (ADS)

    Zhdanov, V. P.

    2010-09-01

    One of the main recent breakthroughs in cellular biology is a discovery of numerous non-coding RNAs (ncR-NAs). We outline abilities of long ncRNAs and articulate that the corresponding kinetics may frequently exhibit stochastic bursts. For example, we scrutinize one of the generic cases when the gene transcription is regulated by competitive attachment of ncRNA and protein to a regulatory site. Our Monte Carlo simulations show that in this case one can observe huge long transcriptional bursts consisting of short bursts.

  19. Non-coding RNAs as the bridge between epigenetic mechanisms, lineages and domains of life

    PubMed Central

    Sela, Mor; Kloog, Yoel; Rechavi, Oded

    2014-01-01

    Many cases of heritable environmental responses have been documented but the underlying mechanisms are largely unknown. Recently, inherited RNA interference has been shown to act as a multigenerational genome surveillance apparatus. We suggest that inheritance of regulatory RNAs is at the root of many other epigenetic phenomena, the trigger that induces other epigenetic mechanisms, such as the depositing of histone modifications and DNA methylation. In addition, we explore the possibility that interacting organisms influence each other's transcriptomes by exchanging heterologous non-coding RNAs. PMID:24882818

  20. 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

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

    PubMed

    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

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

    PubMed

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

    2016-08-25

    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.

  3. Emerging landscape of non-coding RNAs in oral health and disease.

    PubMed

    Perez, P; Jang, S I; Alevizos, I

    2014-04-01

    The world of non-coding RNAs has only recently started being discovered. For the past 40 years, coding genes, mRNA, and proteins have been the center of cellular and molecular biology, and pathologic alterations were attributed to either the aberration of gene sequence or altered promoter activity. It was only after the completion of the human genome sequence that the scientific community started seriously wondering why only a very small portion of the genome corresponded to protein-coding genes. New technologies such as the whole-genome and whole-transcriptome sequencing demonstrated that at least 90% of the genome is actively transcribed. The identification and cataloguing of multiple kinds of non-coding RNA (ncRNA) have exponentially increased, and it is now widely accepted that ncRNAs play major biological roles in cellular physiology, development, metabolism, and are also implicated in a variety of diseases. The aim of this review is to describe the two major classes (long and short forms) of non-coding RNAs and describe their subclasses in terms of function and their relevance and potential in oral diseases.

  4. 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.

  5. Identification and characterization of small non-coding RNAs from Chinese fir by high throughput sequencing

    PubMed Central

    2012-01-01

    Background Small non-coding RNAs (sRNAs) play key roles in plant development, growth and responses to biotic and abiotic stresses. At least four classes of sRNAs have been well characterized in plants, including repeat-associated siRNAs (rasiRNAs), microRNAs (miRNAs), trans-acting siRNAs (tasiRNAs) and natural antisense transcript-derived siRNAs. Chinese fir (Cunninghamia lanceolata) is one of the most important coniferous evergreen tree species in China. No sRNA from Chinese fir has been described to date. Results To obtain sRNAs in Chinese fir, we sequenced a sRNA library generated from seeds, seedlings, leaves, stems and calli, using Illumina high throughput sequencing technology. A comprehensive set of sRNAs were acquired, including conserved and novel miRNAs, rasiRNAs and tasiRNAs. With BLASTN and MIREAP we identified a total of 115 conserved miRNAs comprising 40 miRNA families and one novel miRNA with precursor sequence. The expressions of 16 conserved and one novel miRNAs and one tasiRNA were detected by RT-PCR. Utilizing real time RT-PCR, we revealed that four conserved and one novel miRNAs displayed developmental stage-specific expression patterns in Chinese fir. In addition, 209 unigenes were predicted to be targets of 30 Chinese fir miRNA families, of which five target genes were experimentally verified by 5' RACE, including a squamosa promoter-binding protein gene, a pentatricopeptide (PPR) repeat-containing protein gene, a BolA-like family protein gene, AGO1 and a gene of unknown function. We also demonstrated that the DCL3-dependent rasiRNA biogenesis pathway, which had been considered absent in conifers, existed in Chinese fir. Furthermore, the miR390-TAS3-ARF regulatory pathway was elucidated. Conclusions We unveiled a complex population of sRNAs in Chinese fir through high throughput sequencing. This provides an insight into the composition and function of sRNAs in Chinese fir and sheds new light on land plant sRNA evolution. PMID:22894611

  6. Role of long non-coding RNAs in the determination of β-cell identity.

    PubMed

    Motterle, A; Sanchez-Parra, C; Regazzi, R

    2016-09-01

    Pancreatic β-cells are highly specialized cells committed to secrete insulin in response to changes in the level of nutrients, hormones and neurotransmitters. Chronic exposure to elevated concentrations of glucose, fatty acids or inflammatory mediators can result in modifications in β-cell gene expression that alter their functional properties. This can lead to the release of insufficient amount of insulin to cover the organism's needs, and thus to the development of diabetes mellitus. Although most of the studies carried out in the last decades to elucidate the causes of β-cell dysfunction under disease conditions have focused on protein-coding genes, we now know that insulin-secreting cells also contain thousands of molecules of RNA that do not encode polypeptides but play key roles in the acquisition and maintenance of a highly differentiated state. In this review, we will highlight the involvement of long non-coding RNAs (lncRNAs), a particular class of non-coding transcripts, in the differentiation of β-cells and in the regulation of their specialized tasks. We will also discuss the crosstalk between the activities of lncRNAs and microRNAs and present the emerging evidence of a potential contribution of particular lncRNAs to the development of both type 1 and type 2 diabetes. PMID:27615130

  7. Non-coding RNAs mediate the rearrangements of genomic DNA in ciliates.

    PubMed

    Feng, Xuezhu; Guang, Shouhong

    2013-10-01

    Most eukaryotes employ a variety of mechanisms to defend the integrity of their genome by recognizing and silencing parasitic mobile nucleic acids. However, recent studies have shown that genomic DNA undergoes extensive rearrangements, including DNA elimination, fragmentation, and unscrambling, during the sexual reproduction of ciliated protozoa. Non-coding RNAs have been identified to program and regulate genome rearrangement events. In Paramecium and Tetrahymena, scan RNAs (scnRNAs) are produced from micronuclei and transported to vegetative macronuclei, in which scnRNA elicits the elimination of cognate genomic DNA. In contrast, Piwi-interacting RNAs (piRNAs) in Oxytricha enable the retention of genomic DNA that exhibits sequence complementarity in macronuclei. An RNA interference (RNAi)-like mechanism has been found to direct these genomic rearrangements. Furthermore, in Oxytricha, maternal RNA templates can guide the unscrambling process of genomic DNA. The non-coding RNA-directed genome rearrangements may have profound evolutionary implications, for example, eliciting the multigenerational inheritance of acquired adaptive traits. PMID:24008384

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

    PubMed

    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

  9. 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.

  10. 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

  11. Integrated analysis of long non-coding RNAs in human colorectal cancer

    PubMed Central

    Chen, Xiaohua; Liu, Binjian; Yang, Rui; Guo, Yong; Li, Feng; Wang, Lin; Hu, Hanyang

    2016-01-01

    Accumulating evidence highlights the role of long non-coding RNAs (lncRNAs) in tumors. However, the genome-wide expression and roles of lncRNAs in colorectal cancer (CRC) remain unknown. Here, we systematically examined the global gene expressions in primary and synchronous liver metastases CRC tissue, in which thousands of aberrantly expressed lncRNAs were characterized. Co-expression analysis revealed that some lncRNAs correlated to their neighboring mRNAs in expression levels, whereas others formed networks with protein-coding genes in trans. We observed H3K4me3 was enriched at expressed lncRNA transcription start sites (TSSs) and correlated to dysregulated lncRNAs. Furthermore, we identified primary and metastasis tumor linked lncRNA signatures positively correlated with poor-prognosis gene set. Finally, functional experiments demonstrated two candidate lncRNAs were required for proliferation and migration of CRC cells. In summary, we provided a new framework for lncRNA associated clinical prognosis evaluation and target selection of gene therapy in CRC. PMID:27004403

  12. Long non-coding RNAs in gastric cancer: versatile mechanisms and potential for clinical translation

    PubMed Central

    Zhao, Jing; Liu, Yongchao; Huang, Guangjian; Cui, Peng; Zhang, Wenhong; Zhang, Ying

    2015-01-01

    Gastric cancer (GC) remains a serious threat to many people, representing the second leading cause of cancer-related death worldwide. The lack of early diagnostic biomarkers, effective prognostic indicators and therapeutic targets all account for the poor prognosis of GC. Therefore, the identification of novel molecular biomarkers for early diagnosis, therapeutic response, and prognosis are urgently needed. High-throughput sequencing has identified a large number of transcribed long non-coding RNAs (lncRNAs) throughout the human genome. Accumulating evidence demonstrates that these lncRNAs play multiple roles in regulating gene expression at the transcriptional, post-transcriptional, and epigenetic levels. Aberrant expression of lncRNAs occurs in various pathological processes, including GC. Many dysregulated lncRNAs in GC have been significantly associated with a larger tumor size, higher degree of tumor invasion, lymph node and distant metastasis, and poorer survival outcome. In this review, we will provide an overview of the pathogenesis of GC, the characteristics and regulatory functions of lncRNAs, and the versatile mechanisms of lncRNAs in GC development, as well as evaluate the translational potential of lncRNAs as novel diagnostic and prognostic biomarkers and therapeutic targets in GC. PMID:26045977

  13. 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.

  14. 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

  15. Long non-coding RNAs: novel targets for nervous system disease diagnosis and therapy.

    PubMed

    Qureshi, Irfan A; Mehler, Mark F

    2013-10-01

    The human genome encodes tens of thousands of long non-coding RNAs (lncRNAs), a novel and important class of genes. Our knowledge of lncRNAs has grown exponentially since their discovery within the last decade. lncRNAs are expressed in a highly cell- and tissue-specific manner, and are particularly abundant within the nervous system. lncRNAs are subject to post-transcriptional processing and inter- and intra-cellular transport. lncRNAs act via a spectrum of molecular mechanisms leveraging their ability to engage in both sequence-specific and conformational interactions with diverse partners (DNA, RNA, and proteins). Because of their size, lncRNAs act in a modular fashion, bringing different macromolecules together within the three-dimensional context of the cell. lncRNAs thus coordinate the execution of transcriptional, post-transcriptional, and epigenetic processes and critical biological programs (growth and development, establishment of cell identity, and deployment of stress responses). Emerging data reveal that lncRNAs play vital roles in mediating the developmental complexity, cellular diversity, and activity-dependent plasticity that are hallmarks of brain. Corresponding studies implicate these factors in brain aging and the pathophysiology of brain disorders, through evolving paradigms including the following: (i) genetic variation in lncRNA genes causes disease and influences susceptibility; (ii) epigenetic deregulation of lncRNAs genes is associated with disease; (iii) genomic context links lncRNA genes to disease genes and pathways; and (iv) lncRNAs are otherwise interconnected with known pathogenic mechanisms. Hence, lncRNAs represent prime targets that can be exploited for diagnosing and treating nervous system diseases. Such clinical applications are in the early stages of development but are rapidly advancing because of existing expertise and technology platforms that are readily adaptable for these purposes.

  16. 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.

  17. 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

  18. Structural insights into Transcriptional Repression by non-coding RNAs that bind to Human Pol II

    PubMed Central

    Kassube, Susanne A.; Fang, Jie; Grob, Patricia; Yakovchuk, Petro; Goodrich, James A.; Nogales, Eva

    2012-01-01

    Gene transcription is regulated in response to environmental changes as well as developmental cues. In mammalian cells subjected to stress conditions such as heat shock, transcription of most protein-coding genes decreases, while the transcription of heat shock protein genes increases. Repression involves direct binding to RNA polymerase II (Pol II) of certain non-coding RNAs (ncRNAs) that are upregulated upon heat shock. Another class of ncRNAs is also upregulated and binds to Pol II, but does not inhibit transcription. Incorporation of repressive ncRNAs into pre-initiation complexes prevents transcription initiation, while non-repressive ncRNAs are displaced from Pol II by TFIIF. Here, we present cryo-EM reconstructions of human Pol II in complex with six different ncRNAs from mouse and human. Our structures show that both repressive and non-repressive ncRNAs bind to a conserved binding site within the cleft of Pol II. The site, also shared with a previously characterized yeast aptamer, is close to the active center and thus in an ideal position to regulate transcription. Importantly, additional RNA elements extend flexibly beyond the docking site. We propose that the differences concerning the repressive activity of the ncRNA analyzed must be due to the distinct character of these more unstructured, flexible segments of the RNA that emanate from the cleft. PMID:22954660

  19. 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

  20. 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.

  1. Discovery of Putative Small Non-Coding RNAs from the Obligate Intracellular Bacterium Wolbachia pipientis

    PubMed Central

    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. PMID:25739023

  2. Long non-coding RNAs-towards precision medicine in diabetic kidney disease?

    PubMed

    Panchapakesan, Usha; Pollock, Carol

    2016-09-01

    Diabetic kidney disease (DKD) is escalating and is the major cause of end stage kidney failure. There is increasing evidence to support the role of epigenetic factors and metabolic memory in linking the environmental and genetic causes of this disease. Although our understanding of this disease has improved, there has been no significant efficacious therapeutic translation in the last decade. Current sequencing technology has allowed interrogation of the human transcriptome. It is evident that although approximately 80% of the genome is transcribed, only 1-2% is read and coded into protein. The remaining non-coding RNA, historically assumed to be 'junk', is now known to have key roles in regulating gene function and orchestrate how and when coding genes are expressed. This largest subset of non-coding RNAs called long non-coding RNAs (LNCRNAs) drives epigenetic changes and has functional relevance best characterized in cancers and cardiovascular disease. This understanding, coupled with the availability and affordability of RNA sequencing, has shifted our therapeutic strategies towards genomic therapy in DKD. The role of LNCRNAs with respect to DKD is only just emerging. In this review we summarize the role of LNCRNAs in DKD and the existing antisense oligonucleotide therapy that may provide precise and targeted medicine to treat DKD in this postgenomic era. PMID:27503944

  3. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  5. 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

  6. 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.

  7. 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

  8. 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

  9. Differential expression of long non-coding RNAs in hyperoxia-induced bronchopulmonary dysplasia.

    PubMed

    Bao, Tian-Ping; Wu, Rong; Cheng, Huai-Ping; Cui, Xian-Wei; Tian, Zhao-Fang

    2016-07-01

    Bronchopulmonary dysplasia (BPD) is a common complication of premature birth that seriously affects the survival rate and quality of life among preterm neonates. Long non-coding RNAs (lncRNAs) have been implicated in many human diseases. However, the role of lncRNAs in the pathogenesis of BPD remains poorly understood. Here, we exposed neonatal C57BL/6J mice to 95% concentrations of ambient oxygen and established a mouse lung injury model that mimicked human BPD. Next, we compared lncRNA and messenger RNA (mRNA) expression profiles between BPD and normal lung tissues using a high-throughput mouse lncRNA + mRNA array system. Compared with the control group, 882 lncRNAs were upregulated, and 887 lncRNAs were downregulated in BPD lung tissues. We validated some candidate BPD-associated lncRNAs by real-time quantitative reverse-transcription polymerase chain reaction analysis in eight pairs of BPD and normal lung tissues. Gene ontology, pathway and bioinformatics analyses revealed that a downregulated lncRNA, namely AK033210, associated with tenascin C may be involved in the pathogenesis of BPD. To the best of our knowledge, our study is the first to reveal differential lncRNA expression in BPD, which provides a foundation for further understanding of the molecular mechanism of BPD development. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27137150

  10. 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

  11. Evolutionary annotation of conserved long non-coding RNAs in major mammalian species.

    PubMed

    Bu, DeChao; Luo, HaiTao; Jiao, Fei; Fang, ShuangSang; Tan, ChengFu; Liu, ZhiYong; Zhao, Yi

    2015-08-01

    Mammalian genomes contain tens of thousands of long non-coding RNAs (lncRNAs) that have been implicated in diverse biological processes. However, the lncRNA transcriptomes of most mammalian species have not been established, limiting the evolutionary annotation of these novel transcripts. Based on RNA sequencing data from six tissues of nine species, we built comprehensive lncRNA catalogs (4,142-42,558 lncRNAs) covering the major mammalian species. Compared to protein- coding RNAs, expression of lncRNAs exhibits striking lineage specificity. Notably, although 30%-99% human lncRNAs are conserved across different species on DNA locus level, only 20%-27% of these conserved lncRNA loci are detected to transcription, which represents a stark contrast to the proportion of conserved protein-coding genes (48%-80%). This finding provides a valuable resource for experimental scientists to study the mechanisms of lncRNAs. Moreover, we constructed lncRNA expression phylogenetic trees across nine mammals and demonstrated that lncRNA expression profiles can reliably determine phylogenic placement in a manner similar to their coding counterparts. Our data also reveal that the evolutionary rate of lncRNA expression varies among tissues and is significantly higher than those for protein-coding genes. To streamline the processes of browsing lncRNAs and detecting their evolutionary statuses, we integrate all the data produced in this study into a database named PhyloNONCODE (http://www.bioinfo.org/phyloNoncode). Our work starts to place mammalian lncRNAs in an evolutionary context and represent a rich resource for comparative and functional analyses of this critical layer of genome.

  12. Long non-coding RNAs expression profiles in hepatocytes of mice after hematopoietic stem cell transplantation.

    PubMed

    Qiao, Jianlin; Yao, Haina; Xia, Yuan; Chu, Peipei; Li, Mingfeng; Wu, Yulu; Li, Wen; Ding, Lan; Qi, Kunming; Li, Depeng; Xu, Kailin; Zeng, Lingyu

    2016-03-01

    Hepatic veno-occlusive disease (HVOD), one serious complication following hematopoietic stem cell transplantation (HSCT), is mainly initiated by the damage to sinusoidal endothelial cells and hepatocytes. Long non-coding RNAs (lncRNAs) play an important role in the proliferation of hepatocytes and liver regeneration. lncRNAs profile in hepatocytes post-HSCT remains unclear. The aim of this study is to evaluate the profile of lncRNAs in hepatocytes of mice after HSCT. Mice HSCT model was established through infusion of 5 × 10(6) bone marrow mononuclear cells. On day 7, 14 and 33 after HSCT, mice were sacrificed for analysis of liver pathology, function and index. Total RNA was extracted from hepatocytes of mice on day 14 for microarray analysis of the expression profiles of lncRNAs by Arraystar Mouse lncRNA Microarray v2.0. Obvious edema and spotty necrosis of hepatocytes with inflammatory cells infiltration were observed post-HSCT. Meanwhile, increased levels of alkaline phosphatase, aspartate transaminase, and total bilirubin, as well as elevated liver index were also found. 2,918 up-regulated and 1,911 down-regulated lncRNAs in hepatocytes were identified. Some of differentially expressed mRNAs had adjacent lncRNAs that were also significantly dysregulated, with the same dysregulation direction. T-cell receptor (up-regulation) and VEGF signaling pathway (down-regulation) were identified as one of the most enriched pathways. Dysregulated lncRNAs might be involved in hepatocytes damage after HSCT, suggesting targeting them might be a novel approach in amelioration of hepatocytes damage.

  13. Identification of Differentially Expressed Long Non-coding RNAs in Polarized Macrophages

    PubMed Central

    Huang, Zikun; Luo, Qing; Yao, Fangyi; Qing, Cheng; Ye, Jianqing; Deng, Yating; Li, Junming

    2016-01-01

    Macrophages display remarkable plasticity, with the ability to undergo dynamic transition between classically and alternatively activated phenotypes. Long non-coding RNAs (lncRNAs) are more than 200 nucleotides in length and play roles in various biological pathways. However, the role of lncRNAs in regulating macrophage polarization has yet to be explored. In this study, lncRNAs expression profiles were determined in human monocyte-derived macrophages (MDMs) incubated in conditions causing activation toward M(IFN-γ + LPS) or M(IL-4) phenotypes. Compared with primary MDMs, 9343 lncRNAs and 5903 mRNAs were deregulated in M(IFN-γ + LPS) group (fold change ≥2.0, P < 0.05), 4592 lncRNAs and 3122 mRNAs were deregulated in M(IL-4) group. RT-qPCR results were generally consistent with the microarray data. Furthermore, we found that TCONS_00019715 is expressed at a higher level in M(IFN-γ + LPS) macrophages than in M(IL-4) macrophages. TCONS_00019715 expression was decreased when M(IFN-γ + LPS) converted to M(IL-4) whereas increased when M(IL-4) converted to M(IFN-γ + LPS). Knockdown of TCONS_00019715 following the activation of THP-1 cellls using IFN-γ and LPS diminished the expression of M(IFN-γ + LPS) markers, and elevated the expression of M(IL-4) markers. These data show a significantly altered lncRNA and mRNA expression profile in macrophages exposure to different activating conditions. Dysregulation of some of these lncRNAs may play important roles in regulating macrophage polarization. PMID:26796525

  14. zflncRNApedia: A Comprehensive Online Resource for Zebrafish Long Non-Coding RNAs.

    PubMed

    Dhiman, Heena; Kapoor, Shruti; Sivadas, Ambily; Sivasubbu, Sridhar; Scaria, Vinod

    2015-01-01

    Recent transcriptome annotation using deep sequencing approaches have annotated a large number of long non-coding RNAs in zebrafish, a popular model organism for human diseases. These studies characterized lncRNAs in critical developmental stages as well as adult tissues. Each of the studies has uncovered a distinct set of lncRNAs, with minor overlaps. The availability of the raw RNA-Seq datasets in public domain encompassing critical developmental time-points and adult tissues provides us with a unique opportunity to understand the spatiotemporal expression patterns of lncRNAs. In the present report, we created a catalog of lncRNAs in zebrafish, derived largely from the three annotation sets, as well as manual curation of literature to compile a total of 2,267 lncRNA transcripts in zebrafish. The lncRNAs were further classified based on the genomic context and relationship with protein coding gene neighbors into 4 categories. Analysis revealed a total of 86 intronic, 309 promoter associated, 485 overlapping and 1,386 lincRNAs. We created a comprehensive resource which houses the annotation of lncRNAs as well as associated information including expression levels, promoter epigenetic marks, genomic variants and retroviral insertion mutants. The resource also hosts a genome browser where the datasets could be browsed in the genome context. To the best of our knowledge, this is the first comprehensive resource providing a unified catalog of lncRNAs in zebrafish. The resource is freely available at URL: http://genome.igib.res.in/zflncRNApedia. PMID:26065909

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

    PubMed

    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.

  16. Non-coding RNAs Enabling Prognostic Stratification and Prediction of Therapeutic Response in Colorectal Cancer Patients.

    PubMed

    Perakis, Samantha O; Thomas, Joseph E; Pichler, Martin

    2016-01-01

    Colorectal cancer (CRC) is a heterogeneous disease and current treatment options for patients are associated with a wide range of outcomes and tumor responses. Although the traditional TNM staging system continues to serve as a crucial tool for estimating CRC prognosis and for stratification of treatment choices and long-term survival, it remains limited as it relies on macroscopic features and cases of surgical resection, fails to incorporate new molecular data and information, and cannot perfectly predict the variety of outcomes and responses to treatment associated with tumors of the same stage. Although additional histopathologic features have recently been applied in order to better classify individual tumors, the future might incorporate the use of novel molecular and genetic markers in order to maximize therapeutic outcome and to provide accurate prognosis. Such novel biomarkers, in addition to individual patient tumor phenotyping and other validated genetic markers, could facilitate the prediction of risk of progression in CRC patients and help assess overall survival. Recent findings point to the emerging role of non-protein-coding regions of the genome in their contribution to the progression of cancer and tumor formation. Two major subclasses of non-coding RNAs (ncRNAs), microRNAs and long non-coding RNAs, are often dysregulated in CRC and have demonstrated their diagnostic and prognostic potential as biomarkers. These ncRNAs are promising molecular classifiers and could assist in the stratification of patients into appropriate risk groups to guide therapeutic decisions and their expression patterns could help determine prognosis and predict therapeutic options in CRC. PMID:27573901

  17. Non-coding RNAs Enabling Prognostic Stratification and Prediction of Therapeutic Response in Colorectal Cancer Patients.

    PubMed

    Perakis, Samantha O; Thomas, Joseph E; Pichler, Martin

    2016-01-01

    Colorectal cancer (CRC) is a heterogeneous disease and current treatment options for patients are associated with a wide range of outcomes and tumor responses. Although the traditional TNM staging system continues to serve as a crucial tool for estimating CRC prognosis and for stratification of treatment choices and long-term survival, it remains limited as it relies on macroscopic features and cases of surgical resection, fails to incorporate new molecular data and information, and cannot perfectly predict the variety of outcomes and responses to treatment associated with tumors of the same stage. Although additional histopathologic features have recently been applied in order to better classify individual tumors, the future might incorporate the use of novel molecular and genetic markers in order to maximize therapeutic outcome and to provide accurate prognosis. Such novel biomarkers, in addition to individual patient tumor phenotyping and other validated genetic markers, could facilitate the prediction of risk of progression in CRC patients and help assess overall survival. Recent findings point to the emerging role of non-protein-coding regions of the genome in their contribution to the progression of cancer and tumor formation. Two major subclasses of non-coding RNAs (ncRNAs), microRNAs and long non-coding RNAs, are often dysregulated in CRC and have demonstrated their diagnostic and prognostic potential as biomarkers. These ncRNAs are promising molecular classifiers and could assist in the stratification of patients into appropriate risk groups to guide therapeutic decisions and their expression patterns could help determine prognosis and predict therapeutic options in CRC.

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

    PubMed

    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

  19. 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

  20. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  2. Regulation of spermatogenesis by small non-coding RNAs: role of the Germ Granule

    PubMed Central

    de Mateo, Sara; Sassone-Corsi, Paolo

    2015-01-01

    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. PMID:24755166

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

    PubMed

    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

  4. 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

  5. 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

  6. Identification of small non-coding RNAs in the planarian Dugesia japonica via deep sequencing.

    PubMed

    Qin, Yun-Fei; Zhao, Jin-Mei; Bao, Zhen-Xia; Zhu, Zhao-Yu; Mai, Jia; Huang, Yi-Bo; Li, Jian-Biao; Chen, Ge; Lu, Ping; Chen, San-Jun; Su, Lin-Lin; Fang, Hui-Min; Lu, Ji-Ke; Zhang, Yi-Zhe; Zhang, Shou-Tao

    2012-05-01

    Freshwater planarian flatworm possesses an extraordinary ability to regenerate lost body parts after amputation; it is perfect organism model in regeneration and stem cell biology. Recently, small RNAs have been an increasing concern and studied in many aspects, including regeneration and stem cell biology, among others. In the current study, the large-scale cloning and sequencing of sRNAs from the intact and regenerative planarian Dugesia japonica are reported. Sequence analysis shows that sRNAs between 18nt and 40nt are mainly microRNAs and piRNAs. In addition, 209 conserved miRNAs and 12 novel miRNAs are identified. Especially, a better screening target method, negative-correlation relationship of miRNAs and mRNA, is adopted to improve target prediction accuracy. Similar to miRNAs, a diverse population of piRNAs and changes in the two samples are also listed. The present study is the first to report on the important role of sRNAs during planarian Dugesia japonica regeneration. PMID:22425900

  7. Non-coding RNAs: novel players in chromatin-regulation during viral latency.

    PubMed

    Eilebrecht, Sebastian; Schwartz, Christian; Rohr, Olivier

    2013-08-01

    Chromatin structure plays an essential role during gene expression regulation not only in the case of the host cellular genome, but also during the viral life cycle. Epigenetic chromatin marks thereby define, whether a gene promoter is accessible for the transcription machinery or whether a repressive heterochromatin state is established. The heterochromatin-mediated repression of lytic viral genes results in viral latency, enabling the virus to persist dormant without being recognized by the host immune system, but keeping the potential for reactivation. Arising new systems biology approaches are starting to uncover an unexpected multiplicity and variety of non-coding (nc)RNAs playing important roles during chromatin structure control, likely constituting a novel layer in epigenetic regulation. In this review we give an overview of chromatin-regulatory viral and host cellular ncRNAs and their links to viral latency. PMID:23660570

  8. 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

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

    PubMed

    Nishikura, Kazuko

    2016-02-01

    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

  10. 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

  11. A 5'-3' terminal stem in small non-coding RNAs extends their lifetime.

    PubMed

    Koval, Anastasia P; Gogolevskaya, Irina K; Tatosyan, Karina A; Kramerov, Dmitri A

    2015-01-25

    4.5SI and 4.5SH are two non-coding RNAs about 100nt long, synthesized by RNA polymerase III in cells of various rodents including mice, rats, and hamsters. The first RNA is long-lived whereas the half-life of the second is only 20min. We previously found that the 16bp double-stranded structure (stem), formed by 4.5SI RNA termini, contributes essentially to the long lifetime of this RNA (Koval et al., 2012). The rapid decay of 4.5SH RNA seems to be related to the lack of a similar structure in this RNA. The aim of this work was to verify whether the lifetime of any other short-lived non-coding RNA can be prolonged following creation of the double-stranded structure with its terminal regions. Here RNAs transcribed by RNA polymerase III from short interspersed elements (SINEs) B2 and Rhin-1 from the genomes of mouse and horseshoe bat, respectively, were used. Replacement of 16nt at the 3'-terminal region by the sequence complementary to the 5' end region of B2 and Rhin-1 RNA increased their half-life more than 4 fold. In addition, we demonstrated that shortening of the terminal stem from 16 to 8bp decreased only slightly the 4.5SI RNA lifetime. Finally, we showed that the disruption of an internal (non-terminal) stem in 4.5SI RNA did not accelerate its decay in cells. Possible mechanisms of the small non-coding RNA lifetime extension are discussed.

  12. 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.

  13. Identification of long non-coding RNAs involved in neuronal development and intellectual disability

    PubMed Central

    D’haene, Eva; Jacobs, Eva Z.; Volders, Pieter-Jan; De Meyer, Tim; Menten, Björn; Vergult, Sarah

    2016-01-01

    Recently, exome sequencing led to the identification of causal mutations in 16–31% of patients with intellectual disability (ID), leaving the underlying cause for many patients unidentified. In this context, the noncoding part of the human genome remains largely unexplored. For many long non-coding RNAs (lncRNAs) a crucial role in neurodevelopment and hence the human brain is anticipated. Here we aimed at identifying lncRNAs associated with neuronal development and ID. Therefore, we applied an integrated genomics approach, harnessing several public epigenetic datasets. We found that the presence of neuron-specific H3K4me3 confers the highest specificity for genes involved in neurodevelopment and ID. Based on the presence of this feature and GWAS hits for CNS disorders, we identified 53 candidate lncRNA genes. Extensive expression profiling on human brain samples and other tissues, followed by Gene Set Enrichment Analysis indicates that at least 24 of these lncRNAs are indeed implicated in processes such as synaptic transmission, nervous system development and neurogenesis. The bidirectional or antisense overlapping orientation relative to multiple coding genes involved in neuronal processes supports these results. In conclusion, we identified several lncRNA genes putatively involved in neurodevelopment and CNS disorders, providing a resource for functional studies. PMID:27319317

  14. Understanding the Functions of Long Non-Coding RNAs through Their Higher-Order Structures

    PubMed Central

    Li, Rui; Zhu, Hongliang; Luo, Yunbo

    2016-01-01

    Although thousands of long non-coding RNAs (lncRNAs) have been discovered in eukaryotes, very few molecular mechanisms have been characterized due to an insufficient understanding of lncRNA structure. Therefore, investigations of lncRNA structure and subsequent elucidation of the regulatory mechanisms are urgently needed. However, since lncRNA are high molecular weight molecules, which makes their crystallization difficult, obtaining information about their structure is extremely challenging, and the structures of only several lncRNAs have been determined so far. Here, we review the structure–function relationships of the widely studied lncRNAs found in the animal and plant kingdoms, focusing on the principles and applications of both in vitro and in vivo technologies for the study of RNA structures, including dimethyl sulfate-sequencing (DMS-seq), selective 2′-hydroxyl acylation analyzed by primer extension-sequencing (SHAPE-seq), parallel analysis of RNA structure (PARS), and fragmentation sequencing (FragSeq). The aim of this review is to provide a better understanding of lncRNA biological functions by studying them at the structural level. PMID:27196897

  15. Understanding the Functions of Long Non-Coding RNAs through Their Higher-Order Structures.

    PubMed

    Li, Rui; Zhu, Hongliang; Luo, Yunbo

    2016-01-01

    Although thousands of long non-coding RNAs (lncRNAs) have been discovered in eukaryotes, very few molecular mechanisms have been characterized due to an insufficient understanding of lncRNA structure. Therefore, investigations of lncRNA structure and subsequent elucidation of the regulatory mechanisms are urgently needed. However, since lncRNA are high molecular weight molecules, which makes their crystallization difficult, obtaining information about their structure is extremely challenging, and the structures of only several lncRNAs have been determined so far. Here, we review the structure-function relationships of the widely studied lncRNAs found in the animal and plant kingdoms, focusing on the principles and applications of both in vitro and in vivo technologies for the study of RNA structures, including dimethyl sulfate-sequencing (DMS-seq), selective 2'-hydroxyl acylation analyzed by primer extension-sequencing (SHAPE-seq), parallel analysis of RNA structure (PARS), and fragmentation sequencing (FragSeq). The aim of this review is to provide a better understanding of lncRNA biological functions by studying them at the structural level. PMID:27196897

  16. Non-coding RNAs in saliva: emerging biomarkers for molecular diagnostics.

    PubMed

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

    2015-04-17

    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.

  17. 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

  18. The fusion of two worlds: non-coding RNAs and extracellular vesicles--diagnostic and therapeutic implications (Review).

    PubMed

    Sato-Kuwabara, Yukie; Melo, Sonia A; Soares, Fernando A; Calin, George A

    2015-01-01

    The role of the extracellular non-coding RNAs, particularly microRNAs present in tumor-derived extravesicles, has been intensively exploited in human cancer as a promising tool for diagnostic and prognostic purposes. Current knowledge on exosomes shows an important role not only as vehicles in the intercellular communication, but the transfer of their content can specifically modulate the surrounding microenvironment, leading to tumor development and progression and affecting therapy response. Based on this, much effort has focused on understanding the mechanisms behind the biology of exosomes and their closely interaction with non-coding RNAs as an efficient tool in tumor diagnostic and therapy. Here we summarize the current knowledge on extracellular and exosomes-enclosed non-coding RNAs, and their importance as potential biomarkers and mediators of intercellular communication in tumor biology.

  19. 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

  20. Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes.

    PubMed

    Su, Xiaoping; Malouf, Gabriel G; Chen, Yunxin; Zhang, Jianping; Yao, Hui; Valero, Vicente; Weinstein, John N; Spano, Jean-Philippe; Meric-Bernstam, Funda; Khayat, David; Esteva, Francisco J

    2014-10-30

    Accumulating evidence highlights the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. However, the role of lncRNA expression in human breast cancer biology, prognosis and molecular classification remains unknown. Herein, we established the lncRNA profile of 658 infiltrating ductal carcinomas of the breast from The Cancer Genome Atlas project. We found lncRNA expression to correlate with the gene expression and chromatin landscape of human mammary epithelial cells (non-transformed) and the breast cancer cell line MCF-7. Unsupervised consensus clustering of lncRNA revealed four subgroups that displayed different prognoses. Gene set enrichment analysis for cis- and trans-acting lncRNAs showed enrichment for breast cancer signatures driven by master regulators of breast carcinogenesis. Interestingly, the lncRNA HOTAIR was significantly overexpressed in the HER2-enriched subgroup, while the lncRNA HOTAIRM1 was significantly overexpressed in the basal-like subgroup. Estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Importantly, almost two thirds of the lncRNAs were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that expressed lncRNA in breast cancer drives carcinogenesis through increased activity of neighboring genes. In summary, our study depicts the first lncRNA subtype classification in breast cancer and provides the framework for future studies to assess the interplay between lncRNAs and the breast cancer epigenome.

  1. Molecular phenotyping of infection-associated small non-coding RNAs.

    PubMed

    Barquist, Lars; Westermann, Alexander J; Vogel, Jörg

    2016-11-01

    Infection is a complicated balance, with both pathogen and host struggling to tilt the result in their favour. Bacterial infection biology has relied on forward genetics for many of its advances, defining phenotype in terms of replication in model systems. However, many known virulence factors fail to produce robust phenotypes, particularly in the systems most amenable to genetic manipulation, such as cell-culture models. This has particularly been limiting for the study of the bacterial regulatory small RNAs (sRNAs) in infection. We argue that new sequencing-based technologies can work around this problem by providing a 'molecular phenotype', defined in terms of the specific transcriptional dysregulation in the infection system induced by gene deletion. We illustrate this using the example of our recent study of the PinT sRNA using dual RNA-seq, that is, simultaneous RNA sequencing of host and pathogen during infection. We additionally discuss how other high-throughput technologies, in particular genetic interaction mapping using transposon insertion sequencing, may be used to further dissect molecular phenotypes. We propose a strategy for how high-throughput technologies can be integrated in the study of non-coding regulators as well as bacterial virulence factors, enhancing our ability to rapidly generate hypotheses with regards to their function.This article is part of the themed issue 'The new bacteriology'.

  2. Molecular phenotyping of infection-associated small non-coding RNAs.

    PubMed

    Barquist, Lars; Westermann, Alexander J; Vogel, Jörg

    2016-11-01

    Infection is a complicated balance, with both pathogen and host struggling to tilt the result in their favour. Bacterial infection biology has relied on forward genetics for many of its advances, defining phenotype in terms of replication in model systems. However, many known virulence factors fail to produce robust phenotypes, particularly in the systems most amenable to genetic manipulation, such as cell-culture models. This has particularly been limiting for the study of the bacterial regulatory small RNAs (sRNAs) in infection. We argue that new sequencing-based technologies can work around this problem by providing a 'molecular phenotype', defined in terms of the specific transcriptional dysregulation in the infection system induced by gene deletion. We illustrate this using the example of our recent study of the PinT sRNA using dual RNA-seq, that is, simultaneous RNA sequencing of host and pathogen during infection. We additionally discuss how other high-throughput technologies, in particular genetic interaction mapping using transposon insertion sequencing, may be used to further dissect molecular phenotypes. We propose a strategy for how high-throughput technologies can be integrated in the study of non-coding regulators as well as bacterial virulence factors, enhancing our ability to rapidly generate hypotheses with regards to their function.This article is part of the themed issue 'The new bacteriology'. PMID:27672158

  3. Expression profile of long non-coding RNAs in pancreatic cancer and their clinical significance as biomarkers.

    PubMed

    Wang, Yingxue; Li, Zhihua; Zheng, Shangyou; Zhou, Yu; Zhao, Lei; Ye, Huilin; Zhao, Xiaohui; Gao, Wenchao; Fu, Zhiqiang; Zhou, Quanbo; Liu, Yimin; Chen, Rufu

    2015-11-01

    Long non-coding RNAs (lncRNAs) have shown great potential as powerful and non-invasive tumor markers. However, little is known about their value as biomarkers in pancreatic cancer (PC). We applied an Arraystar Human LncRNA Microarray which targeting 7419 lncRNAs to determine the lncRNA expression profile in PC and to screen the potential biomarkers. The most increased lncRNAs in PC tissues were HOTTIP-005, XLOC_006390, and RP11-567G11.1. Increased HOTTIP-005 and RP11-567G11.1 expression were poor prognostic factors for patients with PC (n = 144, p < 0.0001). The expression patterns of HOTTIP splice variants in PC were also detected. HOTTIP-005 and HOTTIP-001 were the first and second most increased HOTTIP splice variants, respectively. Plasma HDRF and RDRF (HOTTIP-005 and RP11-567G11.1 derived RNA fragments in plasma/serum) were present in stable form. Their levels were significantly increased in the patients with PC as compared to the healthy controls (n = 127 and 122 respectively, p < 0.0001) and the high levels were derived from PC. HDRF and RDRF levels are promising indicators for distinguishing patients with PC from those without PC. This study identified HOTTIP-005 and RP11-567G11.1 and their plasma fragments with the potential to be used as prognostic and diagnostic biomarkers of PC. Further large-scale prospective studies are needed to confirm our findings.

  4. Identification of non-coding RNAs associated with telomeres using a combination of enChIP and RNA sequencing.

    PubMed

    Fujita, Toshitsugu; Yuno, Miyuki; Okuzaki, Daisuke; Ohki, Rieko; Fujii, Hodaka

    2015-01-01

    Accumulating evidence suggests that RNAs interacting with genomic regions play important roles in the regulation of genome functions, including X chromosome inactivation and gene expression. However, to our knowledge, no non-biased methods of identifying RNAs that interact with a specific genomic region have been reported. Here, we used enChIP-RNA-Seq, a combination of engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) and RNA sequencing (RNA-Seq), to perform a non-biased search for RNAs interacting with telomeres. In enChIP-RNA-Seq, the target genomic regions are captured using an engineered DNA-binding molecule such as a transcription activator-like protein. Subsequently, RNAs that interact with the target genomic regions are purified and sequenced. The RNAs detected by enChIP-RNA-Seq contained known telomere-binding RNAs, including the telomerase RNA component (Terc), the RNA component of mitochondrial RNA processing endoribonuclease (Rmrp), and Cajal body-specific RNAs. In addition, a number of novel telomere-binding non-coding RNAs were also identified. Binding of two candidate non-coding RNAs to telomeres was confirmed by immunofluorescence microscopy and RNA fluorescence in situ hybridization (RNA-FISH) analyses. The novel telomere-binding non-coding RNAs identified here may play important roles in telomere functions. To our knowledge, this study is the first non-biased identification of RNAs associated with specific genomic regions. The results presented here suggest that enChIP-RNA-Seq analyses are useful for the identification of RNAs interacting with specific genomic regions, and may help to contribute to current understanding of the regulation of genome functions.

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

    PubMed

    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; Weichselbaum, Ralph R; Khodarev, Nikolai N

    2016-05-01

    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.

  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. 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

  8. 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.

  9. 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

  10. Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides

    PubMed Central

    Lennox, Kim A.; Behlke, Mark A.

    2016-01-01

    Thousands of long non-coding RNAs (lncRNAs) have been identified in mammalian cells. Some have important functions and their dysregulation can contribute to a variety of disease states. However, most lncRNAs have not been functionally characterized. Complicating their study, lncRNAs have widely varying subcellular distributions: some reside predominantly in the nucleus, the cytoplasm or in both compartments. One method to query function is to suppress expression and examine the resulting phenotype. Methods to suppress expression of mRNAs include antisense oligonucleotides (ASOs) and RNA interference (RNAi). Antisense and RNAi-based gene-knockdown methods vary in efficacy between different cellular compartments. It is not known if this affects their ability to suppress lncRNAs. To address whether localization of the lncRNA influences susceptibility to degradation by either ASOs or RNAi, nuclear lncRNAs (MALAT1 and NEAT1), cytoplasmic lncRNAs (DANCR and OIP5-AS1) and dual-localized lncRNAs (TUG1, CasC7 and HOTAIR) were compared for knockdown efficiency. We found that nuclear lncRNAs were more effectively suppressed using ASOs, cytoplasmic lncRNAs were more effectively suppressed using RNAi and dual-localized lncRNAs were suppressed using both methods. A mixed-modality approach combining ASOs and RNAi reagents improved knockdown efficacy, particularly for those lncRNAs that localize to both nuclear and cytoplasmic compartments. PMID:26578588

  11. Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides.

    PubMed

    Lennox, Kim A; Behlke, Mark A

    2016-01-29

    Thousands of long non-coding RNAs (lncRNAs) have been identified in mammalian cells. Some have important functions and their dysregulation can contribute to a variety of disease states. However, most lncRNAs have not been functionally characterized. Complicating their study, lncRNAs have widely varying subcellular distributions: some reside predominantly in the nucleus, the cytoplasm or in both compartments. One method to query function is to suppress expression and examine the resulting phenotype. Methods to suppress expression of mRNAs include antisense oligonucleotides (ASOs) and RNA interference (RNAi). Antisense and RNAi-based gene-knockdown methods vary in efficacy between different cellular compartments. It is not known if this affects their ability to suppress lncRNAs. To address whether localization of the lncRNA influences susceptibility to degradation by either ASOs or RNAi, nuclear lncRNAs (MALAT1 and NEAT1), cytoplasmic lncRNAs (DANCR and OIP5-AS1) and dual-localized lncRNAs (TUG1, CasC7 and HOTAIR) were compared for knockdown efficiency. We found that nuclear lncRNAs were more effectively suppressed using ASOs, cytoplasmic lncRNAs were more effectively suppressed using RNAi and dual-localized lncRNAs were suppressed using both methods. A mixed-modality approach combining ASOs and RNAi reagents improved knockdown efficacy, particularly for those lncRNAs that localize to both nuclear and cytoplasmic compartments. PMID:26578588

  12. 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.

  13. Genome-wide profiling of miRNAs and other small non-coding RNAs in the Verticillium dahliae-inoculated cotton roots.

    PubMed

    Yin, Zujun; Li, Yan; Han, Xiulan; Shen, Fafu

    2012-01-01

    MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) are short (19-25 nucleotides) non-coding RNA molecules that have large-scale regulatory effects on development and stress responses in plants. Verticillium wilt is a vascular disease in plants caused by the fungal pathogen Verticillium dahliae. The objective of this study is to investigate the transcriptional profile of miRNAs and other small non-coding RNAs in Verticillium-inoculated cotton roots. Four small RNA libraries were constructed from mocked and infected roots of two cotton cultured species which are with different Verticillium wilt tolerance ('Hai-7124', Gossypium barbadense L., a Verticillium-tolerant cultivar, and 'Yi-11', Gossypium hirsutum L. a Verticillium-sensitive cultivar). The length distribution of obtained small RNAs was significantly different between libraries. There were a total of 215 miRNA families identified in the two cotton species. Of them 14 were novel miRNAs. There were >65 families with different expression between libraries. We also identified two trans-acting siRNAs and thousands of endogenous siRNA candidates, and hundred of them exhibited altered expression after inoculation of Verticillium. Interesting, many siRNAs were found with a perfect match with retrotransposon sequences, suggested that retrotransposons maybe one of sources for the generation of plant endogenous siRNAs. The profiling of these miRNAs and other small non-coding RNAs lay the foundation for further understanding of small RNAs function in the regulation of Verticillium defence responses in cotton roots.

  14. Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer

    PubMed Central

    Li, Yongsheng; Zhang, Yunpeng; Li, Shengli; Lu, Jianping; Chen, Juan; Wang, Yuan; Li, Yixue; Xu, Juan; Li, Xia

    2015-01-01

    Despite growing appreciation of the importance of epigenetics in breast cancer, our understanding of epigenetic alterations of non-coding RNAs (ncRNAs) in breast cancer remains limited. Here, we explored the epigenetic patterns of ncRNAs in breast cancers using published sequencing-based methylome data, primarily focusing on the two most commonly studied ncRNA biotypes, long ncRNAs and miRNAs. We observed widely aberrant methylation in the promoters of ncRNAs, and this abnormal methylation was more frequent than that in protein-coding genes. Specifically, intergenic ncRNAs were observed to comprise a majority (51.45% of the lncRNAs and 51.57% of the miRNAs) of the aberrantly methylated ncRNA promoters. Moreover, we summarized five patterns of aberrant ncRNA promoter methylation in the context of genomic CpG islands (CGIs), in which aberrant methylation occurred not only on CGIs, but also in regions flanking CGI and in CGI-lacking promoters. Integration with transcriptional datasets enabled us to determine that the ncRNA promoter methylation events were associated with transcriptional changes. Furthermore, a panel of ncRNAs were identified as biomarkers that discriminated between disease phenotypes. Finally, the potential functions of aberrantly methylated ncRNAs were predicted, suggestiong that ncRNAs and coding genes cooperatively mediate pathway dysregulation during the development and progression of breast cancer. PMID:25739977

  15. Pan-Cancer Analyses Reveal Long Intergenic Non-Coding RNAs Relevant to Tumor Diagnosis, Subtyping and Prognosis.

    PubMed

    Ching, Travers; Peplowska, Karolina; Huang, Sijia; Zhu, Xun; Shen, Yi; Molnar, Janos; Yu, Herbert; Tiirikainen, Maarit; Fogelgren, Ben; Fan, Rong; Garmire, Lana X

    2016-05-01

    Long intergenic noncoding RNAs (lincRNAs) are a relatively new class of non-coding RNAs that have the potential as cancer biomarkers. To seek a panel of lincRNAs as pan-cancer biomarkers, we have analyzed transcriptomes from over 3300 cancer samples with clinical information. Compared to mRNA, lincRNAs exhibit significantly higher tissue specificities that are then diminished in cancer tissues. Moreover, lincRNA clustering results accurately classify tumor subtypes. Using RNA-Seq data from thousands of paired tumor and adjacent normal samples in The Cancer Genome Atlas (TCGA), we identify six lincRNAs as potential pan-cancer diagnostic biomarkers (PCAN-1 to PCAN-6). These lincRNAs are robustly validated using cancer samples from four independent RNA-Seq data sets, and are verified by qPCR in both primary breast cancers and MCF-7 cell line. Interestingly, the expression levels of these six lincRNAs are also associated with prognosis in various cancers. We further experimentally explored the growth and migration dependence of breast and colon cancer cell lines on two of the identified lncRNAs. In summary, our study highlights the emerging role of lincRNAs as potentially powerful and biologically functional pan-cancer biomarkers and represents a significant leap forward in understanding the biological and clinical functions of lincRNAs in cancers.

  16. 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

  17. 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.

  18. Identification of long non-coding RNAs as novel biomarker and potential therapeutic target for atrial fibrillation in old adults.

    PubMed

    Xu, Yingjia; Huang, Ritai; Gu, Jianing; Jiang, Weifeng

    2016-03-01

    Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia disease, which widely leads to exacerbate heart failure and ischemic stroke in elder world. Recently, long non-coding RNAs (lncRNAs), a subclass of noncoding RNAs, have been reported to play critical roles in pathophysiology of cardiac heart. However, little is known of their role in cardiac arrhythmia. In the present study, we investigated the expression levels of lncRNAs of AF patients and healthy people with Agilent Human lncRNA array for the first time. 177 lncRNAs of 78243 and 153 mRNAs of 30215 tested were identified to be differentially expressed (≥ 2-fold change), indicating that the expression of many lncRNAs are upregulated or downregulated in AF. Among these, NONHSAT040387 and NONHSAT098586 were the most upregulated and downregulated lncRNAs. Real time quantitative PCR were employed to validate the microarray analysis findings, and the results confirmed the consistence. GO and KEGG pathway analysis were applied to explore the potential lncRNAs functions, some pathways including oxygen transporter activity and protein heterodimerization activity were speculated to be involved in AF pathogenesis. These results shed some light on lncRNAs' physiologic functions and provide useful information for exploring potential therapeutic treatments for heart rhythm disease.

  19. Crosstalk between transforming growth factor-β signaling pathway and long non-coding RNAs in cancer.

    PubMed

    Wang, Jianbo; Shao, Na; Ding, Xiaowen; Tan, Bingxu; Song, Qingxu; Wang, Nana; Jia, Yibin; Ling, Hongbo; Cheng, Yufeng

    2016-01-28

    The transforming growth factor-β (TGF-β) signaling pathway plays an important role in tumorigenesis by exerting either a tumor-suppressing or tumor-promoting effect. Long non-coding RNAs (lncRNAs), a newly discovered class of non-coding RNAs, have been widely studied in recent years and identified as crucial regulators of various biological processes, including cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Recent evidence, addressing the crosstalk between the TGF-β signaling pathway and lncRNAs in cancer, found that several members of the TGF-β pathway are targeted by lncRNAs, and the production of hundreds of lncRNAs is induced by TGF-β treatment. This review will summarize the latest progress on the investigation of TGF-β pathway and lncRNA network in regulating cancer development. Further study on the network would provide a better understanding of carcinogenesis and have potentials for the prevention and treatment of malignant diseases.

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

    PubMed

    Busch, Albert; Eken, Suzanne M; Maegdefessel, Lars

    2016-06-01

    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

  1. 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

  2. Long non-coding RNAs: An emerging powerhouse in the battle between life and death of tumor cells.

    PubMed

    Xiong, Xing-Dong; Ren, Xingcong; Cai, Meng-Yun; Yang, Jay W; Liu, Xinguang; Yang, Jin-Ming

    2016-05-01

    Long non-coding RNAs (lncRNAs) represent a class of non-protein coding transcripts longer than 200 nucleotides that have aptitude for regulating gene expression at the transcriptional, post-transcriptional or epigenetic levels. In recent years, lncRNAs, which are believed to be the largest transcript class in the transcriptomes, have emerged as important players in a variety of biological processes. Notably, the identification and characterization of numerous lncRNAs in the past decade has revealed a role for these molecules in the regulation of cancer cell survival and death. It is likely that this class of non-coding RNA constitutes a critical contributor to the assorted known or/and unknown mechanisms of intrinsic or acquired drug resistance. Moreover, the expression of lncRNAs is altered in various patho-physiological conditions, including cancer. Therefore, lncRNAs represent potentially important targets in predicting or altering the sensitivity or resistance of cancer cells to various therapies. Here, we provide an overview on the molecular functions of lncRNAs, and discuss their impact and importance in cancer development, progression, and therapeutic outcome. We also provide a perspective on how lncRNAs may alter the efficacy of cancer therapy and the promise of lncRNAs as novel therapeutic targets for overcoming chemoresistance. A better understanding of the functional roles of lncRNA in cancer can ultimately translate to the development of novel, lncRNA-based intervention strategies for the treatment or prevention of drug-resistant cancer.

  3. Identification of novel non-coding small RNAs from Streptococcus pneumoniae TIGR4 using high-resolution genome tiling arrays

    PubMed Central

    2010-01-01

    Background The identification of non-coding transcripts in human, mouse, and Escherichia coli has revealed their widespread occurrence and functional importance in both eukaryotic and prokaryotic life. In prokaryotes, studies have shown that non-coding transcripts participate in a broad range of cellular functions like gene regulation, stress and virulence. However, very little is known about non-coding transcripts in Streptococcus pneumoniae (pneumococcus), an obligate human respiratory pathogen responsible for significant worldwide morbidity and mortality. Tiling microarrays enable genome wide mRNA profiling as well as identification of novel transcripts at a high-resolution. Results Here, we describe a high-resolution transcription map of the S. pneumoniae clinical isolate TIGR4 using genomic tiling arrays. Our results indicate that approximately 66% of the genome is expressed under our experimental conditions. We identified a total of 50 non-coding small RNAs (sRNAs) from the intergenic regions, of which 36 had no predicted function. Half of the identified sRNA sequences were found to be unique to S. pneumoniae genome. We identified eight overrepresented sequence motifs among sRNA sequences that correspond to sRNAs in different functional categories. Tiling arrays also identified approximately 202 operon structures in the genome. Conclusions In summary, the pneumococcal operon structures and novel sRNAs identified in this study enhance our understanding of the complexity and extent of the pneumococcal 'expressed' genome. Furthermore, the results of this study open up new avenues of research for understanding the complex RNA regulatory network governing S. pneumoniae physiology and virulence. PMID:20525227

  4. Long non-coding RNAs as surrogate indicators for chemical stress responses in human-induced pluripotent stem cells.

    PubMed

    Tani, Hidenori; Onuma, Yasuko; Ito, Yuzuru; Torimura, Masaki

    2014-01-01

    In this study, we focused on two biological products as ideal tools for toxicological assessment: long non-coding RNAs (lncRNAs) and human-induced pluripotent stem cells (hiPSCs). lncRNAs are an important class of pervasive non-protein-coding transcripts involved in the molecular mechanisms associated with responses to cellular stresses. hiPSCs possess the capabilities of self-renewal and differentiation into multiple cell types, and they are free of the ethical issues associated with human embryonic stem cells. Here, we identified six novel lncRNAs (CDKN2B-AS1, MIR22HG, GABPB1-AS1, FLJ33630, LINC00152, and LINC0541471_v2) that respond to model chemical stresses (cycloheximide, hydrogen peroxide, cadmium, or arsenic) in hiPSCs. Our results indicated that the lncRNAs responded to general and specific chemical stresses. Compared with typical mRNAs such as p53-related mRNAs, the lncRNAs highly and rapidly responded to chemical stresses. We propose that these lncRNAs have the potential to be surrogate indicators of chemical stress responses in hiPSCs.

  5. Long non-coding RNAs harboring miRNA seed regions are enriched in prostate cancer exosomes.

    PubMed

    Ahadi, Alireza; Brennan, Samuel; Kennedy, Paul J; Hutvagner, Gyorgy; Tran, Nham

    2016-01-01

    Long non-coding RNAs (lncRNAs) form the largest transcript class in the human transcriptome. These lncRNA are expressed not only in the cells, but they are also present in the cell-derived extracellular vesicles such as exosomes. The function of these lncRNAs in cancer biology is not entirely clear, but they appear to be modulators of gene expression. In this study, we characterize the expression of lncRNAs in several prostate cancer exosomes and their parental cell lines. We show that certain lncRNAs are enriched in cancer exosomes with the overall expression signatures varying across cell lines. These exosomal lncRNAs are themselves enriched for miRNA seeds with a preference for let-7 family members as well as miR-17, miR-18a, miR-20a, miR-93 and miR-106b. The enrichment of miRNA seed regions in exosomal lncRNAs is matched with a concomitant high expression of the same miRNA. In addition, the exosomal lncRNAs also showed an over representation of RNA binding protein binding motifs. The two most common motifs belonged to ELAVL1 and RBMX. Given the enrichment of miRNA and RBP sites on exosomal lncRNAs, their interplay may suggest a possible function in prostate cancer carcinogenesis. PMID:27102850

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

    PubMed Central

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

    2016-01-01

    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. PMID:26860696

  7. 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

  8. Long non-coding RNAs harboring miRNA seed regions are enriched in prostate cancer exosomes

    PubMed Central

    Ahadi, Alireza; Brennan, Samuel; Kennedy, Paul J.; Hutvagner, Gyorgy; Tran, Nham

    2016-01-01

    Long non-coding RNAs (lncRNAs) form the largest transcript class in the human transcriptome. These lncRNA are expressed not only in the cells, but they are also present in the cell-derived extracellular vesicles such as exosomes. The function of these lncRNAs in cancer biology is not entirely clear, but they appear to be modulators of gene expression. In this study, we characterize the expression of lncRNAs in several prostate cancer exosomes and their parental cell lines. We show that certain lncRNAs are enriched in cancer exosomes with the overall expression signatures varying across cell lines. These exosomal lncRNAs are themselves enriched for miRNA seeds with a preference for let-7 family members as well as miR-17, miR-18a, miR-20a, miR-93 and miR-106b. The enrichment of miRNA seed regions in exosomal lncRNAs is matched with a concomitant high expression of the same miRNA. In addition, the exosomal lncRNAs also showed an over representation of RNA binding protein binding motifs. The two most common motifs belonged to ELAVL1 and RBMX. Given the enrichment of miRNA and RBP sites on exosomal lncRNAs, their interplay may suggest a possible function in prostate cancer carcinogenesis. PMID:27102850

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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. PMID:25826417

  14. Gene Expression of Protein-Coding and Non-Coding RNAs Related to Polyembryogenesis in the Parasitic Wasp, Copidosoma floridanum

    PubMed Central

    Inoue, Hiroki; Yoshimura, Jin; Iwabuchi, Kikuo

    2014-01-01

    Polyembryony is a unique form of development in which many embryos are clonally produced from a single egg. Polyembryony is known to occur in many animals, but the underlying genetic mechanism responsible is unknown. In a parasitic wasp, Copidosoma floridanum, polyembryogenesis is initiated during the formation and division of the morula. In the present study, cDNA libraries were constructed from embryos at the cleavage and subsequent primary morula stages, times when polyembryogenesis is likely to be controlled genetically. Of 182 and 263 cDNA clones isolated from these embryos, 38% and 70%, respectively, were very similar to protein-coding genes obtained from BLAST analysis and 55 and 65 clones, respectively, were stage-specific. In our libraries we also detected a high frequency of long non-coding RNA. Some of these showed stage-specific expression patterns in reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis. The stage-specificity of expression implies that these protein-coding and non-coding genes are related to polyembryogenesis in C. floridanum. The non-coding genes are not similar to any known non-coding RNAs and so are good candidates as regulators of polyembryogenesis. PMID:25469914

  15. The 5' and 3' ends of alphavirus RNAsnon-coding is not non-functional

    PubMed Central

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

    2015-01-01

    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. PMID:25630058

  16. 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

  17. Long non-coding RNAs, a new important regulator of cardiovascular physiology and pathology.

    PubMed

    Ma, Yidi; Ma, Wenya; Huang, Lina; Feng, Dan; Cai, Benzhi

    2015-06-01

    LncRNAs were previously considered to be the 'noise' of gene transcription having no biological functions, but now it has become evident that lncRNAs function as modulators of gene expression network. LncRNAs may regulate diverse gene expression levels which were roughly summarized to epigenetic, transcriptional and post-transcriptional levels. It has been clarified that some lncRNAs were expressed differentially in cardiovascular diseases, and aberrant changes of those lncRNAs were involved in the development of heart disorders. The role of lncRNAs in this process transcended the tradition of protein regulatory platform to be the orchestrator of cardiac sophisticated governing system of heart development, adaptation and pathological reaction. This review summarizes recent advances in the study of functions and mechanisms of lncRNAs in cardiovascular physiology and pathology. The regulatory roles of lncRNAs in cardiovascular diseases provide new strategy for interventional therapy of heart diseases.

  18. 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.

  19. 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

  20. Non-coding RNAs in marine Synechococcus and their regulation under environmentally relevant stress conditions

    PubMed Central

    Gierga, Gregor; Voss, Björn; Hess, Wolfgang R

    2012-01-01

    Regulatory small RNAs (sRNAs) have crucial roles in the adaptive responses of bacteria to changes in the environment. Thus far, potential regulatory RNAs have been studied mainly in marine picocyanobacteria in genetically intractable Prochlorococcus, rendering their molecular analysis difficult. Synechococcus sp. WH7803 is a model cyanobacterium, representative of the picocyanobacteria from the mesotrophic areas of the ocean. Similar to the closely related Prochlorococcus it possesses a relatively streamlined genome and a small number of genes, but is genetically tractable. Here, a comparative genome analysis was performed for this and four additional marine Synechococcus to identify the suite of possible sRNAs and other RNA elements. Based on the prediction and on complementary microarray profiling, we have identified several known as well as 32 novel sRNAs. Some sRNAs overlap adjacent coding regions, for instance for the central photosynthetic gene psbA. Several of these novel sRNAs responded specifically to environmentally relevant stress conditions. Among them are six sRNAs changing their accumulation level under cold stress, six responding to high light and two to iron limitation. Target predictions suggested genes encoding components of the light-harvesting apparatus as targets of sRNAs originating from genomic islands and that one of the iron-regulated sRNAs might be a functional homolog of RyhB. These data suggest that marine Synechococcus mount adaptive responses to these different stresses involving regulatory sRNAs. PMID:22258101

  1. Non-coding roX RNAs Prevent the Binding of the MSL-complex to Heterochromatic Regions

    PubMed Central

    Figueiredo, Margarida L. A.; Kim, Maria; Philip, Philge; Allgardsson, Anders; Stenberg, Per; Larsson, Jan

    2014-01-01

    Long non-coding RNAs contribute to dosage compensation in both mammals and Drosophila by inducing changes in the chromatin structure of the X-chromosome. In Drosophila melanogaster, roX1 and roX2 are long non-coding RNAs that together with proteins form the male-specific lethal (MSL) complex, which coats the entire male X-chromosome and mediates dosage compensation by increasing its transcriptional output. Studies on polytene chromosomes have demonstrated that when both roX1 and roX2 are absent, the MSL-complex becomes less abundant on the male X-chromosome and is relocated to the chromocenter and the 4th chromosome. Here we address the role of roX RNAs in MSL-complex targeting and the evolution of dosage compensation in Drosophila. We performed ChIP-seq experiments which showed that MSL-complex recruitment to high affinity sites (HAS) on the X-chromosome is independent of roX and that the HAS sequence motif is conserved in D. simulans. Additionally, a complete and enzymatically active MSL-complex is recruited to six specific genes on the 4th chromosome. Interestingly, our sequence analysis showed that in the absence of roX RNAs, the MSL-complex has an affinity for regions enriched in Hoppel transposable elements and repeats in general. We hypothesize that roX mutants reveal the ancient targeting of the MSL-complex and propose that the role of roX RNAs is to prevent the binding of the MSL-complex to heterochromatin. PMID:25501352

  2. 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

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

    PubMed

    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

  4. 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.

  5. GermlncRNA: a unique catalogue of long non-coding RNAs and associated regulations in male germ cell development.

    PubMed

    Luk, Alfred Chun-Shui; Gao, Huayan; Xiao, Sizhe; Liao, Jinyue; Wang, Daxi; Tu, Jiajie; Rennert, Owen M; Chan, Wai-Yee; Lee, Tin-Lap

    2015-01-01

    Spermatogenic failure is a major cause of male infertility, which affects millions of couples worldwide. Recent discovery of long non-coding RNAs (lncRNAs) as critical regulators in normal and disease development provides new clues for delineating the molecular regulation in male germ cell development. However, few functional lncRNAs have been characterized to date. A major limitation in studying lncRNA in male germ cell development is the absence of germ cell-specific lncRNA annotation. Current lncRNA annotations are assembled by transcriptome data from heterogeneous tissue sources; specific germ cell transcript information of various developmental stages is therefore under-represented, which may lead to biased prediction or fail to identity important germ cell-specific lncRNAs. GermlncRNA provides the first comprehensive web-based and open-access lncRNA catalogue for three key male germ cell stages, including type A spermatogonia, pachytene spermatocytes and round spermatids. This information has been developed by integrating male germ transcriptome resources derived from RNA-Seq, tiling microarray and GermSAGE. Characterizations on lncRNA-associated regulatory features, potential coding gene and microRNA targets are also provided. Search results from GermlncRNA can be exported to Galaxy for downstream analysis or downloaded locally. Taken together, GermlncRNA offers a new avenue to better understand the role of lncRNAs and associated targets during spermatogenesis. Database URL: http://germlncrna.cbiit.cuhk.edu.hk/ PMID:25982314

  6. GermlncRNA: a unique catalogue of long non-coding RNAs and associated regulations in male germ cell development

    PubMed Central

    Luk, Alfred Chun-Shui; Gao, Huayan; Xiao, Sizhe; Liao, Jinyue; Wang, Daxi; Tu, Jiajie; Rennert, Owen M.; Chan, Wai-Yee; Lee, Tin-Lap

    2015-01-01

    Spermatogenic failure is a major cause of male infertility, which affects millions of couples worldwide. Recent discovery of long non-coding RNAs (lncRNAs) as critical regulators in normal and disease development provides new clues for delineating the molecular regulation in male germ cell development. However, few functional lncRNAs have been characterized to date. A major limitation in studying lncRNA in male germ cell development is the absence of germ cell-specific lncRNA annotation. Current lncRNA annotations are assembled by transcriptome data from heterogeneous tissue sources; specific germ cell transcript information of various developmental stages is therefore under-represented, which may lead to biased prediction or fail to identity important germ cell-specific lncRNAs. GermlncRNA provides the first comprehensive web-based and open-access lncRNA catalogue for three key male germ cell stages, including type A spermatogonia, pachytene spermatocytes and round spermatids. This information has been developed by integrating male germ transcriptome resources derived from RNA-Seq, tiling microarray and GermSAGE. Characterizations on lncRNA-associated regulatory features, potential coding gene and microRNA targets are also provided. Search results from GermlncRNA can be exported to Galaxy for downstream analysis or downloaded locally. Taken together, GermlncRNA offers a new avenue to better understand the role of lncRNAs and associated targets during spermatogenesis. Database URL: http://germlncrna.cbiit.cuhk.edu.hk/ PMID:25982314

  7. 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

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

    PubMed

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

    2015-10-16

    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.

  9. Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs.

    PubMed

    Ricaño-Ponce, Isis; Zhernakova, Daria V; Deelen, Patrick; Luo, Oscar; Li, Xingwang; Isaacs, Aaron; Karjalainen, Juha; Di Tommaso, Jennifer; Borek, Zuzanna Agnieszka; Zorro, Maria M; Gutierrez-Achury, Javier; Uitterlinden, Andre G; Hofman, Albert; van Meurs, Joyce; Netea, Mihai G; Jonkers, Iris H; Withoff, Sebo; van Duijn, Cornelia M; Li, Yang; Ruan, Yijun; Franke, Lude; Wijmenga, Cisca; Kumar, Vinod

    2016-04-01

    Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases.

  10. The SLE Transcriptome Exhibits Evidence of Chronic Endotoxin Exposure and Has Widespread Dysregulation of Non-Coding and Coding RNAs

    PubMed Central

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

    2014-01-01

    Background 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. Methods 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. Results 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. Conclusions 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. PMID:24796678

  11. 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

    2015-01-01

    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. PMID:26459019

  12. 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.

  13. Development of a prediction model for radiosensitivity using the expression values of genes and long non-coding RNAs.

    PubMed

    Wang, Wei-An; Lai, Liang-Chuan; Tsai, Mong-Hsun; Lu, Tzu-Pin; Chuang, Eric Y

    2016-05-01

    Radiotherapy has become a popular and standard approach for treating cancer patients because it greatly improves patient survival. However, some of the patients receiving radiotherapy suffer from adverse effects and do not obtain survival benefits. This may be attributed to the fact that most radiation treatment plans are designed based on cancer type, without consideration of each individual's radiosensitivity. A model for predicting radiosensitivity would help to address this issue. In this study, the expression levels of both genes and long non-coding RNAs (lncRNAs) were used to build such a prediction model. Analysis of variance and Tukey's honest significant difference tests (P < 0.001) were utilized in immortalized B cells (GSE26835) to identify differentially expressed genes and lncRNAs after irradiation. A total of 41 genes and lncRNAs associated with radiation exposure were revealed by a network analysis algorithm. To develop a predictive model for radiosensitivity, the expression profiles of NCI-60 cell lines along, with their radiation parameters, were analyzed. A genetic algorithm was proposed to identify 20 predictors, and the support vector machine algorithm was used to evaluate their prediction performance. The model was applied to 2 datasets of glioblastoma, The Cancer Genome Atlas and GSE16011, and significantly better survival was observed in patients with greater predicted radiosensitivity.

  14. Development of a prediction model for radiosensitivity using the expression values of genes and long non-coding RNAs

    PubMed Central

    Wang, Wei-An; Lai, Liang-Chuan; Tsai, Mong-Hsun; Lu, Tzu-Pin; Chuang, Eric Y.

    2016-01-01

    Radiotherapy has become a popular and standard approach for treating cancer patients because it greatly improves patient survival. However, some of the patients receiving radiotherapy suffer from adverse effects and do not obtain survival benefits. This may be attributed to the fact that most radiation treatment plans are designed based on cancer type, without consideration of each individual's radiosensitivity. A model for predicting radiosensitivity would help to address this issue. In this study, the expression levels of both genes and long non-coding RNAs (lncRNAs) were used to build such a prediction model. Analysis of variance and Tukey's honest significant difference tests (P < 0.001) were utilized in immortalized B cells (GSE26835) to identify differentially expressed genes and lncRNAs after irradiation. A total of 41 genes and lncRNAs associated with radiation exposure were revealed by a network analysis algorithm. To develop a predictive model for radiosensitivity, the expression profiles of NCI-60 cell lines along, with their radiation parameters, were analyzed. A genetic algorithm was proposed to identify 20 predictors, and the support vector machine algorithm was used to evaluate their prediction performance. The model was applied to 2 datasets of glioblastoma, The Cancer Genome Atlas and GSE16011, and significantly better survival was observed in patients with greater predicted radiosensitivity. PMID:27050376

  15. 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.

  16. Long non-coding RNAs in cancer and development: where do we go from here?

    PubMed

    Haemmerle, Monika; Gutschner, Tony

    2015-01-08

    Recent genome-wide expression profiling studies have uncovered a huge amount of novel, long non-protein-coding RNA transcripts (lncRNA). In general, these transcripts possess a low, but tissue-specific expression, and their nucleotide sequences are often poorly conserved. However, several studies showed that lncRNAs can have important roles for normal tissue development and regulate cellular pluripotency as well as differentiation. Moreover, lncRNAs are implicated in the control of multiple molecular pathways leading to gene expression changes and thus, ultimately modulate cell proliferation, migration and apoptosis. Consequently, deregulation of lncRNA expression contributes to carcinogenesis and is associated with human diseases, e.g., neurodegenerative disorders like Alzheimer's Disease. Here, we will focus on some major challenges of lncRNA research, especially loss-of-function studies. We will delineate strategies for lncRNA gene targeting in vivo, and we will briefly discuss important consideration and pitfalls when investigating lncRNA functions in knockout animal models. Finally, we will highlight future opportunities for lncRNAs research by applying the concept of cross-species comparison, which might contribute to novel disease biomarker discovery and might identify lncRNAs as potential therapeutic targets.

  17. 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.

  18. Global Intersection of Long Non-Coding RNAs with Processed and Unprocessed Pseudogenes in the Human Genome

    PubMed Central

    Milligan, Michael J.; Harvey, Erin; Yu, Albert; Morgan, Ashleigh L.; Smith, Daniela L.; Zhang, Eden; Berengut, Jonathan; Sivananthan, Jothini; Subramaniam, Radhini; Skoric, Aleksandra; Collins, Scott; Damski, Caio; Morris, Kevin V.; Lipovich, Leonard

    2016-01-01

    Pseudogenes are abundant in the human genome and had long been thought of purely as nonfunctional gene fossils. Recent observations point to a role for pseudogenes in regulating genes transcriptionally and post-transcriptionally in human cells. To computationally interrogate the network space of integrated pseudogene and long non-coding RNA regulation in the human transcriptome, we developed and implemented an algorithm to identify all long non-coding RNA (lncRNA) transcripts that overlap the genomic spans, and specifically the exons, of any human pseudogenes in either sense or antisense orientation. As inputs to our algorithm, we imported three public repositories of pseudogenes: GENCODE v17 (processed and unprocessed, Ensembl 72); Retroposed Pseudogenes V5 (processed only), and Yale Pseudo60 (processed and unprocessed, Ensembl 60); two public lncRNA catalogs: Broad Institute, GENCODE v17; NCBI annotated piRNAs; and NHGRI clinical variants. The data sets were retrieved from the UCSC Genome Database using the UCSC Table Browser. We identified 2277 loci containing exon-to-exon overlaps between pseudogenes, both processed and unprocessed, and long non-coding RNA genes. Of these loci we identified 1167 with Genbank EST and full-length cDNA support providing direct evidence of transcription on one or both strands with exon-to-exon overlaps. The analysis converged on 313 pseudogene-lncRNA exon-to-exon overlaps that were bidirectionally supported by both full-length cDNAs and ESTs. In the process of identifying transcribed pseudogenes, we generated a comprehensive, positionally non-redundant encyclopedia of human pseudogenes, drawing upon multiple, and formerly disparate public pseudogene repositories. Collectively, these observations suggest that pseudogenes are pervasively transcribed on both strands and are common drivers of gene regulation. PMID:27047535

  19. 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.

  20. 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. PMID:26056584

  1. Genome-wide identification of novel long non-coding RNAs in Populus tomentosa tension wood, opposite wood and normal wood xylem by RNA-seq.

    PubMed

    Chen, Jinhui; Quan, Mingyang; Zhang, Deqiang

    2015-01-01

    Increasing evidence shows that long non-coding RNAs (lncRNAs) function as important regulatory factors during plant development, but few reports have examined lncRNAs in trees. Here, we report our genome-scale identification and characterization of lncRNAs differentially expressed in the xylem of tension wood, opposite wood and normal wood in Populus tomentosa, by high-throughput RNA sequencing. We identified 1,377 putative lncRNAs by computational analysis, and expression and structure analyses showed that the lncRNAs had lower expression levels and shorter lengths than protein-coding transcripts in Populus. Of the 776 differently expressed (log2FC ≥1 or ≤-1, FDR ≤0.01) lncRNAs, 389 could potentially target 1,151 genes via trans-regulatory effects. Functional annotation of these target genes demonstrated that they are involved in fundamental processes, and in specific mechanisms such as response to stimuli. We also identified 16 target genes involved in wood formation, including cellulose and lignin biosynthesis, suggesting a potential role for lncRNAs in wood formation. In addition, three lncRNAs harbor precursors of four miRNAs, and 25 were potentially targeted by 44 miRNAs where a negative expression relationship between them was detected by qRT-PCR. Thus, a network of interactions among the lncRNAs, miRNAs and mRNAs was constructed, indicating widespread regulatory interactions between non-coding RNAs and mRNAs. Lastly, qRT-PCR validation confirmed the differential expression of these lncRNAs, and revealed that they have tissue-specific expression in P. tomentosa. This study presents the first global identification of lncRNAs and their potential functions in wood formation, providing a starting point for detailed dissection of the functions of lncRNAs in Populus.

  2. Emerging bioinformatics approaches for analysis of NGS-derived coding and non-coding RNAs in neurodegenerative diseases

    PubMed Central

    Guffanti, Alessandro; Simchovitz, Alon; Soreq, Hermona

    2014-01-01

    Neurodegenerative diseases in general and specifically late-onset Alzheimer’s disease (LOAD) involve a genetically complex and largely obscure ensemble of causative and risk factors accompanied by complex feedback responses. The advent of “high-throughput” transcriptome investigation technologies such as microarray and deep sequencing is increasingly being combined with sophisticated statistical and bioinformatics analysis methods complemented by knowledge-based approaches such as Bayesian Networks or network and graph analyses. Together, such “integrative” studies are beginning to identify co-regulated gene networks linked with biological pathways and potentially modulating disease predisposition, outcome, and progression. Specifically, bioinformatics analyses of integrated microarray and genotyping data in cases and controls reveal changes in gene expression of both protein-coding and small and long regulatory RNAs; highlight relevant quantitative transcriptional differences between LOAD and non-demented control brains and demonstrate reconfiguration of functionally meaningful molecular interaction structures in LOAD. These may be measured as changes in connectivity in “hub nodes” of relevant gene networks (Zhang etal., 2013). We illustrate here the open analytical questions in the transcriptome investigation of neurodegenerative disease studies, proposing “ad hoc” strategies for the evaluation of differential gene expression and hints for a simple analysis of the non-coding RNA (ncRNA) part of such datasets. We then survey the emerging role of long ncRNAs (lncRNAs) in the healthy and diseased brain transcriptome and describe the main current methods for computational modeling of gene networks. We propose accessible modular and pathway-oriented methods and guidelines for bioinformatics investigations of whole transcriptome next generation sequencing datasets. We finally present methods and databases for functional interpretations of lncRNAs and

  3. 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.

  4. Characterization of MicA interactions suggests a potential novel means of gene regulation by small non-coding RNAs.

    PubMed

    Henderson, Charlotte A; Vincent, Helen A; Stone, Carlanne M; Phillips, Jack O; Cary, Peter D; Gowers, Darren M; Callaghan, Anastasia J

    2013-03-01

    MicA is a small non-coding RNA that regulates ompA mRNA translation in Escherichia coli. MicA has an inhibitory function, base pairing to the translation initiation region of target mRNAs through short sequences of complementarity, blocking their ribosome-binding sites. The MicA structure contains two stem loops, which impede its interaction with target mRNAs, and it is thought that the RNA chaperone protein Hfq, known to be involved in MicA regulation of ompA, may structurally remodel MicA to reveal the ompA-binding site for cognate pairing. To further characterize these interactions, we undertook biochemical and biophysical studies using native MicA and a 'stabilized' version, modified to mimic the conformational state of MicA where the ompA-binding site is exposed. Our data corroborate two proposed roles for Hfq: first, to bring both MicA and ompA into close proximity, and second, to restructure MicA to allow exposure of the ompA-binding site for pairing, thereby demonstrating the RNA chaperone function of Hfq. Additionally, at accumulated MicA levels, we identified a Mg(2+)-dependent self-association that occludes the ompA-recognition region. We discuss the potential contribution of an Mg(2+)-mediated conformational switch of MicA for the regulation of MicA function.

  5. 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

  6. Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes

    PubMed Central

    2011-01-01

    Background Myelodysplastic Syndromes (MDSS) are pre-leukemic disorders with increasing incident rates worldwide, but very limited treatment options. Little is known about small regulatory RNAs and how they contribute to pathogenesis, progression and transcriptome changes in MDS. Methods Patients' primary marrow cells were screened for short RNAs (RNA-seq) using next generation sequencing. Exon arrays from the same cells were used to profile gene expression and additional measures on 98 patients obtained. Integrative bioinformatics algorithms were proposed, and pathway and ontology analysis performed. Results In low-grade MDS, observations implied extensive post-transcriptional regulation via microRNAs (miRNA) and the recently discovered Piwi interacting RNAs (piRNA). Large expression differences were found for MDS-associated and novel miRNAs, including 48 sequences matching to miRNA star (miRNA*) motifs. The detected species were predicted to regulate disease stage specific molecular functions and pathways, including apoptosis and response to DNA damage. In high-grade MDS, results suggested extensive post-translation editing via transfer RNAs (tRNAs), providing a potential link for reduced apoptosis, a hallmark for this disease stage. Bioinformatics analysis confirmed important regulatory roles for MDS linked miRNAs and TFs, and strengthened the biological significance of miRNA*. The "RNA polymerase II promoters" were identified as the tightest controlled biological function. We suggest their control by a miRNA dominated feedback loop, which might be linked to the dramatically different miRNA amounts seen between low and high-grade MDS. Discussion The presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis. PMID:21342535

  7. 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. PMID:27392411

  8. 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.

  9. 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

  10. Annotation of long non-coding RNAs expressed in Collaborative Cross founder mice in response to respiratory virus infection reveals a new class of interferon-stimulated transcripts

    PubMed Central

    Josset, Laurence; Tchitchek, Nicolas; Gralinski, Lisa E; Ferris, Martin T; Eisfeld, Amie J; Green, Richard R; Thomas, Matthew J; Tisoncik-Go, Jennifer; Schroth, Gary P; Kawaoka, Yoshihiro; Pardo-Manuel de Villena, Fernando; Baric, Ralph S; Heise, Mark T; Peng, Xinxia; Katze, Michael G

    2014-01-01

    The outcome of respiratory virus infection is determined by a complex interplay of viral and host factors. Some potentially important host factors for the antiviral response, whose functions remain largely unexplored, are long non-coding RNAs (lncRNAs). Here we systematically inferred the regulatory functions of host lncRNAs in response to influenza A virus and severe acute respiratory syndrome coronavirus (SARS-CoV) based on their similarity in expression with genes of known function. We performed total RNA-Seq on viral-infected lungs from eight mouse strains, yielding a large data set of transcriptional responses. Overall 5,329 lncRNAs were differentially expressed after infection. Most of the lncRNAs were co-expressed with coding genes in modules enriched in genes associated with lung homeostasis pathways or immune response processes. Each lncRNA was further individually annotated using a rank-based method, enabling us to associate 5,295 lncRNAs to at least one gene set and to predict their potential cis effects. We validated the lncRNAs predicted to be interferon-stimulated by profiling mouse responses after interferon-α treatment. Altogether, these results provide a broad categorization of potential lncRNA functions and identify subsets of lncRNAs with likely key roles in respiratory virus pathogenesis. These data are fully accessible through the MOuse NOn-Code Lung interactive database (MONOCLdb). PMID:24922324

  11. Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain.

    PubMed

    Scheckel, Claudia; Drapeau, Elodie; Frias, Maria A; Park, Christopher Y; Fak, John; Zucker-Scharff, Ilana; Kou, Yan; Haroutunian, Vahram; Ma'ayan, Avi; Buxbaum, Joseph D; Darnell, Robert B

    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. PMID:26894958

  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. 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

  14. Genome wide discovery of long intergenic non-coding RNAs in Diamondback moth (Plutella xylostella) and their expression in insecticide resistant strains

    PubMed Central

    Etebari, Kayvan; Furlong, Michael J.; Asgari, Sassan

    2015-01-01

    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. PMID:26411386

  15. Two non-coding RNAs, MicroRNA-101 and HOTTIP contribute cartilage integrity by epigenetic and homeotic regulation of integrin-α1.

    PubMed

    Kim, Dongkyun; Song, Jinsoo; Han, Jiyeon; Kim, Yunha; Chun, Churl-Hong; Jin, Eun-Jung

    2013-12-01

    Non-coding RNAs have been less studied in cartilage development and destruction regulated by sophisticated molecular events despite their considerable theranostic potential. In this study, we identified significant down-regulation of mR-101 and up-regulation of lncRNA, HOTTIP in the processes of endochondral ossification and osteoarthritic progression. In wing mesenchymal cells, up-expression of miR-101 by TGF-β3 treatment is targeting DNMT-3B and thereby altered the methylation of integrin-α1 addressed as a positive regulator of endochondral ossification in this study. In like manner, down-regulation of miR-101 also coordinately up-regulated DNMT-3B, down-regulated integrin-α1, and resulted in cartilage destruction. In an OA animal model, introduction of lentiviruses that encoded miR-101 or integrin-α1 successfully reduced cartilage destruction. In like manner, long non-coding RNA (lncRNA), HOTTIP, a known regulator for HoxA genes, was highly up-regulated and concurrent down-regulation of HoxA13 displayed the suppression of integrin-α1 in OA chondrocytes. In conclusion, two non-coding RNAs, miR-101 and HOTTIP regulate cartilage development and destruction by modulating integrin-α1 either epigenetically by DNMT-3B or transcriptionally by HoxA13 and data further suggest that these non-coding RNAs could be a potent predictive biomarker for OA as well as a therapeutic target for preventing cartilage-related diseases.

  16. 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

  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. 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

  19. 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

  20. The Tetraodon nigroviridis reference transcriptome: developmental transition, length retention and microsynteny of long non-coding RNAs in a compact vertebrate genome.

    PubMed

    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

  1. A Genome-Wide Survey of Highly Expressed Non-Coding RNAs and Biological Validation of Selected Candidates in Agrobacterium tumefaciens

    PubMed Central

    Lee, Keunsub; Huang, Xiaoqiu; Yang, Chichun; Lee, Danny; Ho, Vincent; Nobuta, Kan; Fan, Jian-Bing; Wang, Kan

    2013-01-01

    Agrobacterium tumefaciens is a plant pathogen that has the natural ability of delivering and integrating a piece of its own DNA into plant genome. Although bacterial non-coding RNAs (ncRNAs) have been shown to regulate various biological processes including virulence, we have limited knowledge of how Agrobacterium ncRNAs regulate this unique inter-Kingdom gene transfer. Using whole transcriptome sequencing and an ncRNA search algorithm developed for this work, we identified 475 highly expressed candidate ncRNAs from A. tumefaciens C58, including 101 trans-encoded small RNAs (sRNAs), 354 antisense RNAs (asRNAs), 20 5′ untranslated region (UTR) leaders including a RNA thermosensor and 6 riboswitches. Moreover, transcription start site (TSS) mapping analysis revealed that about 51% of the mapped mRNAs have 5′ UTRs longer than 60 nt, suggesting that numerous cis-acting regulatory elements might be encoded in the A. tumefaciens genome. Eighteen asRNAs were found on the complementary strands of virA, virB, virC, virD, and virE operons. Fifteen ncRNAs were induced and 7 were suppressed by the Agrobacterium virulence (vir) gene inducer acetosyringone (AS), a phenolic compound secreted by the plants. Interestingly, fourteen of the AS-induced ncRNAs have putative vir box sequences in the upstream regions. We experimentally validated expression of 36 ncRNAs using Northern blot and Rapid Amplification of cDNA Ends analyses. We show functional relevance of two 5′ UTR elements: a RNA thermonsensor (C1_109596F) that may regulate translation of the major cold shock protein cspA, and a thi-box riboswitch (C1_2541934R) that may transcriptionally regulate a thiamine biosynthesis operon, thiCOGG. Further studies on ncRNAs functions in this bacterium may provide insights and strategies that can be used to better manage pathogenic bacteria for plants and to improve Agrobacterum-mediated plant transformation. PMID:23950988

  2. A genome-wide survey of highly expressed non-coding RNAs and biological validation of selected candidates in Agrobacterium tumefaciens.

    PubMed

    Lee, Keunsub; Huang, Xiaoqiu; Yang, Chichun; Lee, Danny; Ho, Vincent; Nobuta, Kan; Fan, Jian-Bing; Wang, Kan

    2013-01-01

    Agrobacterium tumefaciens is a plant pathogen that has the natural ability of delivering and integrating a piece of its own DNA into plant genome. Although bacterial non-coding RNAs (ncRNAs) have been shown to regulate various biological processes including virulence, we have limited knowledge of how Agrobacterium ncRNAs regulate this unique inter-Kingdom gene transfer. Using whole transcriptome sequencing and an ncRNA search algorithm developed for this work, we identified 475 highly expressed candidate ncRNAs from A. tumefaciens C58, including 101 trans-encoded small RNAs (sRNAs), 354 antisense RNAs (asRNAs), 20 5' untranslated region (UTR) leaders including a RNA thermosensor and 6 riboswitches. Moreover, transcription start site (TSS) mapping analysis revealed that about 51% of the mapped mRNAs have 5' UTRs longer than 60 nt, suggesting that numerous cis-acting regulatory elements might be encoded in the A. tumefaciens genome. Eighteen asRNAs were found on the complementary strands of virA, virB, virC, virD, and virE operons. Fifteen ncRNAs were induced and 7 were suppressed by the Agrobacterium virulence (vir) gene inducer acetosyringone (AS), a phenolic compound secreted by the plants. Interestingly, fourteen of the AS-induced ncRNAs have putative vir box sequences in the upstream regions. We experimentally validated expression of 36 ncRNAs using Northern blot and Rapid Amplification of cDNA Ends analyses. We show functional relevance of two 5' UTR elements: a RNA thermonsensor (C1_109596F) that may regulate translation of the major cold shock protein cspA, and a thi-box riboswitch (C1_2541934R) that may transcriptionally regulate a thiamine biosynthesis operon, thiCOGG. Further studies on ncRNAs functions in this bacterium may provide insights and strategies that can be used to better manage pathogenic bacteria for plants and to improve Agrobacterum-mediated plant transformation. PMID:23950988

  3. 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

  4. Functional determinants of the quorum-sensing non-coding RNAs and their roles in target regulation.

    PubMed

    Shao, Yi; Feng, Lihui; Rutherford, Steven T; Papenfort, Kai; Bassler, Bonnie L

    2013-07-31

    Quorum sensing is a chemical communication process that bacteria use to control collective behaviours including bioluminescence, biofilm formation, and virulence factor production. In Vibrio harveyi, five homologous small RNAs (sRNAs) called Qrr1-5, control quorum-sensing transitions. Here, we identify 16 new targets of the Qrr sRNAs. Mutagenesis reveals that particular sequence differences among the Qrr sRNAs determine their target specificities. Modelling coupled with biochemical and genetic analyses show that all five of the Qrr sRNAs possess four stem-loops: the first stem-loop is crucial for base pairing with a subset of targets. This stem-loop also protects the Qrr sRNAs from RNase E-mediated degradation. The second stem-loop contains conserved sequences required for base pairing with the majority of the target mRNAs. The third stem-loop plays an accessory role in base pairing and stability. The fourth stem-loop functions as a rho-independent terminator. In the quorum-sensing regulon, Qrr sRNAs-controlled genes are the most rapid to respond to quorum-sensing autoinducers. The Qrr sRNAs are conserved throughout vibrios, thus insights from this work could apply generally to Vibrio quorum sensing.

  5. The role of non-coding RNAs in the regulation of stem cells and progenitors in the normal mammary gland and in breast tumors

    PubMed Central

    Tordonato, Chiara; Di Fiore, Pier Paolo; Nicassio, Francesco

    2015-01-01

    The outlook on stem cell (SC) biology is shifting from a rigid hierarchical to a more flexible model in which the identity and the behavior of adult SCs, far from being fixed, are determined by the dynamic integration of cell autonomous and non-autonomous mechanisms. Within this framework, the recent discovery of thousands of non-coding RNAs (ncRNAs) with regulatory function is redefining the landscape of transcriptome regulation, highlighting the interplay of epigenetic, transcriptional, and post-transcriptional mechanisms in the specification of cell fate and in the regulation of developmental processes. Furthermore, the expression of ncRNAs is often tissue- or even cell type-specific, emphasizing their involvement in defining space, time and developmental stages in gene regulation. Such a role of ncRNAs has been investigated in embryonic and induced pluripotent SCs, and in numerous types of adult SCs and progenitors, including those of the breast, which will be the topic of this review. We will focus on ncRNAs with an important role in breast cancer, in particular in mammary cancer SCs and progenitors, and highlight the ncRNA-based circuitries whose subversion alters a number of the epigenetic, transcriptional, and post-transcriptional events that control “stemness” in the physiological setting. PMID:25774169

  6. Experimental Identification of Small Non-Coding RNAs in the Model Marine Bacterium Ruegeria pomeroyi DSS-3

    PubMed Central

    Rivers, Adam R.; Burns, Andrew S.; Chan, Leong-Keat; Moran, Mary Ann

    2016-01-01

    In oligotrophic ocean waters where bacteria are often subjected to chronic nutrient limitation, community transcriptome sequencing has pointed to the presence of highly abundant small RNAs (sRNAs). The role of sRNAs in regulating response to nutrient stress was investigated in a model heterotrophic marine bacterium Ruegeria pomeroyi grown in continuous culture under carbon (C) and nitrogen (N) limitation. RNAseq analysis identified 99 putative sRNAs. Sixty-nine were cis-encoded and located antisense to a presumed target gene. Thirty were trans-encoded and initial target prediction was performed computationally. The most prevalent functional roles of genes anti-sense to the cis-sRNAs were transport, cell-cell interactions, signal transduction, and transcriptional regulation. Most sRNAs were transcribed equally under both C and N limitation, and may be involved in a general stress response. However, 14 were regulated differentially between the C and N treatments and may respond to specific nutrient limitations. A network analysis of the predicted target genes of the R. pomeroyi cis-sRNAs indicated that they average fewer connections than typical protein-encoding genes, and appear to be more important in peripheral or niche-defining functions encoded in the pan genome. PMID:27065955

  7. 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

  8. Experimental Identification of Small Non-Coding RNAs in the Model Marine Bacterium Ruegeria pomeroyi DSS-3.

    PubMed

    Rivers, Adam R; Burns, Andrew S; Chan, Leong-Keat; Moran, Mary Ann

    2016-01-01

    In oligotrophic ocean waters where bacteria are often subjected to chronic nutrient limitation, community transcriptome sequencing has pointed to the presence of highly abundant small RNAs (sRNAs). The role of sRNAs in regulating response to nutrient stress was investigated in a model heterotrophic marine bacterium Ruegeria pomeroyi grown in continuous culture under carbon (C) and nitrogen (N) limitation. RNAseq analysis identified 99 putative sRNAs. Sixty-nine were cis-encoded and located antisense to a presumed target gene. Thirty were trans-encoded and initial target prediction was performed computationally. The most prevalent functional roles of genes anti-sense to the cis-sRNAs were transport, cell-cell interactions, signal transduction, and transcriptional regulation. Most sRNAs were transcribed equally under both C and N limitation, and may be involved in a general stress response. However, 14 were regulated differentially between the C and N treatments and may respond to specific nutrient limitations. A network analysis of the predicted target genes of the R. pomeroyi cis-sRNAs indicated that they average fewer connections than typical protein-encoding genes, and appear to be more important in peripheral or niche-defining functions encoded in the pan genome. PMID:27065955

  9. 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

  10. RNA-seq analysis identifies key long non-coding RNAs connected to the pathogenesis of alcohol-associated head and neck squamous cell carcinoma

    PubMed Central

    Yu, Vicky; Singh, Pranav; Rahimy, Elham; Zheng, Hao; Kuo, Selena Z.; Kim, Elizabeth; Wang-Rodriguez, Jessica; Ongkeko, Weg M.

    2016-01-01

    Alcohol consumption has been implicated in the pathogenesis of head and neck squamous cell carcinoma (HNSCC), although its mechanism is poorly understood. Recent advances in the identification and understanding of long non-coding RNAs (lncRNAs) have indicated that these molecules have a profound effect on numerous biological processes, including tumorigenesis and oncogenesis. The present authors hypothesize that alcohol-mediated dysregulation of lncRNAs is a key event in HNSCC pathogenesis. An in silico differential expression analysis utilizing RNA sequencing (RNA-seq) data from 34 HNSCC patients, which included alcohol drinkers and non-alcohol drinkers, identified a panel of lncRNAs that were dysregulated due to alcohol consumption. Normal oral keratinocytes were then exposed to ethanol and acetaldehyde to validate the RNA-seq results. Two lncRNAs that were differentially expressed due to alcohol consumption were identified from RNA-seq analysis of the clinical data: lnc-PSD4-1 and lnc-NETO-1. Oral keratinocytes exposed to alcohol and acetaldehyde demonstrated dysregulation of these two lncRNAs, thus validating the results of RNA-seq analysis. In addition, low expression of the lnc-PSD4-1 isoform, lnc-PSD4-1:14, exhibited a strong correlation with high survival rates in a Cox proportional hazards regression model. Therefore, these lncRNAs may play a key role in the early pathogenesis of HNSCC, since they are dysregulated in both clinical data and in vitro experiments mimicking the effects of alcohol use. PMID:27698869

  11. RNA-seq analysis identifies key long non-coding RNAs connected to the pathogenesis of alcohol-associated head and neck squamous cell carcinoma

    PubMed Central

    Yu, Vicky; Singh, Pranav; Rahimy, Elham; Zheng, Hao; Kuo, Selena Z.; Kim, Elizabeth; Wang-Rodriguez, Jessica; Ongkeko, Weg M.

    2016-01-01

    Alcohol consumption has been implicated in the pathogenesis of head and neck squamous cell carcinoma (HNSCC), although its mechanism is poorly understood. Recent advances in the identification and understanding of long non-coding RNAs (lncRNAs) have indicated that these molecules have a profound effect on numerous biological processes, including tumorigenesis and oncogenesis. The present authors hypothesize that alcohol-mediated dysregulation of lncRNAs is a key event in HNSCC pathogenesis. An in silico differential expression analysis utilizing RNA sequencing (RNA-seq) data from 34 HNSCC patients, which included alcohol drinkers and non-alcohol drinkers, identified a panel of lncRNAs that were dysregulated due to alcohol consumption. Normal oral keratinocytes were then exposed to ethanol and acetaldehyde to validate the RNA-seq results. Two lncRNAs that were differentially expressed due to alcohol consumption were identified from RNA-seq analysis of the clinical data: lnc-PSD4-1 and lnc-NETO-1. Oral keratinocytes exposed to alcohol and acetaldehyde demonstrated dysregulation of these two lncRNAs, thus validating the results of RNA-seq analysis. In addition, low expression of the lnc-PSD4-1 isoform, lnc-PSD4-1:14, exhibited a strong correlation with high survival rates in a Cox proportional hazards regression model. Therefore, these lncRNAs may play a key role in the early pathogenesis of HNSCC, since they are dysregulated in both clinical data and in vitro experiments mimicking the effects of alcohol use.

  12. 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

  13. 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

  14. 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.

  15. Impact of high fat diet on long non-coding RNAs and messenger RNAs expression in the aortas of ApoE(−/−) mice

    PubMed Central

    Bao, Mei-hua; Luo, Huai-qing; Chen, Li-hua; Tang, Liang; Ma, Kui-fen; Xiang, Ju; Dong, Li-ping; Zeng, Jie; Li, Guang-yi; Li, Jian-ming

    2016-01-01

    Atherosclerosis is a chronic multifactorial inflammatory disease with high prevalence worldwide, and has become the leading cause of death. The present study was designed to investigate the impact of high-fat diet on ApoE(−/−) mice exhibiting atherosclerosis by detecting the genome-wide expression profile of lncRNAs and mRNAs. A total of 354 differentially expressed lncRNAs were identified (≥2.0 folds). Simultaneously, 357 differentially expressed mRNAs from the same chip were found. The expression differences of lncRNAs and mRNAs were consistent in both qPCR and microarray detection. Annotation results of the mRNAs which correlated with lncRNAs showed that the commonly related pathways were metabolism and inflammation. Hypergeometric distribution analysis indicated that the differentially expressed lncRNAs had been mostly regulated by transcription factors (TFs) such as Myod1, Rxra, Pparg, Tcf3, etc. Additional lncRNA-target-TFs network analysis was conducted for the top 20 differentially expressed lncRNAs. The results indicated Hnf4a, Ppara, Vdr, and Runx3 as the TFs most likely to regulate the production of these lncRNAs, and might play roles in inflammatory and metabolic processes in atherosclerosis. In a nutshell, the present study identified a panel of dysregulated lncRNAs and mRNAs that may be potential biomarkers or drug targets relevant to the high-fat diet related atherogenesis. PMID:27698357

  16. Tissue-specific Co-expression of Long Non-coding and Coding RNAs Associated with Breast Cancer.

    PubMed

    Wu, Wenting; Wagner, Erin K; Hao, Yangyang; Rao, Xi; Dai, Hongji; Han, Jiali; Chen, Jinhui; Storniolo, Anna Maria V; Liu, Yunlong; He, Chunyan

    2016-01-01

    Inference of the biological roles of lncRNAs in breast cancer development remains a challenge. Here, we analyzed RNA-seq data in tumor and normal breast tissue samples from 18 breast cancer patients and 18 healthy controls and constructed a functional lncRNA-mRNA co-expression network. We revealed two distinctive co-expression patterns associated with breast cancer, reflecting different underlying regulatory mechanisms: (1) 516 pairs of lncRNA-mRNAs have differential co-expression pattern, in which the correlation between lncRNA and mRNA expression differs in tumor and normal breast tissue; (2) 291 pairs have dose-response co-expression pattern, in which the correlation is similar, but the expression level of lncRNA or mRNA differs in the two tissue types. We further validated our findings in TCGA dataset and annotated lncRNAs using TANRIC. One novel lncRNA, AC145110.1 on 8p12, was found differentially co-expressed with 127 mRNAs (including TOX4 and MAEL) in tumor and normal breast tissue and also highly correlated with breast cancer clinical outcomes. Functional enrichment and pathway analyses identified distinct biological functions for different patterns of co-expression regulations. Our data suggested that lncRNAs might be involved in breast tumorigenesis through the modulation of gene expression in multiple pathologic pathways. PMID:27597120

  17. Tissue-specific Co-expression of Long Non-coding and Coding RNAs Associated with Breast Cancer

    PubMed Central

    Wu, Wenting; Wagner, Erin K.; Hao, Yangyang; Rao, Xi; Dai, Hongji; Han, Jiali; Chen, Jinhui; Storniolo, Anna Maria V.; Liu, Yunlong; He, Chunyan

    2016-01-01

    Inference of the biological roles of lncRNAs in breast cancer development remains a challenge. Here, we analyzed RNA-seq data in tumor and normal breast tissue samples from 18 breast cancer patients and 18 healthy controls and constructed a functional lncRNA-mRNA co-expression network. We revealed two distinctive co-expression patterns associated with breast cancer, reflecting different underlying regulatory mechanisms: (1) 516 pairs of lncRNA-mRNAs have differential co-expression pattern, in which the correlation between lncRNA and mRNA expression differs in tumor and normal breast tissue; (2) 291 pairs have dose-response co-expression pattern, in which the correlation is similar, but the expression level of lncRNA or mRNA differs in the two tissue types. We further validated our findings in TCGA dataset and annotated lncRNAs using TANRIC. One novel lncRNA, AC145110.1 on 8p12, was found differentially co-expressed with 127 mRNAs (including TOX4 and MAEL) in tumor and normal breast tissue and also highly correlated with breast cancer clinical outcomes. Functional enrichment and pathway analyses identified distinct biological functions for different patterns of co-expression regulations. Our data suggested that lncRNAs might be involved in breast tumorigenesis through the modulation of gene expression in multiple pathologic pathways. PMID:27597120

  18. 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

  19. 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

  20. 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

  1. Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Non-Coding RNAs

    PubMed Central

    Rinn, John L.; Kertesz, Michael; Wang, Jordon K.; Squazzo, Sharon L.; Xu, Xiao; Brugmann, Samantha A.; Goodnough, Henry; Helms, Jill A.; Farnham, Peggy J.; Segal, Eran; Chang, Howard Y.

    2007-01-01

    SUMMARY Noncoding RNAs (ncRNA) participate in epigenetic regulation but are poorly understood. Here we characterize the transcriptional landscape of the four human HOX loci at five base pair resolution in eleven anatomic sites, and identify 231 HOX ncRNAs that extend known transcribed regions by more than 30 kilobases. HOX ncRNAs are spatially expressed along developmental axes, possess unique sequence motifs, and their expression demarcate broad chromosomal domains of differential histone methylation and RNA polymerase accessibility. We identified a 2.2 kilobase ncRNA residing in the HOXC locus, termed HOTAIR, which represses transcription in trans across 40 kilobases of the HOXD locus. HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and is required for PRC2 occupancy and histone H3 lysine-27 trimethylation of HOXD locus. Thus, transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance; these results have broad implications for gene regulation in development and disease states. PMID:17604720

  2. 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

  3. Association between microRNAs and coronary collateral circulation: is there a new role for the small non-coding RNAs?

    PubMed

    Papageorgiou, Nikolaos; Zacharia, Effimia; Tousoulis, Dimitris

    2016-06-01

    We read with interest the article entitled "Circulating microRNAs characterizing patients with insufficient coronary collateral artery function" which was recently published in the PLOS ONE journal. It was demonstrated for the first time that specific circulating microRNAs (miRNAs) can distinguish patients with sufficient from those with insufficient coronary collateral circulation. Circulating miRNAs in the plasma of patients with stable CAD and chronic CTO could provide information with regard to the coronary collateral artery capacity. However, several aspects need to be taken into consideration before the use of miRNAs in the clinical practice. A risk model that would incorporate risk factors for cardiovascular disease and miRNAs could prove to be very useful. Although an association between the levels of miRNAs and the collateral artery capacity appears promising, it still does not confirm any causal role for miRNAs. Therefore, large clinical studies in populations with CTO are warranted to evaluate this finding. PMID:27384614

  4. 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

  5. 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

  6. Cerebrospinal Fluid Extracellular Vesicles Undergo Age Dependent Declines and Contain Known and Novel Non-coding RNAs

    PubMed Central

    Tietje, Ashlee; Maron, Kourtney N.; Wei, Yanzhang; Feliciano, David M.

    2014-01-01

    Brain development requires precise orchestration of cellular events through the coordinate exchange of information between distally located cells. One mechanism by which intercellular communication is achieved is through the transfer of extracellular vesicles (EVs). Exosomes are EVs that carry lipids, nucleic acids, and proteins and are detectable in most biological fluids including cerebrospinal fluid (CSF). Here we report that CSF EV concentrations undergo age dependent fluctuations. We characterized EV RNA content by next generation small RNA sequencing and miRNA microarray analysis and identified a temporal shift in CSF EV content. CSF EVs encapsulated miRNAs that contain a conserved hnRNPA2/B1 recognition sequence. We found that hnRNPA2/B1-containing EVs were produced by choroid plexus epithelial cells and that hnRNPA2/B1 containing EVs decreased with age. These results provide insight into EV exchange of miRNAs within the central nervous system and a framework to understand how changes in EVs may have an important impact on brain development. PMID:25420022

  7. 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.

  8. 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

  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. Do circulating long non-coding RNAs (lncRNAs) (LincRNA-p21, GAS 5, HOTAIR) predict the treatment response in patients with head and neck cancer treated with chemoradiotherapy?

    PubMed

    Fayda, Merdan; Isin, Mustafa; Tambas, Makbule; Guveli, Murat; Meral, Rasim; Altun, Musa; Sahin, Dilek; Ozkan, Gozde; Sanli, Yasemin; Isin, Husniye; Ozgur, Emre; Gezer, Ugur

    2016-03-01

    Long non-coding RNAs (lncRNAs) have been shown to be aberrantly expressed in head and neck cancer (HNC). The aim of the present study was to evaluate plasma levels of three lncRNA molecules (lincRNA-p21, GAS5, and HOTAIR) in the treatment response in HNC patients treated with radical chemoradiotherapy (CRT). Forty-one patients with HNC were enrolled in the study. Most of the patients had nasopharyngeal carcinoma (n = 27, 65.9 %) and locally advanced disease. Blood was drawn at baseline and treatment evaluation 4.5 months after therapy. lncRNAs in plasma were measured by semiquantitative PCR. Treatment response was evaluated according to clinical examination, RECIST and PERCIST criteria based on magnetic resonance imaging (MRI), and positron emission tomography with computed tomography (PET/CT) findings. Complete response (CR) rates were 73.2, 36.6, and 50 % for clinical investigation, PET/CT-, or MRI-based response evaluation, respectively. Predictive value of lncRNAs was investigated in patients with CR vs. those with partial response (PR)/progressive disease (PD). We found that post-treatment GAS5 levels in patients with PR/PD were significantly higher compared with patients with CR based on clinical investigation (p = 0.01). Receiver operator characteristic (ROC) analysis showed that at a cutoff value of 0.3 of GAS5, sensitivity and specificity for clinical tumor response were 82 and 77 %, respectively. Interestingly, pretreatment GAS5 levels were significantly increased in patients with PR/PD compared to those with CR upon MRI-based response evaluation (p = 0.042). In contrast to GAS5, pretreatment or post-treatment lincRNA-p21 and HOTAIR levels were not informative for treatment response. Our results suggest that circulating GAS5 could be a biomarker in predicting treatment response in HNC patients.

  11. Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay (EMSA) and DNA-affinity Precipitation Assay (DAPA).

    PubMed

    Miller, Daniel E; Patel, Zubin H; Lu, Xiaoming; Lynch, Arthur T; Weirauch, Matthew T; Kottyan, Leah C

    2016-01-01

    Population and family-based genetic studies typically result in the identification of genetic variants that are statistically associated with a clinical disease or phenotype. For many diseases and traits, most variants are non-coding, and are thus likely to act by impacting subtle, comparatively hard to predict mechanisms controlling gene expression. Here, we describe a general strategic approach to prioritize non-coding variants, and screen them for their function. This approach involves computational prioritization using functional genomic databases followed by experimental analysis of differential binding of transcription factors (TFs) to risk and non-risk alleles. For both electrophoretic mobility shift assay (EMSA) and DNA affinity precipitation assay (DAPA) analysis of genetic variants, a synthetic DNA oligonucleotide (oligo) is used to identify factors in the nuclear lysate of disease or phenotype-relevant cells. For EMSA, the oligonucleotides with or without bound nuclear factors (often TFs) are analyzed by non-denaturing electrophoresis on a tris-borate-EDTA (TBE) polyacrylamide gel. For DAPA, the oligonucleotides are bound to a magnetic column and the nuclear factors that specifically bind the DNA sequence are eluted and analyzed through mass spectrometry or with a reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by Western blot analysis. This general approach can be widely used to study the function of non-coding genetic variants associated with any disease, trait, or phenotype. PMID:27585267

  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. PMID:27611072

  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. POTENTIAL ROLE OF HUMAN-SPECIFIC GENES, HUMAN-SPECIFIC MICRORNAS AND HUMAN-SPECIFIC NON-CODING REGULATORY RNAS IN THE PATHOGENESIS OF SYSTEMIC SCLEROSIS AND SJÖGREN'S SYNDROME

    PubMed Central

    Jimenez, Sergio A.; Piera-Velazquez, Sonsoles

    2013-01-01

    The etiology and pathogenesis of human autoimmune diseases remain unknown despite intensive investigations. Although remarkable progress has been accomplished through genome wide association studies in the identification of genetic factors that may predispose to their occurrence or modify their clinical presentation to date no specific gene abnormalities have been conclusively demonstrated to be responsible for these diseases. The completion of the human and chimpanzee genome sequencing has opened up novel opportunities to examine the possible contribution of human specific genes and other regulatory elements unique to the human genome, such as microRNAs and non-coding RNAs, towards the pathogenesis of a variety of human disorders. Thus, it is likely that these human specific genes and non-coding regulatory elements may be involved in the development or the pathogenesis of various disorders that do not occur in non-human primates including certain autoimmune diseases such as Systemic Sclerosis and Primary Sjögren's Syndrome. Here, we discuss recent evidence supporting the notion that human specific genes or human specific microRNA and other non-coding RNA regulatory elements unique to the human genome may participate in the development or in the pathogenesis of Systemic Sclerosis and Primary Sjögren's Syndrome. PMID:23684698

  15. Genome-wide analysis of tomato long non-coding RNAs and identification as endogenous target mimic for microRNA in response to TYLCV infection

    PubMed Central

    Wang, Jinyan; Yu, Wengui; Yang, Yuwen; Li, Xiao; Chen, Tianzi; Liu, Tingli; Ma, Na; Yang, Xu; Liu, Renyi; Zhang, Baolong

    2015-01-01

    Recently, a large number of long noncoding RNAs (lncRNAs) have emerged as important regulators of many biological processes in animals and plants. However, how lncRNAs function during plant DNA virus infection is largely unknown. We performed strand-specific paired-end RNA sequencing of tomato samples infected with Tomato yellow leaf curl virus (TYLCV) with three biological replicates. Overall, we predicted 1565 lncRNAs including long intergenic ncRNAs (lincRNAs) and natural antisense transcripts (lncNATs) and definitively identified lnRNAs that are involved in TYLCV infection by virus-induced gene silencing (VIGS). We also verified the functions of a set of lncRNAs that were differentially expressed between 0 and 7 days post inoculation (dpi). More importantly, we found that several lncRNAs acted as competing endogenous target mimics (eTMs) for tomato microRNAs involved in the TYLCV infection. These results provide new insight into lncRNAs involved in the response to TYLCV infection that are important components of the TYLCV network in tomatoes. PMID:26679690

  16. Genome-wide analysis of tomato long non-coding RNAs and identification as endogenous target mimic for microRNA in response to TYLCV infection.

    PubMed

    Wang, Jinyan; Yu, Wengui; Yang, Yuwen; Li, Xiao; Chen, Tianzi; Liu, Tingli; Ma, Na; Yang, Xu; Liu, Renyi; Zhang, Baolong

    2015-01-01

    Recently, a large number of long noncoding RNAs (lncRNAs) have emerged as important regulators of many biological processes in animals and plants. However, how lncRNAs function during plant DNA virus infection is largely unknown. We performed strand-specific paired-end RNA sequencing of tomato samples infected with Tomato yellow leaf curl virus (TYLCV) with three biological replicates. Overall, we predicted 1565 lncRNAs including long intergenic ncRNAs (lincRNAs) and natural antisense transcripts (lncNATs) and definitively identified lnRNAs that are involved in TYLCV infection by virus-induced gene silencing (VIGS). We also verified the functions of a set of lncRNAs that were differentially expressed between 0 and 7 days post inoculation (dpi). More importantly, we found that several lncRNAs acted as competing endogenous target mimics (eTMs) for tomato microRNAs involved in the TYLCV infection. These results provide new insight into lncRNAs involved in the response to TYLCV infection that are important components of the TYLCV network in tomatoes. PMID:26679690

  17. Non-coding RNA repertoires in malignant pleural mesothelioma.

    PubMed

    Quinn, Leah; Finn, Stephen P; Cuffe, Sinead; Gray, Steven G

    2015-12-01

    Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. There are limited treatment options, with no second line standard of care for those who fail first line chemotherapy. Recent advances have been made to characterise the underlying molecular mechanisms of mesothelioma, in the hope of providing new targets for therapy. With the discovery that non-coding regions of our DNA are more than mere junk, the field of research into non-coding RNAs (ncRNAs) has exploded in recent years. Non-coding RNAs have diverse and important roles in a variety of cellular processes, but are also implicated in malignancy. In the following review, we discuss two types of non-coding RNAs, long non-coding RNAs and microRNAs, in terms of their role in the pathogenesis of MPM and their potential as both biomarkers and as therapeutic targets in this disease. PMID:26791801

  18. Non-coding RNA repertoires in malignant pleural mesothelioma.

    PubMed

    Quinn, Leah; Finn, Stephen P; Cuffe, Sinead; Gray, Steven G

    2015-12-01

    Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. There are limited treatment options, with no second line standard of care for those who fail first line chemotherapy. Recent advances have been made to characterise the underlying molecular mechanisms of mesothelioma, in the hope of providing new targets for therapy. With the discovery that non-coding regions of our DNA are more than mere junk, the field of research into non-coding RNAs (ncRNAs) has exploded in recent years. Non-coding RNAs have diverse and important roles in a variety of cellular processes, but are also implicated in malignancy. In the following review, we discuss two types of non-coding RNAs, long non-coding RNAs and microRNAs, in terms of their role in the pathogenesis of MPM and their potential as both biomarkers and as therapeutic targets in this disease.

  19. 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.

  20. Circulating Non-coding RNA as Biomarkers in Colorectal Cancer.

    PubMed

    Ferracin, Manuela; Lupini, Laura; Mangolini, Alessandra; Negrini, Massimo

    2016-01-01

    Recent studies suggested that colorectal cancer influences the types and quantity of nucleic acids - especially microRNAs - detected in the bloodstream. Concentration of circulating (cell-free) microRNAs, and possibly of other non-coding RNAs, could therefore serve as valuable colorectal cancer biomarker and could deliver insight into the disease process. This chapter addresses the recent discoveries on circulating microRNA and long non-coding RNA as diagnostic or prognostic biomarkers in colorectal cancer. PMID:27573900

  1. 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

  2. Non coding RNA in muscle differentiation and disease.

    PubMed

    Morlando, Mariangela; Rosa, Alessandro; Caffarelli, Elisa; Fatica, Alessandro; Bozzoni, Irene

    2013-01-01

    Non coding RNAs have provided in the last decades a very exciting research field with the discovery that a largely unexplored fraction of our genome encodes for RNA without protein coding activity. Here we revise the current knowledge of how non coding RNAs impact on muscle differentiation and homeostasis in normal and disease conditions and how they can provide powerful tools for therapeutic interventions and disease diagnosis. Moreover, we discuss new insights into additional mechanisms of post-transcriptional regulation involving a new class of long non coding RNAs shown to impact on the distribution of microRNA molecules on their mRNA targets.

  3. Expressional alterations in functional ultra-conserved non-coding rnas in response to all-trans retinoic acid - induced differentiation in neuroblastoma cells

    PubMed Central

    2013-01-01

    strongly indicate that the function of non-coding RNA T-UC.300A is connected with proliferation, invasion and the inhibition of differentiation of neuroblastoma cell lines prior to ATRA treatment. PMID:23565812

  4. 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.

  5. The Regulatory and Kinase Domains but Not the Interdomain Linker Determine Human Double-stranded RNA-activated Kinase (PKR) Sensitivity to Inhibition by Viral Non-coding RNAs.

    PubMed

    Sunita, S; Schwartz, Samantha L; Conn, Graeme L

    2015-11-20

    Double-stranded RNA (dsRNA)-activated protein kinase (PKR) is an important component of the innate immune system that presents a crucial first line of defense against viral infection. PKR has a modular architecture comprising a regulatory N-terminal dsRNA binding domain and a C-terminal kinase domain interposed by an unstructured ∼80-residue interdomain linker (IDL). Guided by sequence alignment, we created IDL deletions in human PKR (hPKR) and regulatory/kinase domain swap human-rat chimeric PKRs to assess the contributions of each domain and the IDL to regulation of the kinase activity by RNA. Using circular dichroism spectroscopy, limited proteolysis, kinase assays, and isothermal titration calorimetry, we show that each PKR protein is properly folded with similar domain boundaries and that each exhibits comparable polyinosinic-cytidylic (poly(rI:rC)) dsRNA activation profiles and binding affinities for adenoviral virus-associated RNA I (VA RNAI) and HIV-1 trans-activation response (TAR) RNA. From these results we conclude that the IDL of PKR is not required for RNA binding or mediating changes in protein conformation or domain interactions necessary for PKR regulation by RNA. In contrast, inhibition of rat PKR by VA RNAI and TAR RNA was found to be weaker than for hPKR by 7- and >300-fold, respectively, and each human-rat chimeric domain-swapped protein showed intermediate levels of inhibition. These findings indicate that PKR sequence or structural elements in the kinase domain, present in hPKR but absent in rat PKR, are exploited by viral non-coding RNAs to accomplish efficient inhibition of PKR.

  6. Small non-coding RNA deregulation in endometrial carcinogenesis.

    PubMed

    Ravo, Maria; Cordella, Angela; Rinaldi, Antonio; Bruno, Giuseppina; Alexandrova, Elena; Saggese, Pasquale; Nassa, Giovanni; Giurato, Giorgio; Tarallo, Roberta; Marchese, Giovanna; Rizzo, Francesca; Stellato, Claudia; Biancardi, Rossella; Troisi, Jacopo; Di Spiezio Sardo, Attilio; Zullo, Fulvio; Weisz, Alessandro; Guida, Maurizio

    2015-03-10

    Small non-coding RNAs (sncRNAs) represent a heterogeneous group of <200nt-long transcripts comprising microRNAs, PIWI-interacting RNAs (piRNAs) and small-nucleolar-RNAs (snoRNAs) involved in physiological and pathological processes such as carcinogenesis and tumor progression. Aberrant sncRNA expression in cancer has been associated with specific clinical phenotypes, grading, staging, metastases development and resistance to therapy.Aim of the present work is to study the role of sncRNAs in endometrial carcinogenesis. Changes in sncRNA expression were identified by high-throughput genomic analysis of paired normal, hyperplastic and cancerous endometrial tissues obtained by endometrial biopsies (n = 10). Using smallRNA sequencing and microarrays we identified significant differences in sncRNA expression pattern between normal, hyperplastic and neoplastic endometrium. This led to the definition of a sncRNA signature (129 microRNAs, 2 of which not previously described, 10 piRNAs and 3 snoRNAs) of neoplastic transformation. Functional bioinformatics analysis identified as downstream targets multiple signaling pathways potentially involved in the hyperplastic and neoplastic tissue responses, including Wnt/β-catenin, and ERK/MAPK and TGF-β-Signaling.Considering the regulatory role of sncRNAs, this newly identified sncRNA signature is likely to reflect the events leading to endometrial cancer, which can be exploited to dissect the carcinogenic process including novel biomarkers for early and non-invasive diagnosis of these tumors. PMID:25686835

  7. Small non-coding RNA deregulation in endometrial carcinogenesis

    PubMed Central

    Ravo, Maria; Cordella, Angela; Rinaldi, Antonio; Bruno, Giuseppina; Alexandrova, Elena; Saggese, Pasquale; Nassa, Giovanni; Giurato, Giorgio; Tarallo, Roberta; Marchese, Giovanna; Rizzo, Francesca; Stellato, Claudia; Biancardi, Rossella; Troisi, Jacopo; Di Spiezio Sardo, Attilio; Zullo, Fulvio; Weisz, Alessandro; Guida, Maurizio

    2015-01-01

    Small non-coding RNAs (sncRNAs) represent a heterogeneous group of <200nt-long transcripts comprising microRNAs, PIWI-interacting RNAs (piRNAs) and small-nucleolar-RNAs (snoRNAs) involved in physiological and pathological processes such as carcinogenesis and tumor progression. Aberrant sncRNA expression in cancer has been associated with specific clinical phenotypes, grading, staging, metastases development and resistance to therapy. Aim of the present work is to study the role of sncRNAs in endometrial carcinogenesis. Changes in sncRNA expression were identified by high-throughput genomic analysis of paired normal, hyperplastic and cancerous endometrial tissues obtained by endometrial biopsies (n = 10). Using smallRNA sequencing and microarrays we identified significant differences in sncRNA expression pattern between normal, hyperplastic and neoplastic endometrium. This led to the definition of a sncRNA signature (129 microRNAs, 2 of which not previously described, 10 piRNAs and 3 snoRNAs) of neoplastic transformation. Functional bioinformatics analysis identified as downstream targets multiple signaling pathways potentially involved in the hyperplastic and neoplastic tissue responses, including Wnt/β-catenin, and ERK/MAPK and TGF-β-Signaling. Considering the regulatory role of sncRNAs, this newly identified sncRNA signature is likely to reflect the events leading to endometrial cancer, which can be exploited to dissect the carcinogenic process including novel biomarkers for early and non-invasive diagnosis of these tumors. PMID:25686835

  8. Non Coding RNA Molecules as Potential Biomarkers in Breast Cancer.

    PubMed

    De Leeneer, Kim; Claes, Kathleen

    2015-01-01

    The pursuit of minimally invasive biomarkers is a challenging but exciting area of research. Clearly, such markers would need to be sensitive and specific enough to aid in the detection of breast cancer at an early stage, would monitor progression of the disease, and could predict the individual patient's response to treatment. Unfortunately, to date, markers with such characteristics have not made it to the clinic for breast cancer. Past years, many studies indicated that the non-coding part of our genome (the so called 'junk' DNA), may be an ideal source for these biomarkers. In this chapter, the potential use of microRNAs and long non-coding RNAs as biomarkers will be discussed. PMID:26530371

  9. Long noncoding RNAs as auxiliary biomarkers for gastric cancer screening: A pooled analysis of individual studies

    PubMed Central

    Cui, Zhaolei; Chen, Yan; Xiao, Zhenzhou; Hu, Minhua; Lin, Yingying; Chen, Yansong; Zheng, Yuhong

    2016-01-01

    Background Long non-coding RNAs (lncRNAs) are highlighted as novel cancer biomarkers with great promise. Herein, we focused on summarizing the overall diagnostic performance of lncRNAs for gastric cancer (GC). Methods Publications fulfilling the search criteria were selected from the online databases. Study quality was assessed according to the Quality Assessment for Studies of Diagnostic Accuracy (QUADAS) checklist. The summary receiver operator characteristic (SROC) curve was plotted using a bivariate meta-analysis model. Statistical analysis was performed based on the platforms of STATA 12.0 and Meta-Disc 1.4 software. Results Fifteen studies with 1252 patients and 1283 matched controls were included. The pooled sensitivity and specificity for lncRNA expression profile in differentiating GC patients from cancer-free individuals were 0.68 (95%CI: 0.61-0.74) and 0.79 (95%CI: 0.72-0.84), respectively, corresponding to an area under curve (AUC) of 0.80. Moreover, the stratified analyses demonstrated that plasma-based lncRNA profiling harbored higher accuracy than that tissue-based assay (specificity: 0.80 versus 0.75; AUC: 0.84 versus 0.77). Conclusions LncRNA profiling hallmarks a moderate diagnostic value in the management of GC and that lncRNA expression patterns may potentially be utilized as auxiliary biomarkers in confirming GC. PMID:27015554

  10. Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs.

    PubMed

    Peric, D; Chvalova, K; Rousselet, G

    2012-04-19

    Micro-RNAs are deregulated in cancer cells, and some are either tumor suppressive or oncogenic. In addition, a link has been established between decreased expression of micro-RNAs and transformation, and several proteins of the RNA interference pathway have been shown to be haploinsufficient tumor suppressors. Oncogenic micro-RNAs (oncomiRs) could represent new therapeutic targets, and their identification is therefore crucial. However, structural and functional redundancy between micro-RNAs hampers approaches relying on individual micro-RNA inhibition. We reasoned that in cancer cells that depend on oncomiRs, impairing the micro-RNA pathway could lead to growth perturbation rather than increased tumorigenesis. Identifying such cells could allow functional analyses of individual micro-RNAs by complementation of the phenotypes observed upon global micro-RNA inhibition. Therefore, we developed episomal vectors coding for small hairpin RNAs targeting either Drosha or DGCR8, the two components of the microprocessor, the nuclear micro-RNA maturation complex. We identified cancer cell lines in which both vectors induced colony growth arrest. We then screened for individual micro-RNAs complementing this growth arrest, and identified miR-19a, miR-19b, miR-20a and miR-27b as major growth-sustaining micro-RNAs. However, the effect of miR-19a and miR-19b was only transient. In addition, embryonic stem cell-derived micro-RNAs with miR-20a seeds were much less efficient than miR-20a in sustaining cancer cell growth, a finding that contrasted with results obtained in stem cells. Finally, we showed that the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10, a shared target of miR-19 and miR-20, was functionally involved in the growth arrest induced by microprocessor inhibition. We conclude that our approach allowed to identify microprocessor-dependent cancer cells, which could be used to screen for growth-sustaining micro-RNAs. This complementation screen

  11. Classification of non-coding RNA using graph representations ofsecondary structure

    SciTech Connect

    Karklin, Yan; Meraz, Richard F.; Holbrook, Stephen R.

    2004-06-07

    Some genes produce transcripts that function directly in regulatory, catalytic, or structural roles in the cell. These non-coding RNAs are prevalent in all living organisms, and methods that aid the understanding of their functional roles are essential. RNA secondary structure, the pattern of base-pairing, contains the critical information for determining the three dimensional structure and function of the molecule. In this work we examine whether the basic geometric and topological properties of secondary structure are sufficient to distinguish between RNA families in a learning framework. First, we develop a labeled dual graph representation of RNA secondary structure by adding biologically meaningful labels to the dual graphs proposed by Gan et al [1]. Next, we define a similarity measure directly on the labeled dual graphs using the recently developed marginalized kernels [2]. Using this similarity measure, we were able to train Support Vector Machine classifiers to distinguish RNAs of known families from random RNAs with similar statistics. For 22 of the 25 families tested, the classifier achieved better than 70% accuracy, with much higher accuracy rates for some families. Training a set of classifiers to automatically assign family labels to RNAs using a one vs. all multi-class scheme also yielded encouraging results. From these initial learning experiments, we suggest that the labeled dual graph representation, together with kernel machine methods, has potential for use in automated analysis and classification of uncharacterized RNA molecules or efficient genome-wide screens for RNA molecules from existing families.

  12. MicroRNA screening identifies circulating microRNAs as potential biomarkers for osteosarcoma

    PubMed Central

    LI, HUI; ZHANG, KUN; LIU, LI-HONG; OUYANG, YURONG; GUO, HONG-BIN; ZHANG, HANCHONG; BU, JIE; XIAO, TAO

    2015-01-01

    MicroRNAs (miRNAs) are a family of small non-protein coding RNAs, which regulate the expression of a wide variety of genes at the post-transcriptional level to control numerous biological and pathological processes. Various circulating miRNAs have been identified as potential diagnostic and prognostic biomarkers in multiple types of cancer and disease. The aim of the present study was to identify potential miRNA biomarkers for the early diagnosis and relapse prediction of osteosarcoma (OS). miRNA profiling was performed on serum from patients with osteosarcoma and healthy controls. All putative miRNAs were verified by reverse transcription-quantitative polymerase chain reaction analysis of 20 pre-therapeutic OS patients and 20 healthy individuals. The expression of miR-106a-5p, miR16-5p, miR-20a-5p, miR-425-5p, miR451a, miR-25-3p and miR139-5p was demonstrated to be downregulated in the serum of OS patients when compared with that of the healthy controls. Receiver-operating characteristic curve analyses indicated that these 7 miRNAs may be used as diagnostic biomarkers with the ability to discriminate between the healthy cohort and patients with OS. These results provide novel insights into the use of miRNAs in early blood screening for OS. PMID:26622728

  13. [Screening of bone-related microRNAs in serum of patients with osteogenesis imperfect].

    PubMed

    Wang, Ziqiang; Lu, Yanqin; Ren, Xiuzhi; Wang, Yanzhou; Li, Zhiliang; Xu, Chao; Han, Jinxiang

    2012-10-01

    We screened differential expression bone-related microRNAs (miRNAs) in serum of patients with osteogenesis imperfect (OI). First, we selected the reference gene (s) fit for quantitative detection of serum miRNAs by using geNorm and several other programmes. Then real-time fluorescent quntitative PCR was used to detect the expression level of bone-related miRNAs gained by means of miRanda, Targetscan and Pictar softwares caculation and reading literature. Then, the results were analyzed with the matched t test. All 6 candidate reference genes had a stable expression level in serum of healthy controls and patients with different characters, and the optimal number of reference genes is 4 (miR-16, let-7a, snRNAU6, miR-92a) after Pairwise Variations analysis (V4/5 = 0.133 < 0.15). For validating the universality of expression stability, we detected the relative expression value of miR-16, let-7a, snRNAU6 and miR-92a in another 8 healthy controls and 16 patients with OI and the result revealed that the expression of 4 genes remained stable (M < 1.5). After measuring serum levels of more than 100 bone-related miRNAs in patients with real-time qPCR, 11 miRNAs showed differential expression, and bioinformatic analysis suggested these altered expressional mioRNAs had possibilities to participate in the process of OI. So the experiment indicated that there existed many differential expression bone-related miRNAs in serum of patients with OI, and these miRNAs had potentials to be promising biomarkers for serologic tests and diagnosis of OI. PMID:23311139

  14. A Tumor-Specific Prognostic Long Non-Coding RNA Signature in Gastric Cancer

    PubMed Central

    Ren, Wu; Zhang, Jian; Li, Wei; Li, Zongcheng; Hu, Shuofeng; Suo, Jian; Ying, Xiaomin

    2016-01-01

    Background Aberrant expression of long non-coding RNAs (lncRNAs) is associated with prognosis of gastric cancer, some of which could be further evaluated as potential biomarkers. In this study, we attempted to identify a specific lncRNA signature to predict the prognosis of gastric cancer. Material/Methods The genome-wide lncRNA expression in the high-throughput RNA-sequencing data was retrieved from the Cancer Genome Atlas (TCGA). Differential expression of lncRNAs was identified using the Limma package. Survival analysis was conducted by use of univariate and multivariate Cox regression models. Functional enrichment analysis of lncRNAs was based on co-expressed mRNAs. DAVID was used to perform gene ontology and KEGG pathway analysis. Results A total of 452 differentially expressed lncRNAs between gastric cancer and matched normal tissues were screened, of which 76 lncRNAs were identified to be gastric cancer-specific from a pan-cancer analysis of 12 types of human cancer. Among these 76 gastric cancer-specific lncRNAs, 5 lncRNAs (CTD-2616J11.14, RP1-90G24.10, RP11-150O12.3, RP11-1149O23.2, and MLK7-AS1) were significantly associated with the overall survival of patients with gastric cancer. A gastric cancer-specific 5-lncRNA signature was deduced to divide the patients into high- and low-risk groups with significantly different survival times (P<0.0001). Multivariate Cox regression analysis showed that this 5-lncRNA signature was an independent predictor of prognosis. Functional enrichment analysis of the 5 lncRNAs showed that they were mainly involved in DNA replication, mitotic cell cycle, programmed cell death, and RNA splicing. Conclusions Our results suggest that this tumor-specific lncRNA signature may be clinically useful in the prediction of gastric cancer prognosis. PMID:27727196

  15. Screening for characteristic microRNAs between pre-invasive and invasive stages of cervical cancer

    PubMed Central

    ZHU, XIAO-LU; WEN, SHANG-YUN; AI, ZHI-HONG; WANG, JUAN; XU, YAN-LI; TENG, YIN-CHENG

    2015-01-01

    The aim of the present study was to investigate the characteristic microRNAs (miRNAs) expressed during the pre-invasive and invasive stages of cervical cancer. A gene expression profile (GSE7803) containing 21 invasive squamous cell cervical carcinoma samples, 10 normal squamous cervical epithelium samples and seven high-grade squamous intraepithelial cervical lesion samples, was obtained from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified using significance analysis of microarray software, and a Gene Ontology (GO) enrichment analysis was conducted using the Database for Annotation, Visualization and Integrated Discovery. The miRNAs that interacted with the identified DEGs were selected, based on the TarBase v5.0 database. Regulatory networks were constructed from these selected miRNAs along with their corresponding target genes among the DEGs. The regulatory networks were visualized using Cytoscape. A total of 1,160 and 756 DEGs were identified in the pre-invasive and invasive stages of cervical cancer, respectively. The results of the GO enrichment demonstrated that the DEGs were predominantly involved in the immune response and the cell cycle, in the pre-invasive and invasive stages, respectively. Furthermore, a total of 18 and 26 characteristic miRNAs were screened in the pre-invasive and invasive stages, respectively. These miRNAs may be potential biomarkers and targets for the diagnosis and treatment of the different stages of cervical cancer. PMID:25695263

  16. Ageing and the Small, Non-Coding RNA World

    PubMed Central

    Kato, Masaomi; Slack, Frank J.

    2012-01-01

    MicroRNAs, a class of small, non-coding RNAs, are now widely known for their importance in many aspects of biology. These small regulatory RNAs have critical functions in diverse biological events, including development and disease. Recent findings show that microRNAs are essential for lifespan determination in the model organisms, C. elegans and Drosophila, suggesting that microRNAs are also involved in the complex process of ageing. Further, short RNA fragments derived from longer parental RNAs, such as transfer RNA cleavage fragments, have now emerged as a novel class of regulatory RNAs that inhibit translation in response to stress. In addition, the RNA editing pathway is likely to act in the double-stranded RNA-mediated silencing machinery to suppress unfavorable RNA interference activity in the ageing process. These multiple, redundant layers in gene regulatory networks may make it possible to both stably and flexibly regulate genetic pathways in ensuring robustness of developmental and ageing processes. PMID:22504407

  17. Loss-of-function screening to identify miRNAs involved in senescence: tumor suppressor activity of miRNA-335 and its new target CARF

    PubMed Central

    Yu, Yue; Gao, Ran; Kaul, Zeenia; Li, Ling; Kato, Yoshio; Zhang, Zhenya; Groden, Joanna; Kaul, Sunil C; Wadhwa, Renu

    2016-01-01

    Significance of microRNAs (miRs), small non-coding molecules, has been implicated in a variety of biological processes. Here, we recruited retroviral insertional mutagenesis to obtain induction of an arbitrary noncoding RNAs, and coupled it with a cell based loss-of-function (5-Aza-2′-deoxycytidine (5Aza-dC)-induced senescence bypass) screening system. Cells that escaped 5-Aza-dC-induced senescence were subjected to miR-microarray analysis with respect to the untreated control. We identified miR-335 as one of the upregulated miRs. In order to characterize the functional significance, we overexpressed miR-335 in human cancer cells and found that it caused growth suppression. We demonstrate that the latter accounted for inhibition of 5-Aza-dC incorporation into the cell genome, enabling them to escape from induction of senescence. We also report that CARF (Collaborator of ARF) is a new target of miR-335 that regulates its growth suppressor function by complex crosstalk with other proteins including p16INK4A, pRB, HDM2 and p21WAF1. PMID:27457128

  18. In silico screening of alleged miRNAs associated with cell competition: an emerging cellular event in cancer.

    PubMed

    Patel, Manish; Antala, Bhavesh; Shrivastava, Neeta

    2015-12-01

    Cell competition is identified as a crucial phenomenon for cancer and organ development. There is a possibility that microRNAs (miRNAs) may play an important role in the regulation of expression of genes involved in cell competition. In silico screening of miRNAs is an effort to abridge, economize and expedite the experimental approaches to identification of potential miRNAs involved in cell competition, as no study has reported involvement of miRNAs in cell competition to date. In this study, we used multiple screening steps as follows: (i) selection of cell competition related genes of Drosophila through a literature survey; (ii) homology study of selected cell competition related genes; (iii) identification of miRNAs that target conserved cell competition-related genes through prediction tools; (iv) sequence conservation analysis of identified miRNAs with human genome; (v) identification of conserved cell competition miRNAs using their expression profiles and exploration of roles of their homologous human miRNAs. This study led to the identification of nine potential cell competition miRNAs in the Drosophila genome. Importantly, eighteen human homologs of these nine potential Drosophila miRNAs are well reported for their involvement in different types of cancers. This confirms their probable involvement in cell competition as well, because cell competition is well justified for its involvement in cancer initiation and maintenance.

  19. The Non-Coding RNA Ontology (NCRO): a comprehensive resource for the unification of non-coding RNA biology.

    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; He, Yongqun; Zhang, Shaojie; Wang, Xiaowei; Liu, Zixing; Borchert, Glen M; Tan, Ming

    2016-01-01

    In recent years, sequencing technologies have enabled the identification of a wide range of non-coding RNAs (ncRNAs). Unfortunately, annotation and integration of ncRNA data has lagged behind their identification. Given the large quantity of information being obtained in this area, there emerges an urgent need to integrate what is being discovered by a broad range of relevant communities. To this end, the Non-Coding RNA Ontology (NCRO) is being developed to provide a systematically structured and precisely defined controlled vocabulary for the domain of ncRNAs, thereby facilitating the discovery, curation, analysis, exchange, and reasoning of data about structures of ncRNAs, their molecular and cellular functions, and their impacts upon phenotypes. The goal of NCRO is to serve as a common resource for annotations of diverse research in a way that will significantly enhance integrative and comparative analysis of the myriad resources currently housed in disparate sources. It is our belief that the NCRO ontology can perform an important role in the comprehensive unification of ncRNA biology and, indeed, fill a critical gap in both the Open Biological and Biomedical Ontologies (OBO) Library and the National Center for Biomedical Ontology (NCBO) BioPortal. Our initial focus is on the ontological representation of small regulatory ncRNAs, which we see as the first step in providing a resource for the annotation of data about all forms of ncRNAs. The NCRO ontology is free and open to all users, accessible at: http://purl.obolibrary.org/obo/ncro.owl. PMID:27152146

  20. Long non-coding RNA-mediated regulation of glucose homeostasis and diabetes

    PubMed Central

    Sun, Xinghui; Wong, Danny

    2016-01-01

    Long non-coding RNAs (lncRNAs) represent an important class of non-coding RNAs that plays key roles in regulating the expression of genes in health and disease. Accumulating genetic, experimental, and epidemiological studies highlight a growing list of lncRNAs that control glucose homeostasis and diabetic pathologies and complications. Through interactions with chromatin, RNA, and protein, lncRNAs modulate chromatin modification, mRNA stability, microRNA activity, and the function of proteins such as transcription factors. This review highlights emerging concepts in lncRNA-mediated control of glucose homeostasis as well as some of the challenges and therapeutic opportunities in the pathogenesis of diabetes and its complications. PMID:27335687

  1. Profiling Caenorhabditis elegans non-coding RNA expression with a combined microarray.

    PubMed

    He, Housheng; Cai, Lun; Skogerbø, Geir; Deng, Wei; Liu, Tao; Zhu, Xiaopeng; Wang, Yudong; Jia, Dong; Zhang, Zhihua; Tao, Yong; Zeng, Haipan; Aftab, Muhammad Nauman; Cui, Yan; Liu, Guozhen; Chen, Runsheng

    2006-01-01

    Small non-coding RNAs (ncRNAs) are encoded by genes that function at the RNA level, and several hundred ncRNAs have been identified in various organisms. Here we describe an analysis of the small non-coding transcriptome of Caenorhabditis elegans, microRNAs excepted. As a substantial fraction of the ncRNAs is located in introns of protein-coding genes in C.elegans, we also analysed the relationship between ncRNA and host gene expression. To this end, we designed a combined microarray, which included probes against ncRNA as well as host gene mRNA transcripts. The microarray revealed pronounced differences in expression profiles, even among ncRNAs with housekeeping functions (e.g. snRNAs and snoRNAs), indicating distinct developmental regulation and stage-specific functions of a number of novel transcripts. Analysis of ncRNA-host mRNA relations showed that the expression of intronic ncRNA loci with conserved upstream motifs was not correlated to (and much higher than) expression levels of their host genes. Even promoter-less intronic ncRNA loci, though showing a clear correlation to host gene expression, appeared to have a surprising amount of 'expressional freedom', depending on host gene function. Taken together, our microarray analysis presents a more complete and detailed picture of a non-coding transcriptome than hitherto has been presented for any other multicellular organism.

  2. A robust screening method for dietary agents that activate tumour-suppressor microRNAs

    PubMed Central

    Hagiwara, Keitaro; Gailhouste, Luc; Yasukawa, Ken; Kosaka, Nobuyoshi; Ochiya, Takahiro

    2015-01-01

    Certain dietary agents, such as natural products, have been reported to show anti-cancer effects. However, the underlying mechanisms of these substances in human cancer remain unclear. We recently found that resveratrol exerts an anti-cancer effect by upregulating tumour-suppressor microRNAs (miRNAs). In the current study, we aimed to identify new dietary products that have the ability to activate tumour-suppressor miRNAs and that therefore may serve as novel tools for the prevention and treatment of human cancers. We describe the generation and use of an original screening system based on a luciferase-based reporter vector for monitoring miR-200c tumour-suppressor activity. By screening a library containing 139 natural substances, three natural compounds — enoxolone, magnolol and palmatine chloride — were identified as being capable of inducing miR-200c expression in breast cancer cells at 10 μM. Moreover, these molecules suppressed the invasiveness of breast cancer cells in vitro. Next, we identified a molecular pathway by which the increased expression of miR-200c induced by natural substances led to ZEB1 inhibition and E-cadherin induction. These results indicate that our method is a valuable tool for a fast identification of natural molecules that exhibit tumour-suppressor activity in human cancer through miRNA activation. PMID:26423775

  3. MicroRNAs in stool samples as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer.

    PubMed

    Yang, Jian-Yu; Sun, Yong-Wei; Liu, De-Jun; Zhang, Jun-Feng; Li, Jiao; Hua, Rong

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR-155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the

  4. Universal screening test based on analysis of circulating organ-enriched microRNAs: a novel approach to diagnostic screening.

    PubMed

    Sheinerman, Kira S; Umansky, Samuil

    2015-03-01

    Early disease detection leads to more effective and cost-efficient treatment. It is especially important for cancer and neurodegenerative diseases, because progression of these pathologies leads to significant and frequently irreversible changes in underlying pathophysiological processes. At the same time, the development of specific screening tests for detection of each of the hundreds of human pathologies in asymptomatic stage may be impractical. Here, we discuss a recently proposed concept: the development of minimally invasive Universal Screening Test (UST) based on analysis of organ-enriched microRNAs in plasma and other bodily fluids. The UST is designed to detect the presence of a pathology in particular organ systems, organs, tissues or cell types without diagnosing a specific disease. Once the pathology is detected, more specific, and if necessary invasive and expensive, tests can be administered to precisely define the nature of the disease. Here, we discuss recent studies and analyze the data supporting the UST approach.

  5. Impact of Nutrition on Non-Coding RNA Epigenetics in Breast and Gynecological Cancer

    PubMed Central

    Krakowsky, Rosanna H. E.; Tollefsbol, Trygve O.

    2015-01-01

    Cancer is the second leading cause of death in females. According to the American Cancer Society, there are 327,660 new cases in breast and gynecological cancers estimated in 2014, placing emphasis on the need for cancer prevention and new cancer treatment strategies. One important approach to cancer prevention involves phytochemicals, biologically active compounds derived from plants. A variety of studies on the impact of dietary compounds found in cruciferous vegetables, green tea, and spices like curry and black pepper have revealed epigenetic changes in female cancers. Thus, an important emerging topic comprises epigenetic changes due to the modulation of non-coding RNA levels. Since it has been shown that non-coding RNAs such as microRNAs and long non-coding RNAs are aberrantly expressed in cancer, and furthermore are linked to distinct cancer phenotypes, understanding the effects of dietary compounds and supplements on the epigenetic modulator non-coding RNA is of great interest. This article reviews the current findings on nutrition-induced changes in breast and gynecological cancers at the non-coding RNA level. PMID:26075205

  6. Telomerase Reverse Transcriptase Regulates microRNAs

    PubMed Central

    Lassmann, Timo; Maida, Yoshiko; Tomaru, Yasuhiro; Yasukawa, Mami; Ando, Yoshinari; Kojima, Miki; Kasim, Vivi; Simon, Christophe; Daub, Carsten O.; Carninci, Piero; Hayashizaki, Yoshihide; Masutomi, Kenkichi

    2015-01-01

    MicroRNAs are small non-coding RNAs that inhibit the translation of target mRNAs. In humans, most microRNAs are transcribed by RNA polymerase II as long primary transcripts and processed by sequential cleavage of the two RNase III enzymes, DROSHA and DICER, into precursor and mature microRNAs, respectively. Although the fundamental functions of microRNAs in RNA silencing have been gradually uncovered, less is known about the regulatory mechanisms of microRNA expression. Here, we report that telomerase reverse transcriptase (TERT) extensively affects the expression levels of mature microRNAs. Deep sequencing-based screens of short RNA populations revealed that the suppression of TERT resulted in the downregulation of microRNAs expressed in THP-1 cells and HeLa cells. Primary and precursor microRNA levels were also reduced under the suppression of TERT. Similar results were obtained with the suppression of either BRG1 (also called SMARCA4) or nucleostemin, which are proteins interacting with TERT and functioning beyond telomeres. These results suggest that TERT regulates microRNAs at the very early phases in their biogenesis, presumably through non-telomerase mechanism(s). PMID:25569094

  7. The functional role of long non-coding RNA in digestive system carcinomas.

    PubMed

    Wang, Guang-Yu; Zhu, Yuan-Yuan; Zhang, Yan-Qiao

    2014-09-01

    In recent years, long non-coding RNAs (lncRNAs) are emerging as either oncogenes or tumor suppressor genes. Recent evidences suggest that lncRNAs play a very important role in digestive system carcinomas. However, the biological function of lncRNAs in the vast majority of digestive system carcinomas remains unclear. Recently, increasing studies has begun to explore their molecular mechanisms and regulatory networks that they are implicated in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in digestive system carcinomas. It is becoming clear that lncRNAs will be exciting and potentially useful for diagnosis and treatment of digestive system carcinomas, some of these lncRNAs might function as both diagnostic markers and the treatment targets of digestive system carcinomas.

  8. Junk DNA and the long non-coding RNA twist in cancer genetics

    PubMed Central

    Ling, Hui; Vincent, Kimberly; Pichler, Martin; Fodde, Riccardo; Berindan-Neagoe, Ioana; Slack, Frank J.; Calin, George A

    2015-01-01

    The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions, and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function, and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual’s susceptibility to cancer. PMID:25619839

  9. NONCODEv4: exploring the world of long non-coding RNA genes

    PubMed Central

    Xie, Chaoyong; Yuan, Jiao; Li, Hui; Li, Ming; Zhao, Guoguang; Bu, Dechao; Zhu, Weimin; Wu, Wei; Chen, Runsheng; Zhao, Yi

    2014-01-01

    NONCODE (http://www.bioinfo.org/noncode/) is an integrated knowledge database dedicated to non-coding RNAs (excluding tRNAs and rRNAs). Non-coding RNAs (ncRNAs) have been implied in diseases and identified to play important roles in various biological processes. Since NONCODE version 3.0 was released 2 years ago, discovery of novel ncRNAs has been promoted by high-throughput RNA sequencing (RNA-Seq). In this update of NONCODE, we expand the ncRNA data set by collection of newly identified ncRNAs from literature published in the last 2 years and integration of the latest version of RefSeq and Ensembl. Particularly, the number of long non-coding RNA (lncRNA) has increased sharply from 73 327 to 210 831. Owing to similar alternative splicing pattern to mRNAs, the concept of lncRNA genes was put forward to help systematic understanding of lncRNAs. The 56 018 and 46 475 lncRNA genes were generated from 95 135 and 67 628 lncRNAs for human and mouse, respectively. Additionally, we present expression profile of lncRNA genes by graphs based on public RNA-seq data for human and mouse, as well as predict functions of these lncRNA genes. The improvements brought to the database also include an incorporation of an ID conversion tool from RefSeq or Ensembl ID to NONCODE ID and a service of lncRNA identification. NONCODE is also accessible through http://www.noncode.org/. PMID:24285305

  10. A Genome-Wide Screen for Dendritically Localized RNAs Identifies Genes Required for Dendrite Morphogenesis.

    PubMed

    Misra, Mala; Edmund, Hendia; Ennis, Darragh; Schlueter, Marissa A; Marot, Jessica E; Tambasco, Janet; Barlow, Ida; Sigurbjornsdottir, Sara; Mathew, Renjith; Vallés, Ana Maria; Wojciech, Waldemar; Roth, Siegfried; Davis, Ilan; Leptin, Maria; Gavis, Elizabeth R

    2016-01-01

    Localizing messenger RNAs at specific subcellular sites is a conserved mechanism for targeting the synthesis of cytoplasmic proteins to distinct subcellular domains, thereby generating the asymmetric protein distributions necessary for cellular and developmental polarity. However, the full range of transcripts that are asymmetrically distributed in specialized cell types, and the significance of their localization, especially in the nervous system, are not known. We used the EP-MS2 method, which combines EP transposon insertion with the MS2/MCP in vivo fluorescent labeling system, to screen for novel localized transcripts in polarized cells, focusing on the highly branched Drosophila class IV dendritic arborization neurons. Of a total of 541 lines screened, we identified 55 EP-MS2 insertions producing transcripts that were enriched in neuronal processes, particularly in dendrites. The 47 genes identified by these insertions encode molecularly diverse proteins, and are enriched for genes that function in neuronal development and physiology. RNAi-mediated knockdown confirmed roles for many of the candidate genes in dendrite morphogenesis. We propose that the transport of mRNAs encoded by these genes into the dendrites allows their expression to be regulated on a local scale during the dynamic developmental processes of dendrite outgrowth, branching, and/or remodeling. PMID:27260999

  11. An expanding universe of the non-coding genome in cancer biology

    PubMed Central

    Xue, Bin; He, Lin

    2014-01-01

    Neoplastic transformation is caused by accumulation of genetic and epigenetic alterations that ultimately convert normal cells into tumor cells with uncontrolled proliferation and survival, unlimited replicative potential and invasive growth [Hanahan,D. et al. (2011) Hallmarks of cancer: the next generation. Cell, 144, 646–674]. Although the majority of the cancer studies have focused on the functions of protein-coding genes, emerging evidence has started to reveal the importance of the vast non-coding genome, which constitutes more than 98% of the human genome. A number of non-coding RNAs (ncRNAs) derived from the ‘dark matter’ of the human genome exhibit cancer-specific differential expression and/or genomic alterations, and it is increasingly clear that ncRNAs, including small ncRNAs and long ncRNAs (lncRNAs), play an important role in cancer development by regulating protein-coding gene expression through diverse mechanisms. In addition to ncRNAs, nearly half of the mammalian genomes consist of transposable elements, particularly retrotransposons. Once depicted as selfish genomic parasites that propagate at the expense of host fitness, retrotransposon elements could also confer regulatory complexity to the host genomes during development and disease. Reactivation of retrotransposons in cancer, while capable of causing insertional mutagenesis and genome rearrangements to promote oncogenesis, could also alter host gene expression networks to favor tumor development. Taken together, the functional significance of non-coding genome in tumorigenesis has been previously underestimated, and diverse transcripts derived from the non-coding genome could act as integral functional components of the oncogene and tumor suppressor network. PMID:24747961

  12. An expanding universe of the non-coding genome in cancer biology.

    PubMed

    Xue, Bin; He, Lin

    2014-06-01

    Neoplastic transformation is caused by accumulation of genetic and epigenetic alterations that ultimately convert normal cells into tumor cells with uncontrolled proliferation and survival, unlimited replicative potential and invasive growth [Hanahan,D. et al. (2011) Hallmarks of cancer: the next generation. Cell, 144, 646-674]. Although the majority of the cancer studies have focused on the functions of protein-coding genes, emerging evidence has started to reveal the importance of the vast non-coding genome, which constitutes more than 98% of the human genome. A number of non-coding RNAs (ncRNAs) derived from the 'dark matter' of the human genome exhibit cancer-specific differential expression and/or genomic alterations, and it is increasingly clear that ncRNAs, including small ncRNAs and long ncRNAs (lncRNAs), play an important role in cancer development by regulating protein-coding gene expression through diverse mechanisms. In addition to ncRNAs, nearly half of the mammalian genomes consist of transposable elements, particularly retrotransposons. Once depicted as selfish genomic parasites that propagate at the expense of host fitness, retrotransposon elements could also confer regulatory complexity to the host genomes during development and disease. Reactivation of retrotransposons in cancer, while capable of causing insertional mutagenesis and genome rearrangements to promote oncogenesis, could also alter host gene expression networks to favor tumor development. Taken together, the functional significance of non-coding genome in tumorigenesis has been previously underestimated, and diverse transcripts derived from the non-coding genome could act as integral functional components of the oncogene and tumor suppressor network.

  13. Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia.

    PubMed

    Zhang, J; Yuan, L; Zhang, X; Hamblin, M H; Zhu, T; Meng, F; Li, Y; Chen, Y E; Yin, K J

    2016-03-01

    The brain endothelium is an important therapeutic target for the inhibition of cerebrovascular dysfunction in ischemic stroke. Previously, we documented the important regulatory roles of microRNAs in the cerebral vasculature, in particular the cerebral vascular endothelium. However, the functional significance and molecular mechanisms of other classes of non-coding RNAs in the regulation of cerebrovascular endothelial pathophysiology after stroke are completely unknown. Using RNA sequencing (RNA-seq) technology, we profiled long non-coding RNA (lncRNA) expressional signatures in primary brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD), an in vitro mimic of ischemic stroke conditions. After 16h of OGD exposure, the expression levels for 362 of the 10,677 lncRNAs analyzed changed significantly, including a total of 147 lncRNAs increased and 70 lncRNAs decreased by more than 2-fold. Among them, the most highly upregulated lncRNAs include Snhg12, Malat1, and lnc-OGD 1006, whereas the most highly downregulated lncRNAs include 281008D09Rik, Peg13, and lnc-OGD 3916. Alteration of the most highly upregulated/downregulated ODG-responsive lncRNAs was further confirmed in cultured BMECs after OGD as well as isolated cerebral microvessels in mice following transient middle cerebral artery occlusion (MCAO) and 24h reperfusion by the quantitative real-time PCR approach. Moreover, promoter analysis of altered ODG-responsive endothelial lncRNA genes by bioinformatics showed substantial transcription factor binding sites on lncRNAs, implying potential transcriptional regulation of those lncRNAs. These findings are the first to identify OGD-responsive brain endothelial lncRNAs, which suggest potential pathological roles for these lncRNAs in mediating endothelial responses to ischemic stimuli. Endothelial-selective lncRNAs may function as a class of novel master regulators in cerebrovascular endothelial pathologies after ischemic stroke.

  14. Comprehensive Reconstruction and Visualization of Non-Coding Regulatory Networks in Human

    PubMed Central

    Bonnici, Vincenzo; Russo, Francesco; Bombieri, Nicola; Pulvirenti, Alfredo; Giugno, Rosalba

    2014-01-01

    Research attention has been powered to understand the functional roles of non-coding RNAs (ncRNAs). Many studies have demonstrated their deregulation in cancer and other human disorders. ncRNAs are also present in extracellular human body fluids such as serum and plasma, giving them a great potential as non-invasive biomarkers. However, non-coding RNAs have been relatively recently discovered and a comprehensive database including all of them is still missing. Reconstructing and visualizing the network of ncRNAs interactions are important steps to understand their regulatory mechanism in complex systems. This work presents ncRNA-DB, a NoSQL database that integrates ncRNAs data interactions from a large number of well established on-line repositories. The interactions involve RNA, DNA, proteins, and diseases. ncRNA-DB is available at http://ncrnadb.scienze.univr.it/ncrnadb/. It is equipped with three interfaces: web based, command-line, and a Cytoscape app called ncINetView. By accessing only one resource, users can search for ncRNAs and their interactions, build a network annotated with all known ncRNAs and associated diseases, and use all visual and mining features available in Cytoscape. PMID:25540777

  15. Comprehensive reconstruction and visualization of non-coding regulatory networks in human.

    PubMed

    Bonnici, Vincenzo; Russo, Francesco; Bombieri, Nicola; Pulvirenti, Alfredo; Giugno, Rosalba

    2014-01-01

    Research attention has been powered to understand the functional roles of non-coding RNAs (ncRNAs). Many studies have demonstrated their deregulation in cancer and other human disorders. ncRNAs are also present in extracellular human body fluids such as serum and plasma, giving them a great potential as non-invasive biomarkers. However, non-coding RNAs have been relatively recently discovered and a comprehensive database including all of them is still missing. Reconstructing and visualizing the network of ncRNAs interactions are important steps to understand their regulatory mechanism in complex systems. This work presents ncRNA-DB, a NoSQL database that integrates ncRNAs data interactions from a large number of well established on-line repositories. The interactions involve RNA, DNA, proteins, and diseases. ncRNA-DB is available at http://ncrnadb.scienze.univr.it/ncrnadb/. It is equipped with three interfaces: web based, command-line, and a Cytoscape app called ncINetView. By accessing only one resource, users can search for ncRNAs and their interactions, build a network annotated with all known ncRNAs and associated diseases, and use all visual and mining features available in Cytoscape.

  16. Comprehensive reconstruction and visualization of non-coding regulatory networks in human.

    PubMed

    Bonnici, Vincenzo; Russo, Francesco; Bombieri, Nicola; Pulvirenti, Alfredo; Giugno, Rosalba

    2014-01-01

    Research attention has been powered to understand the functional roles of non-coding RNAs (ncRNAs). Many studies have demonstrated their deregulation in cancer and other human disorders. ncRNAs are also present in extracellular human body fluids such as serum and plasma, giving them a great potential as non-invasive biomarkers. However, non-coding RNAs have been relatively recently discovered and a comprehensive database including all of them is still missing. Reconstructing and visualizing the network of ncRNAs interactions are important steps to understand their regulatory mechanism in complex systems. This work presents ncRNA-DB, a NoSQL database that integrates ncRNAs data interactions from a large number of well established on-line repositories. The interactions involve RNA, DNA, proteins, and diseases. ncRNA-DB is available at http://ncrnadb.scienze.univr.it/ncrnadb/. It is equipped with three interfaces: web based, command-line, and a Cytoscape app called ncINetView. By accessing only one resource, users can search for ncRNAs and their interactions, build a network annotated with all known ncRNAs and associated diseases, and use all visual and mining features available in Cytoscape. PMID:25540777

  17. p53-dependent non-coding RNA networks in chronic lymphocytic leukemia.

    PubMed

    Blume, C J; Hotz-Wagenblatt, A; Hüllein, J; Sellner, L; Jethwa, A; Stolz, T; Slabicki, M; Lee, K; Sharathchandra, A; Benner, A; Dietrich, S; Oakes, C C; Dreger, P; te Raa, D; Kater, A P; Jauch, A; Merkel, O; Oren, M; Hielscher, T; Zenz, T

    2015-10-01

    Mutations of the tumor suppressor p53 lead to chemotherapy resistance and a dismal prognosis in chronic lymphocytic leukemia (CLL). Whereas p53 targets are used to identify patient subgroups with impaired p53 function, a comprehensive assessment of non-coding RNA targets of p53 in CLL is missing. We exploited the impaired transcriptional activity of mutant p53 to map out p53 targets in CLL by small RNA sequencing. We describe the landscape of p53-dependent microRNA/non-coding RNA induced in response to DNA damage in CLL. Besides the key p53 target miR-34a, we identify a set of p53-dependent microRNAs (miRNAs; miR-182-5p, miR-7-5p and miR-320c/d). In addition to miRNAs, the long non-coding RNAs (lncRNAs) nuclear enriched abundant transcript 1 (NEAT1) and long intergenic non-coding RNA p21 (lincRNA-p21) are induced in response to DNA damage in the presence of functional p53 but not in CLL with p53 mutation. Induction of NEAT1 and lincRNA-p21 are closely correlated to the induction of cell death after DNA damage. We used isogenic lymphoma cell line models to prove p53 dependence of NEAT1 and lincRNA-p21. The current work describes the p53-dependent miRNome and identifies lncRNAs NEAT1 and lincRNA-p21 as novel elements of the p53-dependent DNA damage response machinery in CLL and lymphoma.

  18. Systematic Genome-wide Screening and Prediction of microRNAs in EBOV During the 2014 Ebolavirus Outbreak.

    PubMed

    Teng, Yue; Wang, Yuzhuo; Zhang, Xianglilan; Liu, Wenli; Fan, Hang; Yao, Hongwu; Lin, Baihan; Zhu, Ping; Yuan, Wenjun; Tong, Yigang; Cao, Wuchun

    2015-05-26

    Recently, several thousand people have been killed by the Ebolavirus disease (EVD) in West Africa, yet no current antiviral medications and treatments are available. Systematic investigation of ebolavirus whole genomes during the 2014 outbreak may shed light on the underlying mechanisms of EVD development. Here, using the genome-wide screening in ebolavirus genome sequences, we predicted four putative viral microRNA precursors (pre-miRNAs) and seven putative mature microRNAs (miRNAs). Combing bioinformatics analysis and prediction of the potential ebolavirus miRNA target genes, we suggest that two ebolavirus coding possible miRNAs may be silence and down-regulate the target genes NFKBIE and RIPK1, which are the central mediator of the pathways related with host cell defense mechanism. Additionally, the ebolavirus exploits the miRNAs to inhibit the NF-kB and TNF factors to evade the host defense mechanisms that limit replication by killing infected cells, or to conversely trigger apoptosis as a mechanism to increase virus spreading. This is the first study to use the genome-wide scanning to predict microRNAs in the 2014 outbreak EVD and then to apply systematic bioinformatics to analyze their target genes. We revealed a potential mechanism of miRNAs in ebolavirus infection and possible therapeutic targets for Ebola viral infection treatment.

  19. An Emerging Role for Long Non-Coding RNA Dysregulation in Neurological Disorders

    PubMed Central

    Fenoglio, Chiara; Ridolfi, Elisa; Galimberti, Daniela; Scarpini, Elio

    2013-01-01

    A novel class of transcripts, long non coding RNAs (lncRNAs), has recently emerged as key players in several biological processes, including dosage compensation, genomic imprinting, chromatin regulation, embryonic development and segmentation, stem cell pluripotency, cell fate determination and potentially many other biological processes, which still are to be elucidated. LncRNAs are pervasively transcribed in the genome and several lines of evidence correlate dysregulation of different lncRNAs to human diseases including neurological disorders. Although their mechanisms of action are yet to be fully elucidated, evidence suggests lncRNA contributions to the pathogenesis of a number of diseases. In this review, the current state of knowledge linking lncRNAs to different neurological disorders is discussed and potential future directions are considered. PMID:24129177

  20. TFIIS-Dependent Non-coding Transcription Regulates Developmental Genome Rearrangements.

    PubMed

    Maliszewska-Olejniczak, Kamila; Gruchota, Julita; Gromadka, Robert; Denby Wilkes, Cyril; Arnaiz, Olivier; Mathy, Nathalie; Duharcourt, Sandra; Bétermier, Mireille; Nowak, Jacek K

    2015-07-01

    Because of their nuclear dimorphism, ciliates provide a unique opportunity to study the role of non-coding RNAs (ncRNAs) in the communication between germline and somatic lineages. In these unicellular eukaryotes, a new somatic nucleus develops at each sexual cycle from a copy of the zygotic (germline) nucleus, while the old somatic nucleus degenerates. In the ciliate Paramecium tetraurelia, the genome is massively rearranged during this process through the reproducible elimination of repeated sequences and the precise excision of over 45,000 short, single-copy Internal Eliminated Sequences (IESs). Different types of ncRNAs resulting from genome-wide transcription were shown to be involved in the epigenetic regulation of genome rearrangements. To understand how ncRNAs are produced from the entire genome, we have focused on a homolog of the TFIIS elongation factor, which regulates RNA polymerase II transcriptional pausing. Six TFIIS-paralogs, representing four distinct families, can be found in P. tetraurelia genome. Using RNA interference, we showed that TFIIS4, which encodes a development-specific TFIIS protein, is essential for the formation of a functional somatic genome. Molecular analyses and high-throughput DNA sequencing upon TFIIS4 RNAi demonstrated that TFIIS4 is involved in all kinds of genome rearrangements, including excision of ~48% of IESs. Localization of a GFP-TFIIS4 fusion revealed that TFIIS4 appears specifically in the new somatic nucleus at an early developmental stage, before IES excision. RT-PCR experiments showed that TFIIS4 is necessary for the synthesis of IES-containing non-coding transcripts. We propose that these IES+ transcripts originate from the developing somatic nucleus and serve as pairing substrates for germline-specific short RNAs that target elimination of their homologous sequences. Our study, therefore, connects the onset of zygotic non coding transcription to the control of genome plasticity in Paramecium, and establishes for

  1. DIANA-LncBase v2: indexing microRNA targets on non-coding transcripts

    PubMed Central

    Paraskevopoulou, Maria D.; Vlachos, Ioannis S.; Karagkouni, Dimitra; Georgakilas, Georgios; Kanellos, Ilias; Vergoulis, Thanasis; Zagganas, Konstantinos; Tsanakas, Panayiotis; Floros, Evangelos; Dalamagas, Theodore; Hatzigeorgiou, Artemis G.

    2016-01-01

    microRNAs (miRNAs) are short non-coding RNAs (ncRNAs) that act as post-transcriptional regulators of coding gene expression. Long non-coding RNAs (lncRNAs) have been recently reported to interact with miRNAs. The sponge-like function of lncRNAs introduces an extra layer of complexity in the miRNA interactome. DIANA-LncBase v1 provided a database of experimentally supported and in silico predicted miRNA Recognition Elements (MREs) on lncRNAs. The second version of LncBase (www.microrna.gr/LncBase) presents an extensive collection of miRNA:lncRNA interactions. The significantly enhanced database includes more than 70 000 low and high-throughput, (in)direct miRNA:lncRNA experimentally supported interactions, derived from manually curated publications and the analysis of 153 AGO CLIP-Seq libraries. The new experimental module presents a 14-fold increase compared to the previous release. LncBase v2 hosts in silico predicted miRNA targets on lncRNAs, identified with the DIANA-microT algorithm. The relevant module provides millions of predicted miRNA binding sites, accompanied with detailed metadata and MRE conservation metrics. LncBase v2 caters information regarding cell type specific miRNA:lncRNA regulation and enables users to easily identify interactions in 66 different cell types, spanning 36 tissues for human and mouse. Database entries are also supported by accurate lncRNA expression information, derived from the analysis of more than 6 billion RNA-Seq reads. PMID:26612864

  2. High-Throughput Screening of Effective siRNAs Using Luciferase-Linked Chimeric mRNA

    PubMed Central

    Pang, Shen; Pokomo, Lauren; Chen, Kevin; Kamata, Masakazu; Mao, Si-Hua; Zhang, Hong; Razi, Elliot; An, Dong Sung; Chen, Irvin S. Y.

    2014-01-01

    The use of siRNAs to knock down gene expression can potentially be an approach to treat various diseases. To avoid siRNA toxicity the less transcriptionally active H1 pol III promoter, rather than the U6 promoter, was proposed for siRNA expression. To identify highly efficacious siRNA sequences, extensive screening is required, since current computer programs may not render ideal results. Here, we used CCR5 gene silencing as a model to investigate a rapid and efficient screening approach. We constructed a chimeric luciferase-CCR5 gene for high-throughput screening of siRNA libraries. After screening approximately 900 shRNA clones, 12 siRNA sequences were identified. Sequence analysis demonstrated that most (11 of the 12 sequences) of these siRNAs did not match those identified by available siRNA prediction algorithms. Significant inhibition of CCR5 in a T-lymphocyte cell line and primary T cells by these identified siRNAs was confirmed using the siRNA lentiviral vectors to infect these cells. The inhibition of CCR5 expression significantly protected cells from R5 HIV-1JRCSF infection. These results indicated that the high-throughput screening method allows efficient identification of siRNA sequences to inhibit the target genes at low levels of expression. PMID:24831610

  3. Genome-Wide CRISPR-Cas9 Screen Identifies MicroRNAs That Regulate Myeloid Leukemia Cell Growth

    PubMed Central

    Wallace, Jared; Hu, Ruozhen; Mosbruger, Timothy L.; Dahlem, Timothy J.; Stephens, W. Zac; Rao, Dinesh S.; Round, June L.; O’Connell, Ryan M.

    2016-01-01

    Mammalian microRNA expression is dysregulated in human cancer. However, the functional relevance of many microRNAs in the context of tumor biology remains unclear. Using CRISPR-Cas9 technology, we performed a global loss-of-function screen to simultaneously test the functions of individual microRNAs and protein-coding genes during the growth of a myeloid leukemia cell line. This approach identified evolutionarily conserved human microRNAs that suppress or promote cell growth, revealing that microRNAs are extensively integrated into the molecular networks that control tumor cell physiology. miR-155 was identified as a top microRNA candidate promoting cellular fitness, which we confirmed with two distinct miR-155-targeting CRISPR-Cas9 lentiviral constructs. Further, we performed anti-correlation functional profiling to predict relevant microRNA-tumor suppressor gene or microRNA-oncogene interactions in these cells. This analysis identified miR-150 targeting of p53, a connection that was experimentally validated. Taken together, our study describes a powerful genetic approach by which the function of individual microRNAs can be assessed on a global level, and its use will rapidly advance our understanding of how microRNAs contribute to human disease. PMID:27081855

  4. Genome-Wide CRISPR-Cas9 Screen Identifies MicroRNAs That Regulate Myeloid Leukemia Cell Growth.

    PubMed

    Wallace, Jared; Hu, Ruozhen; Mosbruger, Timothy L; Dahlem, Timothy J; Stephens, W Zac; Rao, Dinesh S; Round, June L; O'Connell, Ryan M

    2016-01-01

    Mammalian microRNA expression is dysregulated in human cancer. However, the functional relevance of many microRNAs in the context of tumor biology remains unclear. Using CRISPR-Cas9 technology, we performed a global loss-of-function screen to simultaneously test the functions of individual microRNAs and protein-coding genes during the growth of a myeloid leukemia cell line. This approach identified evolutionarily conserved human microRNAs that suppress or promote cell growth, revealing that microRNAs are extensively integrated into the molecular networks that control tumor cell physiology. miR-155 was identified as a top microRNA candidate promoting cellular fitness, which we confirmed with two distinct miR-155-targeting CRISPR-Cas9 lentiviral constructs. Further, we performed anti-correlation functional profiling to predict relevant microRNA-tumor suppressor gene or microRNA-oncogene interactions in these cells. This analysis identified miR-150 targeting of p53, a connection that was experimentally validated. Taken together, our study describes a powerful genetic approach by which the function of individual microRNAs can be assessed on a global level, and its use will rapidly advance our understanding of how microRNAs contribute to human disease.

  5. Long Non-coding RNA in Neurons: New Players in Early Response to BDNF Stimulation

    PubMed Central

    Aliperti, Vincenza; Donizetti, Aldo

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin family member that is highly expressed and widely distributed in the brain. BDNF is critical for neural survival and plasticity both during development and in adulthood, and dysfunction in its signaling may contribute to a number of neurodegenerative disorders. Deep understanding of the BDNF-activated molecular cascade may thus help to find new biomarkers and therapeutic targets. One interesting direction is related to the early phase of BDNF-dependent gene expression regulation, which is responsible for the activation of selective gene programs that lead to stable functional and structural remodeling of neurons. Immediate-early coding genes activated by BDNF are under investigation, but the involvement of the non-coding RNAs is largely unexplored, especially the long non-coding RNAs (lncRNAs). lncRNAs are emerging as key regulators that can orchestrate different aspects of nervous system development, homeostasis, and plasticity, making them attractive candidate markers and therapeutic targets for brain diseases. We used microarray technology to identify differentially expressed lncRNAs in the immediate response phase of BDNF stimulation in a neuronal cell model. Our observations on the putative functional role of lncRNAs provide clues to their involvement as master regulators of gene expression cascade triggered by BDNF. PMID:26973456

  6. LncRNAs and cancer

    PubMed Central

    Zhang, Rui; Xia, Li Qiong; Lu, Wen Wen; Zhang, Jing; Zhu, Jin-Shui

    2016-01-01

    Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs composed of >200 nucleotides. Recent studies have revealed that lncRNAs exert an important role in the development and progression of cancer. In this review, the involvement of the most extensively investigated lncRNAs in cancers of the digestive, respiratory, reproductive, urinary and central nervous systems are discussed. LncRNAs function via molecular and biochemical mechanisms that include cis- and trans-regulation of gene expression, epigenetic modulation in the nucleus and post-transcriptional control in the cytoplasm. Although the detailed biological functions and molecular mechanisms of the majority of lncRNAs remain to be elucidated, this review aims to provide a novel insight into the diagnosis and treatment of cancer using lncRNAs. PMID:27446422

  7. Screening of Target Genes and Regulatory Function of miRNAs as Prognostic Indicators for Prostate Cancer.

    PubMed

    Xiaoli, Zhang; Yawei, Wei; Lianna, Liu; Haifeng, Li; Hui, Zhang

    2015-01-01

    BACKGROUND MicroRNAs expression profiling of prostate cancer is becoming increasingly used due to its usefulness in diagnosis, staging, prognosis, and response to treatment. The aim of this study was to screen differentially expressed miRNAs in prostate cancer and analyze the functions and signal pathways of their target genes. MATERIAL AND METHODS High-throughput data of miRNAs were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 551 samples (52 normal and 499 prostate cancer cases) and 1046 miRNAs expression values were selected for further analysis. Differentially expressed miRNAs between normal and prostate cancer tissues were identified using SAMR. StarBase and TargetScan software were used to predict the miRNAs' target group and target genes, respectively. GO functional and KEGG pathway analysis was conducted on up/down-regulated expressed miRNA with DAVID. Finally, survival analysis was performed to evaluate the association of differently expressed miRNAs signature and overall survival of prostate cancer patients. RESULTS A total of 162 miRNAs were differentially expressed between normal and prostate cancer samples, including 128 up-regulated and 38 down-regulated ones; hsa-mir-153-2, hsa-mir-92a-1, and hsa-mir-182 (up-regulated); and hsa-mir-29a, hsa-mir-10a, and hsa-mir-221 (down-regulated) were identified as good biomarkers. In GO and KEGG analysis, target genes of down-regulated miRNAs were significantly enriched in positive ion combination and JAK-STAT pathway annotation, respectively; the ones with up-regulated miRNAs were significantly enriched in the function of plasma membrane and MARK signaling pathway annotation, respectively. Patients were categorized into low- or high-score groups according to their risk scores from each miRNA. The patients in the low-score group had better overall survival compared with those in high-score group. CONCLUSIONS The 6 differentially expressed miRNAs and their target genes were used to define

  8. De novo transcriptome assembly from inflorescence of Orchis italica: analysis of coding and non-coding transcripts.

    PubMed

    De Paolo, Sofia; Salvemini, Marco; Gaudio, Luciano; Aceto, Serena

    2014-01-01

    The floral transcriptome of Orchis italica, a wild orchid species, was obtained using Illumina RNA-seq technology and specific de novo assembly and analysis tools. More than 100 million raw reads were processed resulting in 132,565 assembled transcripts and 86,079 unigenes with an average length of 606 bp and N50 of 956 bp. Functional annotation assigned 38,984 of the unigenes to records present in the NCBI non-redundant protein database, 32,161 of them to Gene Ontology terms, 15,775 of them to Eukaryotic Orthologous Groups (KOG) and 7,143 of them to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The in silico expression analysis based on the Fragments Per Kilobase of transcript per Million mapped reads (FPKM) was confirmed by real-time RT-PCR experiments on 10 selected unigenes, which showed high and statistically significant positive correlation with the RNA-seq based expression data. The prediction of putative long non-coding RNAs was assessed using two different software packages, CPC and Portrait, resulting in 7,779 unannotated unigenes that matched the threshold values for both of the analyses. Among the predicted long non-coding RNAs, one is the homologue of TAS3, a long non-coding RNA precursor of trans-acting small interfering RNAs (ta-siRNAs). The differential expression pattern observed for the selected putative long non-coding RNAs suggests their possible functional role in different floral tissues.

  9. MicroRNAs and PIWI-interacting RNAs in oncology

    PubMed Central

    Liu, Yong

    2016-01-01

    RNA molecules that are unable to translate into proteins are classified as non-coding RNA. Non-coding RNA (ncRNA) genes include highly abundant and functionally important RNAs such as transfer RNAs, microRNAs (miRNAs), siRNAs, snRNAs, exRNAs and piRNAs. The number of ncRNAs encoded within the human genome is unknown; however, recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs. Furthermore, small ncRNAs, including miRNAs and PIWI-interacting RNAs (piRNAs), play an imperative role in the regulation of gene expression of numerous biological and pathological processes. Investigation into the expression and function of small RNA in cancer cells has contributed to gaining a greater understanding of the roles of small RNAs in carcinogenesis. The present review is aimed primarily to discuss the importance of the expression and functions of these small RNAs in carcinogenesis. These studies may provide useful information for future therapies in cancer. PMID:27698791

  10. MicroRNAs and PIWI-interacting RNAs in oncology

    PubMed Central

    Liu, Yong

    2016-01-01

    RNA molecules that are unable to translate into proteins are classified as non-coding RNA. Non-coding RNA (ncRNA) genes include highly abundant and functionally important RNAs such as transfer RNAs, microRNAs (miRNAs), siRNAs, snRNAs, exRNAs and piRNAs. The number of ncRNAs encoded within the human genome is unknown; however, recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs. Furthermore, small ncRNAs, including miRNAs and PIWI-interacting RNAs (piRNAs), play an imperative role in the regulation of gene expression of numerous biological and pathological processes. Investigation into the expression and function of small RNA in cancer cells has contributed to gaining a greater understanding of the roles of small RNAs in carcinogenesis. The present review is aimed primarily to discuss the importance of the expression and functions of these small RNAs in carcinogenesis. These studies may provide useful information for future therapies in cancer.

  11. Non-coding genome functions in diabetes.

    PubMed

    Cebola, Inês; Pasquali, Lorenzo

    2016-01-01

    Most of the genetic variation associated with diabetes, through genome-wide association studies, does not reside in protein-coding regions, making the identification of functional variants and their eventual translation to the clinic challenging. In recent years, high-throughput sequencing-based methods have enabled genome-scale high-resolution epigenomic profiling in a variety of human tissues, allowing the exploration of the human genome outside of the well-studied coding regions. These experiments unmasked tens of thousands of regulatory elements across several cell types, including diabetes-relevant tissues, providing new insights into their mechanisms of gene regulation. Regulatory landscapes are highly dynamic and cell-type specific and, being sensitive to DNA sequence variation, can vary with individual genomes. The scientific community is now in place to exploit the regulatory maps of tissues central to diabetes etiology, such as pancreatic progenitors and adult islets. This giant leap forward in the understanding of pancreatic gene regulation is revolutionizing our capacity to discriminate between functional and non-functional non-coding variants, opening opportunities to uncover regulatory links between sequence variation and diabetes susceptibility. In this review, we focus on the non-coding regulatory landscape of the pancreatic endocrine cells and provide an overview of the recent developments in this field. PMID:26438568

  12. Long non-coding RNA-dependent transcriptional regulation in neuronal development and disease

    PubMed Central

    Clark, Brian S.; Blackshaw, Seth

    2014-01-01

    Comprehensive analysis of the mammalian transcriptome has revealed that long non-coding RNAs (lncRNAs) may make up a large fraction of cellular transcripts. Recent years have seen a surge of studies aimed at functionally characterizing the role of lncRNAs in development and disease. In this review, we discuss new findings implicating lncRNAs in controlling development of the central nervous system (CNS). The evolution of the higher vertebrate brain has been accompanied by an increase in the levels and complexities of lncRNAs expressed within the developing nervous system. Although a limited number of CNS-expressed lncRNAs are now known to modulate the activity of proteins important for neuronal differentiation, the function of the vast majority of neuronal-expressed lncRNAs is still unknown. Topics of intense current interest include the mechanism by which CNS-expressed lncRNAs might function in epigenetic and transcriptional regulation during neuronal development, and how gain and loss of function of individual lncRNAs contribute to neurological diseases. PMID:24936207

  13. Non-coding genetic variants in human disease

    PubMed Central

    Zhang, Feng; Lupski, James R.

    2015-01-01

    Genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), in the non-coding regions of the human genome can play an important role in human traits and complex diseases. Most of the genome-wide association study (GWAS) signals map to non-coding regions and potentially point to non-coding variants, whereas their functional interpretation is challenging. In this review, we discuss the human non-coding variants and their contributions to human diseases in the following four parts. (i) Functional annotations of non-coding SNPs mapped by GWAS: we discuss recent progress revealing some of the molecular mechanisms for GWAS signals affecting gene function. (ii) Technical progress in interpretation of non-coding variants: we briefly describe some of the technologies for functional annotations of non-coding variants, including the methods for genome-wide mapping of chromatin interaction, computational tools for functional predictions and the new genome editing technologies useful for dissecting potential functional consequences of non-coding variants. (iii) Non-coding CNVs in human diseases: we review our emerging understanding the role of non-coding CNVs in human disease. (iv) Compound inheritance of large genomic deletions and non-coding variants: compound inheritance at a locus consisting of coding variants plus non-coding ones is described. PMID:26152199

  14. Origin and evolution of the long non-coding genes in the X-inactivation center.

    PubMed

    Romito, Antonio; Rougeulle, Claire

    2011-11-01

    Random X chromosome inactivation (XCI), the eutherian mechanism of X-linked gene dosage compensation, is controlled by a cis-acting locus termed the X-inactivation center (Xic). One of the striking features that characterize the Xic landscape is the abundance of loci transcribing non-coding RNAs (ncRNAs), including Xist, the master regulator of the inactivation process. Recent comparative genomic analyses have depicted the evolutionary scenario behind the origin of the X-inactivation center, revealing that this locus evolved from a region harboring protein-coding genes. During mammalian radiation, this ancestral protein-coding region was disrupted in the marsupial group, whilst it provided in eutherian lineage the starting material for the non-translated RNAs of the X-inactivation center. The emergence of non-coding genes occurred by a dual mechanism involving loss of protein-coding function of the pre-existing genes and integration of different classes of mobile elements, some of which modeled the structure and sequence of the non-coding genes in a species-specific manner. The rising genes started to produce transcripts that acquired function in regulating the epigenetic status of the X chromosome, as shown for Xist, its antisense Tsix, Jpx, and recently suggested for Ftx. Thus, the appearance of the Xic, which occurred after the divergence between eutherians and marsupials, was the basis for the evolution of random X inactivation as a strategy to achieve dosage compensation.

  15. Screening of Target Genes and Regulatory Function of miRNAs as Prognostic Indicators for Prostate Cancer

    PubMed Central

    Xiaoli, Zhang; Yawei, Wei; Lianna, Liu; Haifeng, Li; Hui, Zhang

    2015-01-01

    Background MicroRNAs expression profiling of prostate cancer is becoming increasingly used due to its usefulness in diagnosis, staging, prognosis, and response to treatment. The aim of this study was to screen differentially expressed miRNAs in prostate cancer and analyze the functions and signal pathways of their target genes. Material/Methods High-throughput data of miRNAs were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 551 samples (52 normal and 499 prostate cancer cases) and 1046 miRNAs expression values were selected for further analysis. Differentially expressed miRNAs between normal and prostate cancer tissues were identified using SAMR. StarBase and TargetScan software were used to predict the miRNAs’ target group and target genes, respectively. GO functional and KEGG pathway analysis was conducted on up/down-regulated expressed miRNA with DAVID. Finally, survival analysis was performed to evaluate the association of differently expressed miRNAs signature and overall survival of prostate cancer patients. Results A total of 162 miRNAs were differentially expressed between normal and prostate cancer samples, including 128 up-regulated and 38 down-regulated ones; hsa-mir-153-2, hsa-mir-92a-1, and hsa-mir-182 (up-regulated); and hsa-mir-29a, hsa-mir-10a, and hsa-mir-221 (down-regulated) were identified as good biomarkers. In GO and KEGG analysis, target genes of down-regulated miRNAs were significantly enriched in positive ion combination and JAK-STAT pathway annotation, respectively; the ones with up-regulated miRNAs were significantly enriched in the function of plasma membrane and MARK signaling pathway annotation, respectively. Patients were categorized into low- or high-score groups according to their risk scores from each miRNA. The patients in the low-score group had better overall survival compared with those in high-score group. Conclusions The 6 differentially expressed miRNAs and their target genes were used to define

  16. Non-coding RNA in Ovarian Development and Disease.

    PubMed

    Fitzgerald, J Browning; George, Jitu; Christenson, Lane K

    2016-01-01

    The ovary's primary function is to produce the mature female gamete, the oocyte that, following fertilization, can develop into an embryo, implant within the uterus and ultimately allow the mother's genetic material to be passed along to subsequent generations. In addition to supporting the generation of the oocyte, the ovary and specific ephemeral tissues within it, follicles and corpora lutea, produce steroids that regulate all aspects of the reproductive system, including the hypothalamic/pituitary axis, the reproductive tract (uterus, oviduct, cervix), secondary sex characteristics all of which are also essential for pregnancy and subsequent nurturing of the offspring. To accomplish these critical roles, ovarian development and function are tightly regulated by a number of exogenous (hypothalamic/pituitary) and endogenous (intraovarian) hormones. Within ovarian cells, intricate signalling cascades and transcriptional and post-transcriptional gene regulatory networks respond to these hormonal influences to provide the exquisite control over all of the temporal and spatial events that must be synchronized to allow this organ to successfully complete its function. This book chapter will focus specifically on the role of non-coding RNAs, their identification and described functional roles within the ovary with respect to normal function and their possible involvement in diseases, which involve the ovary.

  17. Recombinant Pseudorabies Virus (PRV) Expressing Firefly Luciferase Effectively Screened for CRISPR/Cas9 Single Guide RNAs and Antiviral Compounds.

    PubMed

    Tang, Yan-Dong; Liu, Ji-Ting; Fang, Qiong-Qiong; Wang, Tong-Yun; Sun, Ming-Xia; An, Tong-Qing; Tian, Zhi-Jun; Cai, Xue-Hui

    2016-04-01

    A Pseudorabies virus (PRV) variant has emerged in China since 2011 that is not protected by commercial vaccines, and has not been well studied. The PRV genome is large and difficult to manipulate, but it is feasible to use clustered, regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology. However, identification of single guide RNA (sgRNA) through screening is critical to the CRISPR/Cas9 system, and is traditionally time and labor intensive, and not suitable for rapid and high throughput screening of effective PRV sgRNAs. In this study, we developed a recombinant PRV strain expressing firefly luciferase and enhanced green fluorescent protein (EGFP) as a reporter virus for PRV-specific sgRNA screens and rapid evaluation of antiviral compounds. Luciferase activity was apparent as soon as 4 h after infection and was stably expressed through 10 passages. In a proof of the principle screen, we were able to identify several PRV specific sgRNAs and confirmed that they inhibited PRV replication using traditional methods. Using the reporter virus, we also identified PRV variants lacking US3, US2, and US9 gene function, and showed anti-PRV activity for chloroquine. Our results suggest that the reporter PRV strain will be a useful tool for basic virology studies, and for developing PRV control and prevention measures. PMID:27043610

  18. Regulatory non-coding RNA: new instruments in the orchestration of cell death.

    PubMed

    Su, Ye; Wu, Haijiang; Pavlosky, Alexander; Zou, Ling-Lin; Deng, Xinna; Zhang, Zhu-Xu; Jevnikar, Anthony M

    2016-01-01

    Non-coding RNA (ncRNA) comprises a substantial portion of primary transcripts that are generated by genomic transcription, but are not translated into protein. The possible functions of these once considered 'junk' molecules have incited considerable interest and new insights have emerged. The two major members of ncRNAs, namely micro RNA (miRNA) and long non-coding RNA (lncRNA), have important regulatory roles in gene expression and many important physiological processes, which has recently been extended to programmed cell death. The previous paradigm of programmed cell death only by apoptosis has recently expanded to include modalities of regulated necrosis (RN), and particularly necroptosis. However, most research efforts in this field have been on protein regulators, leaving the role of ncRNAs largely unexplored. In this review, we discuss important findings concerning miRNAs and lncRNAs that modulate apoptosis and RN pathways, as well as the miRNA-lncRNA interactions that affect cell death regulation. PMID:27512954

  19. Long non-coding RNA PANDAR correlates with poor prognosis and promotes tumorigenesis in hepatocellular carcinoma.

    PubMed

    Peng, Wei; Fan, Hong

    2015-05-01

    Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. Long non-coding RNAs (lncRNAs) are new-found non-coding RNAs longer than 200 nucleotides, and have emerged as important players in tumorigenesis. However, the clinical significance and molecular mechanism of lncRNAs in HCC remain largely elusive. The aim of this study was to determine the expression pattern and clinical value of PANDAR, a novel lncRNA, in HCC. qRT-PCR was conducted in tissues and cell lines. Then, associations between PANDAR expression and clinicopathological features of HCC patients were further analyzed. Next, ROC curve was constructed to evaluate diagnostic values. Finally, effects of PANDAR on HCC cell phenotypes were verified. PANDAR was overexpressed in HCC tissues and cell lines. Moreover, its expression level was significantly correlated with liver cirrhosis, HBsAg, AFP, tumor nodule, vascular invasion and TNM stage. PANDAR overexpression was associated with poorer survival and shorter recurrence. Importantly, the area under the ROC curve of PANDAR was up to 0.9564. Furthermore, PANDAR knockdown significantly repressed cell proliferation, colony formation and cycle progression of HCC in vitro. PANDAR was a powerful tumor biomarker, which highlighted its potential clinical utility as a promising prognostic biomarker and therapeutic target.

  20. Long Non-Coding RNA Expression Profile in the Kidneys of Male, Low Birth Weight Rats Exposed to Maternal Protein Restriction at Postnatal Day 1 and Day 10

    PubMed Central

    Li, Yanhong; Wang, Xueqin; Li, Mengxia; Pan, Jian; Jin, Meifang; Wang, Jian; Li, Xiaozhong; Feng, Xing

    2015-01-01

    Background Long non-coding RNAs (lncRNAs), which are involved in a variety of biological functions and aberrantly expressed in many types of diseases, are required for postnatal development. In this study, we aimed to investigate the lncRNA profiles in low birth weight (LBW) rats with reduced nephron endowment induced by the restriction of maternal protein intake. LBW by reduced nephron endowment is a risk factor for hypertension and end-stage renal disease in adulthood. Methods Kidneys were obtained from LBW rats fed a low-protein diet throughout gestation and lactation as well as from normal control rats born from dams fed normal protein diets at postnatal day 1 (p1) and 10 (p10). The total number of glomeruli in the kidneys was counted at p10. LncRNA expression profiles were analyzed by sequencing and screening using the Agilent Rat lncRNA Array. Quantitative real-time PCR (qRT-PCR) analysis of these lncRNAs confirmed the identity of some genes. Results The total number of glomeruli per kidney at p10 was significantly lower in LBW rats than in controls. A total of 42 lncRNAs were identified to be significantly differentially expressed, with fold-changes ≥2.0, between the two groups. According to correlation analysis between the differentially expressed lncRNAs and mRNAs involved in kidney development, we randomly selected a number of lncRNAs for comparison analysis between LBW and control kidneys at the two time-points, p1 and p10, using qRT-PCR. Three lncRNAs (TCONS_00014139, TCONS_00014138, and TCONS_00017119), which were significantly correlated with the mRNA expression of mitogen-activated protein kinase 4, were aberrantly expressed in LBW rats, compared with controls, at both p1 and p10. Conclusions LncRNAs are aberrantly expressed in the kidneys of LBW rats, compared with controls, during nephron development, which indicates that lncRNAs might be involved in impaired nephron endowment. PMID:25826617

  1. Detection of small RNAs in Xylella fastidiosa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Non-coding small RNAs (sRNAs) are regarded as ubiquitous regulatory elements in bacteria. For Xylella fastidiosa, a plant pathogen causing many economically important crop diseases, research attention to sRNAs has been limited. With the availability of whole genome sequences and increasing bioinfor...

  2. MicroRNAs in apoptosis, autophagy and necroptosis

    PubMed Central

    2015-01-01

    MicroRNAs (miRNAs) are endogenous 22 nt non-coding RNAs that target mRNAs for cleavage or translational repression. Numerous miRNAs regulate programmed cell death including apoptosis, autophagy and necroptosis. We summarize how miRNAs regulate apoptotic, autophagic and necroptotic pathways and cancer progression. We also discuss how miRNAs link different types of cell death. PMID:25893379

  3. A two-dimensional mutate-and-map strategy for non-coding RNA structure

    NASA Astrophysics Data System (ADS)

    Kladwang, Wipapat; Vanlang, Christopher C.; Cordero, Pablo; Das, Rhiju

    2011-12-01

    Non-coding RNAs fold into precise base-pairing patterns to carry out critical roles in genetic regulation and protein synthesis, but determining RNA structure remains difficult. Here, we show that coupling systematic mutagenesis with high-throughput chemical mapping enables accurate base-pair inference of domains from ribosomal RNA, ribozymes and riboswitches. For a six-RNA benchmark that has challenged previous chemical/computational methods, this ‘mutate-and-map’ strategy gives secondary structures that are in agreement with crystallography (helix error rates, 2%), including a blind test on a double-glycine riboswitch. Through modelling of partially ordered states, the method enables the first test of an interdomain helix-swap hypothesis for ligand-binding cooperativity in a glycine riboswitch. Finally, the data report on tertiary contacts within non-coding RNAs, and coupling to the Rosetta/FARFAR algorithm gives nucleotide-resolution three-dimensional models (helix root-mean-squared deviation, 5.7 Å) of an adenine riboswitch. These results establish a promising two-dimensional chemical strategy for inferring the secondary and tertiary structures that underlie non-coding RNA behaviour.

  4. JAK-STAT signaling in cancer: From cytokines to non-coding genome.

    PubMed

    Pencik, Jan; Pham, Ha Thi Thanh; Schmoellerl, Johannes; Javaheri, Tahereh; Schlederer, Michaela; Culig, Zoran; Merkel, Olaf; Moriggl, Richard; Grebien, Florian; Kenner, Lukas

    2016-11-01

    In the past decades, studies of the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling have uncovered highly conserved programs linking cytokine signaling to the regulation of essential cellular mechanisms such as proliferation, invasion, survival, inflammation and immunity. Inhibitors of the JAK/STAT pathway are used for treatment of autoimmune diseases, such as rheumatoid arthritis or psoriasis. Aberrant JAK/STAT signaling has been identified to contribute to cancer progression and metastatic development. Targeting of JAK/STAT pathway is currently one of the most promising therapeutic strategies in prostate cancer (PCa), hematopoietic malignancies and sarcomas. Notably, newly identified regulators of JAK/STAT signaling, the non-coding RNAs transcripts and their role as important targets and potential clinical biomarkers are highlighted in this review. In addition to the established role of the JAK/STAT signaling pathway in traditional cytokine signaling the non-coding RNAs add yet another layer of hidden regulation and function. Understanding the crosstalk of non-coding RNA with JAK/STAT signaling in cancer is of critical importance and may result in better patient stratification not only in terms of prognosis but also in the context of therapy. PMID:27349799

  5. JAK-STAT signaling in cancer: From cytokines to non-coding genome.

    PubMed

    Pencik, Jan; Pham, Ha Thi Thanh; Schmoellerl, Johannes; Javaheri, Tahereh; Schlederer, Michaela; Culig, Zoran; Merkel, Olaf; Moriggl, Richard; Grebien, Florian; Kenner, Lukas

    2016-11-01

    In the past decades, studies of the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling have uncovered highly conserved programs linking cytokine signaling to the regulation of essential cellular mechanisms such as proliferation, invasion, survival, inflammation and immunity. Inhibitors of the JAK/STAT pathway are used for treatment of autoimmune diseases, such as rheumatoid arthritis or psoriasis. Aberrant JAK/STAT signaling has been identified to contribute to cancer progression and metastatic development. Targeting of JAK/STAT pathway is currently one of the most promising therapeutic strategies in prostate cancer (PCa), hematopoietic malignancies and sarcomas. Notably, newly identified regulators of JAK/STAT signaling, the non-coding RNAs transcripts and their role as important targets and potential clinical biomarkers are highlighted in this review. In addition to the established role of the JAK/STAT signaling pathway in traditional cytokine signaling the non-coding RNAs add yet another layer of hidden regulation and function. Understanding the crosstalk of non-coding RNA with JAK/STAT signaling in cancer is of critical importance and may result in better patient stratification not only in terms of prognosis but also in the context of therapy.

  6. Unveiling the hidden function of long non-coding RNA by identifying its major partner-protein.

    PubMed

    Yang, Yongfang; Wen, Liwei; Zhu, Hongliang

    2015-01-01

    Tens of thousands of long non-coding RNAs (lncRNAs) have been discovered in eukarya, but their functions are largely unknown. Fortunately, lncRNA-protein interactions may offer details of how lncRNAs play important roles in various biological processes, thus identifying proteins associated with lncRNA is critical. Here we review progress of molecular archetypes that lncRNAs execute as guides, scaffolds, or decoys for protein, focusing on advantages, shortcomings and applications of various conventional and emerging technologies to probe lncRNAs and protein interactions, including protein-centric biochemistry approaches such as nRIP and CLIP, and RNA-centric biochemistry approaches such as ChIRP, CHART and RAP. Overall, this review provides strategies for probing interactions between lncRNAs and protein. PMID:26500759

  7. Development and utilization of non-coding RNA-small molecule interactions.

    PubMed

    Georgianna, Wesleigh E; Young, Douglas D

    2011-12-01

    RNA plays a crucial role in cellular biology as a carrier of genetic information. However, beyond this passive role, RNA has been shown to regulate various cellular processes in a form that is not translated into protein. Non-coding RNA (ncRNA) has been shown to be important in gene regulation, and its aberrant activity has been associated with several disease states. As such, ncRNAs represent a novel target for small molecule regulation and recently, significant advances have been made towards elucidating small molecule regulators of ncRNAs. Herein, we provide an overview of miRNA, siRNA, RNA aptamers, riboswitches, and ribozymes, within the context of recent findings regarding the exogenous regulation of these ncRNAs by small molecules. The development of these small molecule tools has far-reaching applications in the advancement of molecular therapeutics.

  8. Small Non-coding Transfer RNA-Derived RNA Fragments (tRFs): Their Biogenesis, Function and Implication in Human Diseases

    PubMed Central

    Fu, Yu; Lee, Inhan

    2015-01-01

    tRNA-derived RNA fragments (tRFs) are an emerging class of non-coding RNAs (ncRNAs). A growing number of reports have shown that tRFs are not random degradation products but are functional ncRNAs made of specific tRNA cleavage. They play regulatory roles in several biological contexts such as cancer, innate immunity, stress responses, and neurological disorders. In this review, we summarize the biogenesis and functions of tRFs. PMID:26865839

  9. Small Non-coding Transfer RNA-Derived RNA Fragments (tRFs): Their Biogenesis, Function and Implication in Human Diseases.

    PubMed

    Fu, Yu; Lee, Inhan; Lee, Yong Sun; Bao, Xiaoyong

    2015-12-01

    tRNA-derived RNA fragments (tRFs) are an emerging class of non-coding RNAs (ncRNAs). A growing number of reports have shown that tRFs are not random degradation products but are functional ncRNAs made of specific tRNA cleavage. They play regulatory roles in several biological contexts such as cancer, innate immunity, stress responses, and neurological disorders. In this review, we summarize the biogenesis and functions of tRFs.

  10. TFIIS-Dependent Non-coding Transcription Regulates Developmental Genome Rearrangements

    PubMed Central

    Maliszewska-Olejniczak, Kamila; Gruchota, Julita; Gromadka, Robert; Denby Wilkes, Cyril; Arnaiz, Olivier; Mathy, Nathalie; Duharcourt, Sandra; Bétermier, Mireille; Nowak, Jacek K.

    2015-01-01

    Because of their nuclear dimorphism, ciliates provide a unique opportunity to study the role of non-coding RNAs (ncRNAs) in the communication between germline and somatic lineages. In these unicellular eukaryotes, a new somatic nucleus develops at each sexual cycle from a copy of the zygotic (germline) nucleus, while the old somatic nucleus degenerates. In the ciliate Paramecium tetraurelia, the genome is massively rearranged during this process through the reproducible elimination of repeated sequences and the precise excision of over 45,000 short, single-copy Internal Eliminated Sequences (IESs). Different types of ncRNAs resulting from genome-wide transcription were shown to be involved in the epigenetic regulation of genome rearrangements. To understand how ncRNAs are produced from the entire genome, we have focused on a homolog of the TFIIS elongation factor, which regulates RNA polymerase II transcriptional pausing. Six TFIIS-paralogs, representing four distinct families, can be found in P. tetraurelia genome. Using RNA interference, we showed that TFIIS4, which encodes a development-specific TFIIS protein, is essential for the formation of a functional somatic genome. Molecular analyses and high-throughput DNA sequencing upon TFIIS4 RNAi demonstrated that TFIIS4 is involved in all kinds of genome rearrangements, including excision of ~48% of IESs. Localization of a GFP-TFIIS4 fusion revealed that TFIIS4 appears specifically in the new somatic nucleus at an early developmental stage, before IES excision. RT-PCR experiments showed that TFIIS4 is necessary for the synthesis of IES-containing non-coding transcripts. We propose that these IES+ transcripts originate from the developing somatic nucleus and serve as pairing substrates for germline-specific short RNAs that target elimination of their homologous sequences. Our study, therefore, connects the onset of zygotic non coding transcription to the control of genome plasticity in Paramecium, and establishes for

  11. TFIIS-Dependent Non-coding Transcription Regulates Developmental Genome Rearrangements.

    PubMed

    Maliszewska-Olejniczak, Kamila; Gruchota, Julita; Gromadka, Robert; Denby Wilkes, Cyril; Arnaiz, Olivier; Mathy, Nathalie; Duharcourt, Sandra; Bétermier, Mireille; Nowak, Jacek K

    2015-07-01

    Because of their nuclear dimorphism, ciliates provide a unique opportunity to study the role of non-coding RNAs (ncRNAs) in the communication between germline and somatic lineages. In these unicellular eukaryotes, a new somatic nucleus develops at each sexual cycle from a copy of the zygotic (germline) nucleus, while the old somatic nucleus degenerates. In the ciliate Paramecium tetraurelia, the genome is massively rearranged during this process through the reproducible elimination of repeated sequences and the precise excision of over 45,000 short, single-copy Internal Eliminated Sequences (IESs). Different types of ncRNAs resulting from genome-wide transcription were shown to be involved in the epigenetic regulation of genome rearrangements. To understand how ncRNAs are produced from the entire genome, we have focused on a homolog of the TFIIS elongation factor, which regulates RNA polymerase II transcriptional pausing. Six TFIIS-paralogs, representing four distinct families, can be found in P. tetraurelia genome. Using RNA interference, we showed that TFIIS4, which encodes a development-specific TFIIS protein, is essential for the formation of a functional somatic genome. Molecular analyses and high-throughput DNA sequencing upon TFIIS4 RNAi demonstrated that TFIIS4 is involved in all kinds of genome rearrangements, including excision of ~48% of IESs. Localization of a GFP-TFIIS4 fusion revealed that TFIIS4 appears specifically in the new somatic nucleus at an early developmental stage, before IES excision. RT-PCR experiments showed that TFIIS4 is necessary for the synthesis of IES-containing non-coding transcripts. We propose that these IES+ transcripts originate from the developing somatic nucleus and serve as pairing substrates for germline-specific short RNAs that target elimination of their homologous sequences. Our study, therefore, connects the onset of zygotic non coding transcription to the control of genome plasticity in Paramecium, and establishes for

  12. The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia.

    PubMed

    Durinck, Kaat; Wallaert, Annelynn; Van de Walle, Inge; Van Loocke, Wouter; Volders, Pieter-Jan; Vanhauwaert, Suzanne; Geerdens, Ellen; Benoit, Yves; Van Roy, Nadine; Poppe, Bruce; Soulier, Jean; Cools, Jan; Mestdagh, Pieter; Vandesompele, Jo; Rondou, Pieter; Van Vlierberghe, Pieter; Taghon, Tom; Speleman, Frank

    2014-12-01

    Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting a role as an essential driver for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34(+) thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from ex vivo isolated Notch active CD34(+) and Notch inactive CD4(+)CD8(+) thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publicly available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T cells. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way for the development of novel therapeutic strategies that target hyperactive Notch signaling in human T-cell acute lymphoblastic leukemia.

  13. Integration of Expressed Sequence Tag Data Flanking Predicted RNA Secondary Structures Facilitates Novel Non-Coding RNA Discovery

    PubMed Central

    Krzyzanowski, Paul M.; Price, Feodor D.; Muro, Enrique M.; Rudnicki, Michael A.; Andrade-Navarro, Miguel A.

    2011-01-01

    Many computational methods have been used to predict novel non-coding RNAs (ncRNAs), but none, to our knowledge, have explicitly investigated the impact of integrating existing cDNA-based Expressed Sequence Tag (EST) data that flank structural RNA predictions. To determine whether flanking EST data can assist in microRNA (miRNA) prediction, we identified genomic sites encoding putative miRNAs by combining functional RNA predictions with flanking ESTs data in a model consistent with miRNAs undergoing cleavage during maturation. In both human and mouse genomes, we observed that the inclusion of flanking ESTs adjacent to and not overlapping predicted miRNAs significantly improved the performance of various methods of miRNA prediction, including direct high-throughput sequencing of small RNA libraries. We analyzed the expression of hundreds of miRNAs predicted to be expressed during myogenic differentiation using a customized microarray and identified several known and predicted myogenic miRNA hairpins. Our results indicate that integrating ESTs flanking structural RNA predictions improves the quality of cleaved miRNA predictions and suggest that this strategy can be used to predict other non-coding RNAs undergoing cleavage during maturation. PMID:21698286

  14. Non-coding RNA regulation in pathogenic bacteria located inside eukaryotic cells

    PubMed Central

    Ortega, Álvaro D.; Quereda, Juan J.; Pucciarelli, M. Graciela; García-del Portillo, Francisco

    2014-01-01

    Intracellular bacterial pathogens have evolved distinct lifestyles inside eukaryotic cells. Some pathogens coexist with the infected cell in an obligate intracellular state, whereas others transit between the extracellular and intracellular environment. Adaptation to these intracellular lifestyles is regulated in both space and time. Non-coding small RNAs (sRNAs) are post-transcriptional regulatory molecules that fine-tune important processes in bacterial physiology including cell envelope architecture, intermediate metabolism, bacterial communication, biofilm formation, and virulence. Recent studies have shown production of defined sRNA species by intracellular bacteria located inside eukaryotic cells. The molecules targeted by these sRNAs and their expression dynamics along the intracellular infection cycle remain, however, poorly characterized. Technical difficulties linked to the isolation of “intact” intracellular bacteria from infected host cells might explain why sRNA regulation in these specialized pathogens is still a largely unexplored field. Transition from the extracellular to the intracellular lifestyle provides an ideal scenario in which regulatory sRNAs are intended to participate; so much work must be done in this direction. This review focuses on sRNAs expressed by intracellular bacterial pathogens during the infection of eukaryotic cells, strategies used with these pathogens to identify sRNAs required for virulence, and the experimental technical challenges associated to this type of studies. We also discuss varied techniques for their potential application to study RNA regulation in intracellular bacterial infections. PMID:25429360

  15. Non-coding RNA regulation in pathogenic bacteria located inside eukaryotic cells.

    PubMed

    Ortega, Alvaro D; Quereda, Juan J; Pucciarelli, M Graciela; García-del Portillo, Francisco

    2014-01-01

    Intracellular bacterial pathogens have evolved distinct lifestyles inside eukaryotic cells. Some pathogens coexist with the infected cell in an obligate intracellular state, whereas others transit between the extracellular and intracellular environment. Adaptation to these intracellular lifestyles is regulated in both space and time. Non-coding small RNAs (sRNAs) are post-transcriptional regulatory molecules that fine-tune important processes in bacterial physiology including cell envelope architecture, intermediate metabolism, bacterial communication, biofilm formation, and virulence. Recent studies have shown production of defined sRNA species by intracellular bacteria located inside eukaryotic cells. The molecules targeted by these sRNAs and their expression dynamics along the intracellular infection cycle remain, however, poorly characterized. Technical difficulties linked to the isolation of "intact" intracellular bacteria from infected host cells might explain why sRNA regulation in these specialized pathogens is still a largely unexplored field. Transition from the extracellular to the intracellular lifestyle provides an ideal scenario in which regulatory sRNAs are intended to participate; so much work must be done in this direction. This review focuses on sRNAs expressed by intracellular bacterial pathogens during the infection of eukaryotic cells, strategies used with these pathogens to identify sRNAs required for virulence, and the experimental technical challenges associated to this type of studies. We also discuss varied techniques for their potential application to study RNA regulation in intracellular bacterial infections.

  16. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

    PubMed Central

    Holdt, Lesca M.; Stahringer, Anika; Sass, Kristina; Pichler, Garwin; Kulak, Nils A.; Wilfert, Wolfgang; Kohlmaier, Alexander; Herbst, Andreas; Northoff, Bernd H.; Nicolaou, Alexandros; Gäbel, Gabor; Beutner, Frank; Scholz, Markus; Thiery, Joachim; Musunuru, Kiran; Krohn, Knut; Mann, Matthias; Teupser, Daniel

    2016-01-01

    Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease. PMID:27539542

  17. LOC401317, a p53-Regulated Long Non-Coding RNA, Inhibits Cell Proliferation and Induces Apoptosis in the Nasopharyngeal Carcinoma Cell Line HNE2

    PubMed Central

    Gong, Zhaojian; Zhang, Shanshan; Zeng, Zhaoyang; Wu, Hanjiang; Yang, Qian; Xiong, Fang; Shi, Lei; Yang, Jianbo; Zhang, Wenling; Zhou, Yanhong; Zeng, Yong; Li, Xiayu; Xiang, Bo; Peng, Shuping; Zhou, Ming; Li, Xiaoling; Tan, Ming; Li, Yong; Xiong, Wei; Li, Guiyuan

    2014-01-01

    Recent studies have revealed that long non-coding RNAs participate in all steps of cancer initiation and progression by regulating protein-coding genes at the epigenetic, transcriptional, and post-transcriptional levels. Long non-coding RNAs are in turn regulated by other genes, forming a complex regulatory network. The regulation networks between the p53 tumor suppressor and these RNAs in nasopharyngeal carcinoma remains unclear. The aims of this study were to investigate the regulatory roles of the TP53 gene in regulating long non-coding RNA expression profiles and to study the function of a TP53-regulated long non-coding RNA (LOC401317) in the nasopharyngeal carcinoma cell line HNE2. Long non-coding RNA expression profiling indicated that 133 long non-coding RNAs were upregulated in the human NPC cell line HNE2 cells following TP53 overexpression, while 1057 were downregulated. Among these aberrantly expressed long non-coding RNAs, LOC401317 was the most significantly upregulated one. Further studies indicated that LOC401317 is directly regulated by p53 and that ectopic expression of LOC401317 inhibits HNE2 cell proliferation in vitro and in vivo by inducing cell cycle arrest and apoptosis. LOC401317 inhibited cell cycle progression by increasing p21 expression and decreasing cyclin D1 and cyclin E1 expression and promoted apoptosis through the induction of poly(ADP-ribose) polymerase and caspase-3 cleavage. Collectively, these results suggest that LOC401317 is directly regulated by p53 and exerts antitumor effects in HNE2 nasopharyngeal carcinoma cells. PMID:25422887

  18. Non-coding RNA interact to regulate neuronal development and function

    PubMed Central

    Iyengar, Bharat R.; Choudhary, Ashwani; Sarangdhar, Mayuresh A.; Venkatesh, K. V.; Gadgil, Chetan J.; Pillai, Beena

    2014-01-01

    The human brain is one of the most complex biological systems, and the cognitive abilities have greatly expanded compared to invertebrates without much expansion in the number of protein coding genes. This suggests that gene regulation plays a very important role in the development and function of nervous system, by acting at multiple levels such as transcription and translation. In this article we discuss the regulatory roles of three classes of non-protein coding RNAs (ncRNAs)—microRNAs (miRNAs), piwi-interacting RNA (piRNAs) and long-non-coding RNA (lncRNA), in the process of neurogenesis and nervous function including control of synaptic plasticity and potential roles in neurodegenerative diseases. miRNAs are involved in diverse processes including neurogenesis where they channelize the cellular physiology toward neuronal differentiation. miRNAs can also indirectly influence neurogenesis by regulating the proliferation and self renewal of neural stem cells and are dysregulated in several neurodegenerative diseases. miRNAs are also known to regulate synaptic plasticity and are usually found to be co-expressed with their targets. The dynamics of gene regulation is thus dependent on the local architecture of the gene regulatory network (GRN) around the miRNA and its targets. piRNAs had been classically known to regulate transposons in the germ cells. However, piRNAs have been, recently, found to be expressed in the brain and possibly function by imparting epigenetic changes by DNA methylation. piRNAs are known to be maternally inherited and we assume that they may play a role in early development. We also explore the possible function of piRNAs in regulating the expansion of transposons in the brain. Brain is known to express several lncRNA but functional roles in brain development are attributed to a few lncRNA while functions of most of the them remain unknown. We review the roles of some known lncRNA and explore the other possible functions of lncRNAs

  19. Stable intronic sequence RNAs (sisRNAs): a new layer of gene regulation.

    PubMed

    Osman, Ismail; Tay, Mandy Li-Ian; Pek, Jun Wei

    2016-09-01

    Upon splicing, introns are rapidly degraded. Hence, RNAs derived from introns are commonly deemed as junk sequences. However, the discoveries of intronic-derived small nucleolar RNAs (snoRNAs), small Cajal body associated RNAs (scaRNAs) and microRNAs (miRNAs) suggested otherwise. These non-coding RNAs are shown to play various roles in gene regulation. In this review, we highlight another class of intron-derived RNAs known as stable intronic sequence RNAs (sisRNAs). sisRNAs have been observed since the 1980 s; however, we are only beginning to understand their biological significance. Recent studies have shown or suggested that sisRNAs regulate their own host's gene expression, function as molecular sinks or sponges, and regulate protein translation. We propose that sisRNAs function as an additional layer of gene regulation in the cells. PMID:27147469

  20. Non-coding functions of alternative pre-mRNA splicing in development

    PubMed Central

    Mockenhaupt, Stefan; Makeyev, Eugene V.

    2015-01-01

    A majority of messenger RNA precursors (pre-mRNAs) in the higher eukaryotes undergo alternative splicing to generate more than one mature product. By targeting the open reading frame region this process increases diversity of protein isoforms beyond the nominal coding capacity of the genome. However, alternative splicing also frequently controls output levels and spatiotemporal features of cellular and organismal gene expression programs. Here we discuss how these non-coding functions of alternative splicing contribute to development through regulation of mRNA stability, translational efficiency and cellular localization. PMID:26493705

  1. Multisubunit RNA Polymerases IV and V: Purveyors of Non-Coding RNA for Plant Gene Silencing

    SciTech Connect

    Haag, Jeremy R.; Pikaard, Craig S.

    2011-08-01

    In all eukaryotes, nuclear DNA-dependent RNA polymerases I, II and III synthesize the myriad RNAs that are essential for life. Remarkably, plants have evolved two additional multisubunit RNA polymerases, RNA polymerases IV and V, which orchestrate non-coding RNA-mediated gene silencing processes affecting development, transposon taming, antiviral defence and allelic crosstalk. Biochemical details concerning the templates and products of RNA polymerases IV and V are lacking. However, their subunit compositions reveal that they evolved as specialized forms of RNA polymerase II, which provides the unique opportunity to study the functional diversification of a eukaryotic RNA polymerase family.

  2. RNA sequencing identifies specific PIWI-interacting small non-coding RNA expression patterns in breast cancer

    PubMed Central

    Marchese, Giovanna; Ravo, Maria; Tarallo, Roberta; Nassa, Giovanni; Giurato, Giorgio; Santamaria, Gianluca; Cordella, Angela; Cantarella, Concita; Weisz, Alessandro

    2014-01-01

    PIWI-interacting small non-coding RNAs (piRNAs) are genetic and epigenetic regulatory factors in germline cells, where they maintain genome stability, are involved in RNA silencing and regulate gene expression. We found that the piRNA biogenesis and effector pathway are present in human breast cancer (BC) cells and, analyzing smallRNA-Seq data generated from BC cell lines and tumor biopsies, we identified >100 BC piRNAs, including some very abundant and/or differentially expressed in mammary epithelial compared to BC cells, where this was influenced by estrogen or estrogen receptor β, and in cancer respect to normal breast tissues. A search for mRNAs targeted by the BC piRNome revealed that eight piRNAs showing a specific expression pattern in breast tumors target key cancer cell pathways. Evidence of an active piRNA pathway in BC suggests that these small non-coding RNAs do exert transcriptional and post-transcriptional gene regulatory actions also in cancer cells. PMID:25313140

  3. RNA sequencing identifies specific PIWI-interacting small non-coding RNA expression patterns in breast cancer.

    PubMed

    Hashim, Adnan; Rizzo, Francesca; Marchese, Giovanna; Ravo, Maria; Tarallo, Roberta; Nassa, Giovanni; Giurato, Giorgio; Santamaria, Gianluca; Cordella, Angela; Cantarella, Concita; Weisz, Alessandro

    2014-10-30

    PIWI-interacting small non-coding RNAs (piRNAs) are genetic and epigenetic regulatory factors in germline cells, where they maintain genome stability, are involved in RNA silencing and regulate gene expression. We found that the piRNA biogenesis and effector pathway are present in human breast cancer (BC) cells and, analyzing smallRNA-Seq data generated from BC cell lines and tumor biopsies, we identified >100 BC piRNAs, including some very abundant and/or differentially expressed in mammary epithelial compared to BC cells, where this was influenced by estrogen or estrogen receptor β, and in cancer respect to normal breast tissues. A search for mRNAs targeted by the BC piRNome revealed that eight piRNAs showing a specific expression pattern in breast tumors target key cancer cell pathways. Evidence of an active piRNA pathway in BC suggests that these small non-coding RNAs do exert transcriptional and post-transcriptional gene regulatory actions also in cancer cells. PMID:25313140

  4. Identification and functional screening of microRNAs highly deregulated in colorectal cancer

    PubMed Central

    Faltejskova, Petra; Svoboda, Marek; Srutova, Klara; Mlcochova, Jitka; Besse, Andrej; Nekvindova, Jana; Radova, Lenka; Fabian, Pavel; Slaba, Katerina; Kiss, Igor; Vyzula, Rostislav; Slaby, Ondrej

    2012-01-01

    MicroRNAs (miRNAs) constitute a robust regulatory network with post-transcriptional regulatory efficiency for almost one half of human coding genes, including oncogenes and tumour suppressors. We determined the expression profile of 667 miRNAs in colorectal cancer (CRC) tissues and paired non-tumoural tissues and identified 42 differentially expressed miRNAs. We chose miR-215, miR-375, miR-378, miR-422a and miR-135b for further validation on an independent cohort of 125 clinically characterized CRC patients and for in vitro analyses. MiR-215, miR-375, miR-378 and miR-422a were significantly decreased, whereas miR-135b was increased in CRC tumour tissues. Levels of miR-215 and miR-422a correlated with clinical stage. MiR-135b was associated with higher pre-operative serum levels of CEA and CA19-9. In vitro analyses showed that ectopic expression of miR-215 decreases viability and migration, increases apoptosis and promotes cell cycle arrest in DLD-1 and HCT-116 colon cancer cell lines. Similarly, overexpression of miR-375 and inhibition of miR-135b led to decreased viability. Finally, restoration of miR-378, miR-422a and miR-375 inhibited G1/S transition. These findings indicate that miR-378, miR-375, miR-422a and miR-215 play an important role in CRC as tumour suppressors, whereas miR-135b functions as an oncogene; both groups of miRNA contribute to CRC pathogenesis. PMID:22469014

  5. The new world of RNAs

    PubMed Central

    Dogini, Danyella Barbosa; Pascoal, Vinícius D’Avila Bittencourt; Avansini, Simoni Helena; Vieira, André Schwambach; Pereira, Tiago Campos; Lopes-Cendes, Iscia

    2014-01-01

    One of the major developments that resulted from the human genome sequencing projects was a better understanding of the role of non-coding RNAs (ncRNAs). NcRNAs are divided into several different categories according to size and function; however, one shared feature is that they are not translated into proteins. In this review, we will discuss relevant aspects of ncRNAs, focusing on two main types: i) microRNAs, which negatively regulate gene expression either by translational repression or target mRNA degradation, and ii) small interfering RNAs (siRNAs), which are involved in the biological process of RNA interference (RNAi). Our knowledge regarding these two types of ncRNAs has increased dramatically over the past decade, and they have a great potential to become therapeutic alternatives for a variety of human conditions. PMID:24764762

  6. Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma.

    PubMed

    Fu, Xue-Liang; Liu, De-Jun; Yan, Ting-Ting; Yang, Jian-Yu; Yang, Min-Wei; Li, Jiao; Huo, Yan-Miao; Liu, Wei; Zhang, Jun-Feng; Hong, Jie; Hua, Rong; Chen, Hao-Yan; Sun, Yong-Wei

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients' clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC. PMID:27628540

  7. Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma

    PubMed Central

    Fu, Xue-Liang; Liu, De-Jun; Yan, Ting-Ting; Yang, Jian-Yu; Yang, Min-Wei; Li, Jiao; Huo, Yan-Miao; Liu, Wei; Zhang, Jun-Feng; Hong, Jie; Hua, Rong; Chen, Hao-Yan; Sun, Yong-Wei

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients’ clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC. PMID:27628540

  8. Characterization of Small RNAs Derived from tRNAs, rRNAs and snoRNAs and Their Response to Heat Stress in Wheat Seedlings

    PubMed Central

    Sun, Qixin; Yao, Yingyin

    2016-01-01

    Small RNAs (sRNAs) derived from non-coding RNAs (ncRNAs), such as tRNAs, rRNAs and snoRNAs, have been identified in various organisms. Several observations have indicated that cleavage of tRNAs and rRNAs is induced by various stresses. To clarify whether sRNAs in wheat derived from tRNAs (stRNAs), rRNAs (srRNAs) and snoRNAs (sdRNAs) are produced specifically in association with heat stress responses, we carried out a bioinformatic analysis of sRNA libraries from wheat seedlings and performed comparisons between control and high-temperature-treated samples to measure the differential abundance of stRNAs, srRNAs and sdRNAs. We found that the production of sRNAs from tRNAs, 5.8S rRNAs, and 28S rRNAs was more specific than that from 5S rRNAs and 18S rRNAs, and more than 95% of the stRNAs were processed asymmetrically from the 3’ or 5’ ends of mature tRNAs. We identified 333 stRNAs and 8,822 srRNAs that were responsive to heat stress. Moreover, the expression of stRNAs derived from tRNA-Val-CAC, tRNA-Thr-UGU, tRNA-Tyr-GUA and tRNA-Ser-UGA was not only up-regulated under heat stress but also induced by osmotic stress, suggesting that the increased cleavage of tRNAs might be a mechanism that developed in wheat seedlings to help them cope with adverse environmental conditions. PMID:26963812

  9. Exploring the stability of long intergenic non-coding RNA in K562 cells by comparative studies of RNA-Seq datasets

    PubMed Central

    2014-01-01

    Background The stability of long intergenic non-coding RNAs (lincRNAs) that possess tissue/cell-specific expression, might be closely related to their physiological functions. However, the mechanism associated with stability of lincRNA remains elusive. In this study, we try to study the stability of lincRNA in K562 cells, an important model cell, through comparing two K562 transcriptomes which are obtained from ENCODE Consortium and our sequenced RNA-Seq dataset (PH) respectively. Results By lincRNAs analysis pipeline, 1804 high-confidence lincRNAs involving 1564 annotated lincRNAs and 240 putative novel lincRNAs were identified in PH, and 1587 high-confidence lincRNAs including 1429 annotated lincRNAs and 158 putative novel lincRNAs in ENCODE. There are 1009 unique lincRNAs in PH, 792 unique lincRNAs were in ENCODE, and 795 overlapping lincRNAs in both datasets. The analysis of differences in minimum free energy distribution and lincRNA half-life showed that a large proportion of overlapping lincRNAs were more stable than the unique lincRNAs. Most lincRNAs were more unstable than protein-coding RNAs through comparing their minimum free energy. Conclusions Identification of overlapping and unique lincRNAs can be helpful to classify the stability of lincRNAs. Our results suggest that overlapping lincRNAs (relatively stable linRNAs) and unique lincRNAs (relatively unstable lincRNAs) might be involved in different cellular processes. Reviewers This article has been reviewed by Prof. Oliviero Carugo, Dr. Alistair Forrest and Prof. Manju Bansal. PMID:24996425

  10. Long non-coding RNA produced by RNA polymerase V determines boundaries of heterochromatin

    PubMed Central

    Böhmdorfer, Gudrun; Sethuraman, Shriya; Rowley, M Jordan; Krzyszton, Michal; Rothi, M Hafiz; Bouzit, Lilia; Wierzbicki, Andrzej T

    2016-01-01

    RNA-mediated transcriptional gene silencing is a conserved process where small RNAs target transposons and other sequences for repression by establishing chromatin modifications. A central element of this process are long non-coding RNAs (lncRNA), which in Arabidopsis thaliana are produced by a specialized RNA polymerase known as Pol V. Here we show that non-coding transcription by Pol V is controlled by preexisting chromatin modifications located within the transcribed regions. Most Pol V transcripts are associated with AGO4 but are not sliced by AGO4. Pol V-dependent DNA methylation is established on both strands of DNA and is tightly restricted to Pol V-transcribed regions. This indicates that chromatin modifications are established in close proximity to Pol V. Finally, Pol V transcription is preferentially enriched on edges of silenced transposable elements, where Pol V transcribes into TEs. We propose that Pol V may play an important role in the determination of heterochromatin boundaries. DOI: http://dx.doi.org/10.7554/eLife.19092.001 PMID:27779094

  11. Long non-coding RNA regulation of reproduction and development.

    PubMed

    Taylor, David H; Chu, Erin Tsi-Jia; Spektor, Roman; Soloway, Paul D

    2015-12-01

    Noncoding RNAs (ncRNAs) have long been known to play vital roles in eukaryotic gene regulation. Studies conducted over a decade ago revealed that maturation of spliced, polyadenylated coding mRNA occurs by reactions involving small nuclear RNAs and small nucleolar RNAs; mRNA translation depends on activities mediated by transfer RNAs and ribosomal RNAs, subject to negative regulation by micro RNAs; transcriptional competence of sex chromosomes and some imprinted genes is regulated in cis by ncRNAs that vary by species; and both small-interfering RNAs and piwi-interacting RNAs bound to Argonaute-family proteins regulate post-translational modifications on chromatin and local gene expression states. More recently, gene-regulating noncoding RNAs have been identified, such as long intergenic and long noncoding RNAs (collectively referred to as lncRNAs)--a class totaling more than 100,000 transcripts in humans, which include some of the previously mentioned RNAs that regulate dosage compensation and imprinted gene expression. Here, we provide an overview of lncRNA activities, and then review the role of lncRNAs in processes vital to reproduction, such as germ cell specification, sex determination and gonadogenesis, sex hormone responses, meiosis, gametogenesis, placentation, non-genetic inheritance, and pathologies affecting reproductive tissues. Results from many species are presented to illustrate the evolutionarily conserved processes lncRNAs are involved in.

  12. Up-regulation of Long Non-coding RNA TUG1 in Hibernating Thirteen-lined Ground Squirrels.

    PubMed

    Frigault, Jacques J; Lang-Ouellette, Daneck; Morin, Pier

    2016-04-01

    Mammalian hibernation is associated with multiple physiological, biochemical, and molecular changes that allow animals to endure colder temperatures. We hypothesize that long non-coding RNAs (lncRNAs), a group of non-coding transcripts with diverse functions, are differentially expressed during hibernation. In this study, expression levels of lncRNAsH19 and TUG1 were assessed via qRT-PCR in liver, heart, and skeletal muscle tissues of the hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus). TUG1 transcript levels were significantly elevated 1.94-fold in skeletal muscle of hibernating animals when compared with euthermic animals. Furthermore, transcript levels of HSF2 also increased 2.44-fold in the skeletal muscle in hibernating animals. HSF2 encodes a transcription factor that can be negatively regulated by TUG1 levels and that influences heat shock protein expression. Thus, these observations support the differential expression of the TUG1-HSF2 axis during hibernation. To our knowledge, this study provides the first evidence for differential expression of lncRNAs in torpid ground squirrels, adding lncRNAs as another group of transcripts modulated in this mammalian species during hibernation. PMID:27132145

  13. A long non-coding RNA, BC048612 and a microRNA, miR-203 coordinate the gene expression of neuronal growth regulator 1 (NEGR1) adhesion protein.

    PubMed

    Kaur, Prameet; Tan, Jun Rong; Karolina, Dwi Setyowati; Sepramaniam, Sugunavathi; Armugam, Arunmozhiarasi; Wong, Peter T-H; Jeyaseelan, Kandiah

    2016-04-01

    The regulatory roles for non-coding RNAs, the long non-coding RNAs and microRNAs, are emerging as crucial determinants of central nervous system development and function. Neuronal growth regulator 1 (NEGR1) is a cell adhesion molecule that has been shown to play an important role in neurite outgrowth during neuronal development. Precise expression of the Negr1 gene is crucial for proper brain development and is dysregulated during brain injury. Hence, we attempted to elucidate the non-coding RNAs that control Negr1 gene expression. A long non-coding RNA, BC048612, transcribed from the bidirectional GC-rich Negr1 gene promoter was found to influence Negr1 mRNA expression. In vitro knockdown of the long non-coding RNA resulted in significant down-regulation of Negr1 mRNA expression, NEGR1 protein levels and neurite length whereas over-expression enhanced Negr1 mRNA expression, NEGR1 protein levels and increased neurite length. Meanwhile, another non-coding RNA, microRNA-203, was found to target the 3' untranslated region of the Negr1 mRNA. Inhibition of microRNA-203 led to increased expression of Negr1 mRNA, elevated NEGR1 protein levels and increased neurite length. Conversely, microRNA-203 over-expression decreased the level of Negr1 mRNA, NEGR1 protein and neurite length. Neither microRNA-203 nor the long non-coding RNA, BC048612 could influence each other's expression. Hence, the long non-coding RNA, BC048612, and microRNA-203 were determined to be positive and negative regulators of Negr1 gene expression respectively. These processes have a direct effect on NEGR1 protein levels and neurite length, thus highlighting the importance of the regulatory non-coding RNAs in modulating Negr1 gene expression for precise neuronal development. PMID:26723899

  14. Identification of long non-coding RNA involved in osteogenic differentiation from mesenchymal stem cells using RNA-Seq data.

    PubMed

    Song, W Q; Gu, W Q; Qian, Y B; Ma, X; Mao, Y J; Liu, W J

    2015-01-01

    The aim of this study was to identify long non-coding RNA (lncRNA) associated with osteogenic differentiation from mesenchymal stem cells (MSCs) using high-throughput RNA sequencing (RNA-Seq) data. RNA-Seq dataset was obtained from the European Bioinformatics Institute (accession No. PRJEB4496), including two replicates each for immortalized mesenchymal stem cells iMSC#3 cultured in growth medium (GM) and differentiation medium (DM) for 28 days. The clean reads were aligned to a hg19 reference genome by Tophat and assembled by Cufflinks to identify the known and novel transcripts. RPKM values were calculated to screen for differentially expressed RNA. Novel lncRNA were screened based on various filter criteria. Subsequently, the underlying function of novel lncRNAs were predicted by functional annotation by ERPIN, a co-expression network was constructed by WGCNA and the KEGG pathway enriched by KOBAS. A total of 3171 RNA differentially expressed between the DM and GM groups (2597 mRNA and 574 lncRNA) were identified. Among the 574 differentially expressed lncRNA, 357 were known and 217 were novel lncRNA. Furthermore, 32 novel lncRNA were found to be miRNA precursors (including miR-689, miR-640, miR-601, and miR-544). A total of 14,275 co-expression relationships and 217 co-expression networks were obtained between novel lncRNA and mRNA. The differentially expressed lncRNA and mRNA were enriched into 6 significant pathways, including those for cancer, ECM-receptor interaction, and focal adhesion. Therefore, novel lncRNAwere identified and their underlying function predicted, which may provide the basis for future analyses of the role of lncRNA in osteoblastic differentiation.

  15. MicroRNAs: new players in IBD

    PubMed Central

    Kalla, R; Ventham, N T; Kennedy, N A; Quintana, J F; Nimmo, E R; Buck, A H; Satsangi, J

    2015-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs, 18–23 nucleotides long, which act as post-transcriptional regulators of gene expression. miRNAs are strongly implicated in the pathogenesis of many common diseases, including IBDs. This review aims to outline the history, biogenesis and regulation of miRNAs. The role of miRNAs in the development and regulation of the innate and adaptive immune system is discussed, with a particular focus on mechanisms pertinent to IBD and the potential translational applications. PMID:25475103

  16. A pathophysiological view of the long non-coding RNA world.

    PubMed

    Di Gesualdo, Federico; Capaccioli, Sergio; Lulli, Matteo

    2014-11-30

    Because cells are constantly exposed to micro-environmental changes, they require the ability to adapt to maintain a dynamic equilibrium. Proteins are considered critical for the regulation of gene expression, which is a fundamental process in determining the cellular responses to stimuli. Recently, revolutionary findings in RNA research and the advent of high-throughput genomic technologies have revealed a pervasive transcription of the human genome, which generates many long non-coding RNAs (lncRNAs) whose roles are largely undefined. However, there is evidence that lncRNAs are involved in several cellular physiological processes such as adaptation to stresses, cell differentiation, maintenance of pluripotency and apoptosis. The correct balance of lncRNA levels is crucial for the maintenance of cellular equilibrium, and the dysregulation of lncRNA expression is linked to many disorders; certain transcripts are useful prognostic markers for some of these pathologies. This review revisits the classic concept of cellular homeostasis from the perspective of lncRNAs specifically to understand how this novel class of molecules contributes to cellular balance and how its dysregulated expression can lead to the onset of pathologies such as cancer.

  17. Non-Coding RNA: Sequence-Specific Guide for Chromatin Modification and DNA Damage Signaling

    PubMed Central

    Francia, Sofia

    2015-01-01

    Chromatin conformation shapes the environment in which our genome is transcribed into RNA. Transcription is a source of DNA damage, thus it often occurs concomitantly to DNA damage signaling. Growing amounts of evidence suggest that different types of RNAs can, independently from their protein-coding properties, directly affect chromatin conformation, transcription and splicing, as well as promote the activation of the DNA damage response (DDR) and DNA repair. Therefore, transcription paradoxically functions to both threaten and safeguard genome integrity. On the other hand, DNA damage signaling is known to modulate chromatin to suppress transcription of the surrounding genetic unit. It is thus intriguing to understand how transcription can modulate DDR signaling while, in turn, DDR signaling represses transcription of chromatin around the DNA lesion. An unexpected player in this field is the RNA interference (RNAi) machinery, which play roles in transcription, splicing and chromatin modulation in several organisms. Non-coding RNAs (ncRNAs) and several protein factors involved in the RNAi pathway are well known master regulators of chromatin while only recent reports show their involvement in DDR. Here, we discuss the experimental evidence supporting the idea that ncRNAs act at the genomic loci from which they are transcribed to modulate chromatin, DDR signaling and DNA repair. PMID:26617633

  18. A pathophysiological view of the long non-coding RNA world

    PubMed Central

    Di Gesualdo, Federico; Capaccioli, Sergio; Lulli, Matteo

    2014-01-01

    Because cells are constantly exposed to micro-environmental changes, they require the ability to adapt to maintain a dynamic equilibrium. Proteins are considered critical for the regulation of gene expression, which is a fundamental process in determining the cellular responses to stimuli. Recently, revolutionary findings in RNA research and the advent of high-throughput genomic technologies have revealed a pervasive transcription of the human genome, which generates many long non-coding RNAs (lncRNAs) whose roles are largely undefined. However, there is evidence that lncRNAs are involved in several cellular physiological processes such as adaptation to stresses, cell differentiation, maintenance of pluripotency and apoptosis. The correct balance of lncRNA levels is crucial for the maintenance of cellular equilibrium, and the dysregulation of lncRNA expression is linked to many disorders; certain transcripts are useful prognostic markers for some of these pathologies. This review revisits the classic concept of cellular homeostasis from the perspective of lncRNAs specifically to understand how this novel class of molecules contributes to cellular balance and how its dysregulated expression can lead to the onset of pathologies such as cancer. PMID:25428918

  19. RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity.

    PubMed

    Pefanis, Evangelos; Wang, Jiguang; Rothschild, Gerson; Lim, Junghyun; Kazadi, David; Sun, Jianbo; Federation, Alexander; Chao, Jaime; Elliott, Oliver; Liu, Zhi-Ping; Economides, Aris N; Bradner, James E; Rabadan, Raul; Basu, Uttiya

    2015-05-01

    We have ablated the cellular RNA degradation machinery in differentiated B cells and pluripotent embryonic stem cells (ESCs) by conditional mutagenesis of core (Exosc3) and nuclear RNase (Exosc10) components of RNA exosome and identified a vast number of long non-coding RNAs (lncRNAs) and enhancer RNAs (eRNAs) with emergent functionality. Unexpectedly, eRNA-expressing regions accumulate R-loop structures upon RNA exosome ablation, thus demonstrating the role of RNA exosome in resolving deleterious DNA/RNA hybrids arising from active enhancers. We have uncovered a distal divergent eRNA-expressing element (lncRNA-CSR) engaged in long-range DNA interactions and regulating IgH 3' regulatory region super-enhancer function. CRISPR-Cas9-mediated ablation of lncRNA-CSR transcription decreases its chromosomal looping-mediated association with the IgH 3' regulatory region super-enhancer and leads to decreased class switch recombination efficiency. We propose that the RNA exosome protects divergently transcribed lncRNA expressing enhancers by resolving deleterious transcription-coupled secondary DNA structures, while also regulating long-range super-enhancer chromosomal interactions important for cellular function.

  20. Bioinformatics of prokaryotic RNAs.

    PubMed

    Backofen, Rolf; Amman, Fabian; Costa, Fabrizio; Findeiß, Sven; Richter, Andreas S; Stadler, Peter F

    2014-01-01

    The genome of most prokaryotes gives rise to surprisingly complex transcriptomes, comprising not only protein-coding mRNAs, often organized as operons, but also harbors dozens or even hundreds of highly structured small regulatory RNAs and unexpectedly large levels of anti-sense transcripts. Comprehensive surveys of prokaryotic transcriptomes and the need to characterize also their non-coding components is heavily dependent on computational methods and workflows, many of which have been developed or at least adapted specifically for the use with bacterial and archaeal data. This review provides an overview on the state-of-the-art of RNA bioinformatics focusing on applications to prokaryotes.

  1. Bioinformatics of prokaryotic RNAs

    PubMed Central

    Backofen, Rolf; Amman, Fabian; Costa, Fabrizio; Findeiß, Sven; Richter, Andreas S; Stadler, Peter F

    2014-01-01

    The genome of most prokaryotes gives rise to surprisingly complex transcriptomes, comprising not only protein-coding mRNAs, often organized as operons, but also harbors dozens or even hundreds of highly structured small regulatory RNAs and unexpectedly large levels of anti-sense transcripts. Comprehensive surveys of prokaryotic transcriptomes and the need to characterize also their non-coding components is heavily dependent on computational methods and workflows, many of which have been developed or at least adapted specifically for the use with bacterial and archaeal data. This review provides an overview on the state-of-the-art of RNA bioinformatics focusing on applications to prokaryotes. PMID:24755880

  2. Bioinformatics of prokaryotic RNAs.

    PubMed

    Backofen, Rolf; Amman, Fabian; Costa, Fabrizio; Findeiß, Sven; Richter, Andreas S; Stadler, Peter F

    2014-01-01

    The genome of most prokaryotes gives rise to surprisingly complex transcriptomes, comprising not only protein-coding mRNAs, often organized as operons, but also harbors dozens or even hundreds of highly structured small regulatory RNAs and unexpectedly large levels of anti-sense transcripts. Comprehensive surveys of prokaryotic transcriptomes and the need to characterize also their non-coding components is heavily dependent on computational methods and workflows, many of which have been developed or at least adapted specifically for the use with bacterial and archaeal data. This review provides an overview on the state-of-the-art of RNA bioinformatics focusing on applications to prokaryotes. PMID:24755880

  3. Genomewide mapping and screening of Kaposi's sarcoma-associated herpesvirus (KSHV) 3' untranslated regions identify bicistronic and polycistronic viral transcripts as frequent targets of KSHV microRNAs.

    PubMed

    Bai, Zhiqiang; Huang, Yufei; Li, Wan; Zhu, Ying; Jung, Jae U; Lu, Chun; Gao, Shou-Jiang

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) encodes over 90 genes and 25 microRNAs (miRNAs). The KSHV life cycle is tightly regulated to ensure persistent infection in the host. In particular, miRNAs, which primarily exert their effects