Non-Coding RNA

12 Key excerpts on "Non-Coding RNA"

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  Micrornas In Development And Cancer

  • Frank J Slack(Author)
  • 2010(Publication Date)
  • ICP

    (Publisher)

  2.1 Introduction to Non-Coding RNAs The central dogma of molecular biology which was first introduced by Francis Crick in 1958 has stated that genetic information encoded in DNA is transcribed to form messenger RNA (mRNA) molecules, which then serve as a template to produce unique amino acid sequences that consti-tute individual proteins (i.e. one gene — mRNA Intermediate — one protein). However, as early as the 1960s, this view began to be challenged by the discovery of Non-Coding RNAs which do not code for proteins but rather function as RNA molecules (i.e. ribosomal RNA (rRNA) and trans-fer RNA (tRNA), and small nucleolar RNAs (snoRNAs)). Several new classes and examples of small Non-Coding RNAs have burgeoned in the post-genomic era as microRNAs (miRNAs) which are involved in transla-tional repression, small interfering RNAs (siRNAs) that regulate RNA transcript levels and Piwi-associated RNAs (piRNAs) which silence trans-posons during germ cells differentiation. Recent advancements in new technologies such as microarray technology and high-throughput sequencing have revealed a whole new type of Non-Coding RNA: large ncRNAs (Figures 2.1 and 2.2). Although the first functional large ncRNA, XIST, was discovered in the early 1990s and serves to silence an entire X chromosome in females, it is now clear that there are many more thou-sands of these large ncRNA molecules encoded throughout the genome. In sharp contrast to the progress made in understanding small RNAs, very little is known about large ncRNAs which consist of intronic ncRNAs, large intergenic Non-Coding RNAs (lincRNAs), bidirectional ncRNAs and natural antisense transcripts (NATs) which usually overlap with protein-coding genes (see Figure 2.2 and Tables 2.1 and 2.2). At the beginning of the twenty-first century, new technologies emerged that allowed the examination of RNA transcription on a whole genome level revealing a massive number of large ncRNAs.

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  Toxicoepigenetics

  Core Principles and Applications

  • Shaun D. McCullough, Dana Dolinoy, Shaun D. Mccullough(Authors)
  • 2018(Publication Date)
  • Academic Press

    (Publisher)

  Section 3 Noncoding RNAs Passage contains an image

  Chapter 3-1

  The Role of Noncoding RNAs in Gene Regulation

  Emily Woolard⁎ ; Brian N. Chorley†     

  ⁎ Oak Ridge Institute for Science and Education at US Environmental Protection Agency, RTP, NC, United States

  † National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, RTP, NC, United States

  Abstract

  The genome contains regions of noncoding RNAs (ncRNAs) that have critical regulatory roles for gene transcription and protein translation. In this chapter, we will briefly review the forms of ncRNA with a focus on microRNAs (miRNAs), small ncRNAs that have important roles in regulating gene expression and cellular phenotype and may serve as important biomarkers in toxicology. In addition, we highlight current theories of biogenesis and emerging areas of research describing the varied and unique biological roles of miRNA, including enhanced function through molecular feedback loops and cell-to-cell communication through biofluids.

  Keywords

  Noncoding RNAs; MicroRNA; Biogenesis; Gene regulation; Feedback loops; Biofluids; Biomarkers

  Outline

  • Introduction
  • Overview of Noncoding RNAs
    • Transfer and Ribosomal RNA
    • Long Noncoding RNA (lncRNA)
    • Short Noncoding RNA
  • MicroRNA Discovery
  • MicroRNA Biogenesis and Regulation
    • Pri-miRNA Transcription and Regulation
    • Pri-miRNA Processing and Nuclear Export
    • Maturation of miRNA RISC Formation
    • Regulation of Mature miRNA by ceRNA
  • Biological Roles of MicroRNA
    • Gene Target Silencing
    • Enhanced Biological Impact of miRNAs Through Feedback Loops
    • Biofluid-Based Biomarkers and Cell Communication
  • Concluding Remarks and Future Directions
  • Acknowledgments
  • References

  Acknowledgments

  The authors wish to thank Dr. Stephanie Padilla and Dr. Charles Wood for their critical reviews of this manuscript. We are also grateful to Molly Windsor and John Havel for their assistance with the figures. This manuscript has been reviewed by the US Environmental Protection Agency and approved for publication. Approval does not signify that the contents reflect the views of the agency, nor mention of trade names or commercial products does not constitute endorsement or recommendation of use.

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  Cancer Epigenetics

  • Trygve Tollefsbol(Author)
  • 2008(Publication Date)
  • CRC Press

    (Publisher)

  The processing and decoding information contained in mRNA requires participation of several RNA species. Ribosomal RNAs (rRNA) and transfer RNAs (tRNA) are key elements of the machinery responsible for protein biosynthesis on ribosomes. Small nuclear RNAs (snRNA), small nucleolar RNAs (snoRNA), and RNase P RNA participate in maturation and modi fi cation of primary transcripts. Several other RNAs have been implicated in other cellular processes including protein transport, synthesis of telomeres, and quality control of protein biosynthesis. 217 Thus, based on the criterion of their utilization as templates in protein biosynthesis, all transcripts produced in a cell can be divided into two groups, coding and noncoding. The collective name ‘‘ noncoding RNAs ’’ (ncRNAs) may, therefore, be used to describe all transcripts or their fragments that do not constitute parts of open reading frames. According to this de fi nition ncRNAs would include all housekeeping RNAs (tRNAs, rRNAs, snRNAs, snoRNAs, etc.) as well as nonprotein-coding regions of protein-coding genes (introns, 3 0 -and 5 0 -UTRs). In this text, we use ncRNA in a narrow sense referring to RNAs with con fi rmed or suspected regulatory activity. 12.1.1 R EGULATORY RNA S For a long time it was believed that nonmessenger RNAs play only an accessory role in protein biosynthesis providing means for deciphering the genetic code and structural scaffolds of ribonu-cleoprotein particles including the ribosome. As such they could be viewed as molecular fossils preserved from the ancient RNA-world. The discovery of catalytic RNAs implicated in self-splicing of group I introns and tRNA maturation shed a new light on the role of RNAs in the cell and demonstrated that enzymatic functions are not exclusively limited to proteins [3,4].

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  RNA-seq Data Analysis

  A Practical Approach

  • Eija Korpelainen, Jarno Tuimala, Panu Somervuo, Mikael Huss, Garry Wong(Authors)
  • 2014(Publication Date)
  • Chapman and Hall/CRC

    (Publisher)

  237 C H A P T E R 12 Small Noncoding RNAs 12.1 INTRODUCTION Noncoding small RNAs are composed of multiple classes of biologically active molecules that control and modify biological functions ranging from early developmental timing to programmed cell death. They are expressed from before the first cell division to the final stages of aging. They can be found in oocytes, stem cells, neurons, glial cells, somatic cells, and also in cancer cells. Although early studies have focused on the identification and elucidation of the function of small RNAs in transla-tion (tRNAs, snoRNAs), more recent studies have placed an emphasis of noncoding RNAs that provide control or modify transcription (miRNAs, piRNAs, endo-siRNAs). Early studies have also relied heavily on tradi-tional molecular biology methods such as cloning and dideoxy sequenc-ing to identify class members. More recent RNA-seq methodologies now provide unprecedented breadth and depth for sequencing small-RNA class members. With the tremendous advancements in throughput and accuracy of next-generation sequencing methodologies, the challenge now becomes identifying, annotating, and profiling the known small RNAs and discovering the novel RNAs within a sequencing data set. Current small-RNA-seq methods do not easily discriminate between small-RNA classes, therefore knowledge of the different classes, their characteristics, and relation to one another is beneficial for planning and performing experiments aimed at identifying and quantifying members of a particular small noncoding RNA class. Below, we describe the major small noncoding RNA classes. In the descriptions, we emphasize animal 238 ◾ RNA-seq Data Analysis systems. A summary of the different classes is presented in Table 12.1. As the amount of small-RNA sequencing data available explodes upon us, it is becoming obvious that many different classes on noncoding RNA exist with new classes in the process of discovery.

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  Epigenetics in Aquaculture

  • Francesc Piferrer, Hanping Wang(Authors)
  • 2023(Publication Date)
  • Wiley

    (Publisher)

  This chapter follows the ncRNA definition by length since distinguishing categories per functionality presents difficulties due to the crossover of properties. Thus, sncRNAs are less than 200 nucleotides (nt) and are further categorized again according to their length, while long lncRNAs are noncoding transcripts with a length of more than 200 nt. Some of the best‐known and well‐studied lncRNA are shown in Figure 3.3. Major terms and ncRNA types are described in Box 3.1. 3.2 Major Types of ncRNAs 3.2.1 Small Noncoding RNA (sncRNA) The main role of sncRNAs is the regulation of gene expression through either RNA interference, RNA modification, or spliceosomal involvement. Consequently, their expression can change according to the individual’s particular condition. The most extensively studied sncRNA class is microRNAs (miRNAs) and will therefore be described in more detail within this chapter. Another upcoming popular sncRNA group discussed in more detail here is the class of P‐element‐induced wimpy testis (Piwi)‐interacting RNA (piRNA). Other sncRNA classes are the small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), transfer RNA (tRNA), and transfer RNA (tRNA)‐derived fragments (tRFs), which are shortly discussed hereafter. Figure 3.3 Schematic overview of RNA types divided into noncoding and coding RNAs. Noncoding RNA is further grouped into small noncoding RNA (sncRNA), including microRNA (miRNA), P‐element‐induced wimpy testis (Piwi)‐interacting RNA (piRNA), transfer RNA (tRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), as well as transfer RNA‐derived RNA fragments (tRFs), and long noncoding RNA (lncRNA), comprising ribosomal RNA (rRNA), circular RNA (circRNA), intergenic lncRNAs (lincRNAs), intronic lncRNAs, antisense lncRNAs (aslncRNA), bidirectional lncRNAs, and enhancer RNAs (eRNAs). Box 3.1 Major ncRNA Terms Circular RNA (circRNA): A unique type of noncoding RNA molecule

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  Post-Transcriptional Gene Regulation

  RNA Processing in Eukaryotes

  • Jane Wu(Author)
  • 2013(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  Following concepts that origin of life started from an “RNA World” [11], it is tempting to assume that the discovery of ncRNAs as well as new functions for RNA domains demonstrate an evolutionary maintained importance of RNA to biological processes. Starting originally from individual RNA molecules, RNA adopted multiple functions to act in complex organisms often in direct interaction with other RNA molecules, DNA, and proteins. We are still standing at the very beginning of getting an overview on all RNA functions, but the young field of ncRNA exploration has already made fundamental contributions to our understanding of biological processes. In this chapter, we want to provide the readers with an introduction into our present knowledge on ncRNAs, methods for ncRNA discovery, and give examples on how in particular long ncRNAs can function in the cell.

  8.2 What is ncRNA?

  In principle, ncRNA should include from our viewpoint any RNA that lacks any coding potential, is not translated into a protein or otherwise cannot be translated, or its functions are unrelated to its coding potential. Such a wide definition goes beyond the most obvious concept, that an ncRNA should per se lack any ORF. However, most primary transcripts are processed in the cell into different functional RNAs, out of which only some may act as ncRNAs. Therefore, a too strict definition of ncRNAs may ignore new concepts on how RNAs could function and possibilities for “multifunctional transcripts” derived from one gene. Ongoing efforts in RNA discovery still keep on finding new potentially noncoding transcripts, whereas genome annotations have largely underestimated the number of such genes [12–16], mostly ignoring noncoding transcripts due to their lack of CDSs and lower sequence conservation. Therefore, it is presently difficult to predict how many ncRNAs could be encoded in genomes, and what type of features they will have to group them into well-defined ncRNA families. Beyond the concept of defining ncRNA families, the community will further need to discuss how to integrate those ncRNA families into new concepts on how to define “genes” in the genome [2].

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  Epigenomics in Health and Disease

  • Mario Fraga, Agustin Fernandez Fernandez(Authors)
  • 2015(Publication Date)
  • Academic Press

    (Publisher)

  Chapter 5

  Noncoding RNA Regulation of Health and Disease

  Nicolas Léveillé1 , Carlos A. Melo1 , 2 and Sonia A. Melo3 , 4 ,    

  1 Division of Gene Regulation, The Netherlands Cancer Institute, Amsterdam, The Netherlands

  ,    

  2 Doctoral Programme in Biomedicine and Experimental Biology, Centre for Neuroscience and Cell Biology, Coimbra, Portugal

  ,    

  3 Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA

  ,    

  4 Instituto de Investigação e Inovação em Saúde and Institute of Pathology and Molecular Immunology of the University of Porto, Porto, Portugal

  Abstract

  The advent of next-generation sequencing (NSG) techniques revealed the existence of a large portion of transcribed noncoding elements in our genome. Often referred to as the “dark matter” of the genome, these noncoding RNAs (ncRNAs) have recently emerged as key players in regulatory mechanisms governing varied cellular processes. Importantly, alteration of ncRNA expression has been found in a myriad of diseases, such as diabetes, Alzheimer disease, and cancer. In addition, a growing body of evidence demonstrated the presence of ncRNAs in extracellular vesicles, which opens new disease-specific diagnostic and prognostic possibilities and promotes the potential of liquid biopsy in modern medicine. In this chapter, we review the current knowledge on noncoding RNAs and their potential as disease-associated biomarkers and highlight their future application in anticancer therapy.

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  RNA-Based Regulation in Human Health and Disease

  • (Author)
  • 2020(Publication Date)
  • Academic Press

    (Publisher)

  Interestingly, several of ncRNA genes are now known which not only function as ncRNAs but also perform additional functions through the short peptides that are produced by functional ORFs in their sequences. Such RNAs have been named as coding-non-coding or bi-functional RNAs [ 55, 248, 466, 467 ]. Some of the bacterial sRNAs, besides functioning as base pairing sRNAs, also encode a small protein with additional regulatory functions: therefore, they have also been named as dual-function RNAs [ 458 ]. Specific regions in mRNAs of typical protein coding genes can also perform independent functions by providing platform/s for binding of specific regulatory proteins which in turn would have wider implications [ 55, 248 ]. Varied and overlapping modes of actions of lncRNAs Examples of lncRNAs in diverse eukaryotes are expanding very fast. Nearly all of the newly discovered human lncRNAs are found to be associated with one or the other disease. Association of their mis-expression with disease implies that they are important for normal life of a cell or tissue so that any perturbation causes abnormality. As the above few examples illustrate, modes of actions of lncRNAs in regulatory networks are as diverse as the targets on which they act. Several lncRNAs bring about their effects through modification of the state of condensation of the entire chromosome or of a limited genomic region through their binding with specific chromatin /histone modifying protein complexes on one hand and with specific chromatin sites on the other. The latter may be achieved via a protein or direct sequence complementarity and DNA:RNA triplex formation [ 468 ]. Another set of lncRNAs provide platforms on which specific proteins, especially those with disordered domains, can associate and assemble the phase-separated liquid-droplet membrane less organelles which serve not only to compartmentalize the proteins but also to regulate their dynamic availability for activity

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  Computational Biology and Bioinformatics

  Gene Regulation

  • Ka-Chun Wong(Author)
  • 2016(Publication Date)
  • CRC Press

    (Publisher)

  Furthermore, despite the development of modern technologies, the analysis of the transcriptome by different methods and technology is primitive, as these methods do not allow full-length sequencing of all the transcripts. The identification of new ncRNAs, their interactions with other transcripts forming networks, assigning bio-logical roles to all ncRNAs coded by a genome and studying their modes of regula-tory networks is a daunting task and a significant challenge faced today. With the advent of technologies, it is expected that the rising genomics and bioinformatics approaches will help in uncovering and deciphering their functionality. The construction of a disease-specific ncRNA-mediated regulatory network requires proper understanding of biological meaning of the data to be used, associat-ing appropriate regulatory interactions and their accurate data mining. Apart from these, an extensive functional annotation of the generated network as well as appro-priate integration of inter-disciplinary approaches will also significantly add to the understanding of network biology. References Agostini, F., Zanzoni, A., Klus, P., Marchese, D., Cirillo, D., and G.G. Tartaglia, 2013. catRAPID omics: a web server for large-scale prediction of protein-RNA interac-tions. Bioinformatics 29, 2928-2930. Aguda, B.D., Kim, Y., Piper-Hunter, M.G., Friedman, A., and C.B. Marsh, 2008. MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proc Natl Acad Sci U S A 105, 19678-19683. Ambros, V. 2008. The evolution of our thinking about microRNAs. Nat Med 14, 1036-1040. Angeli, D., Ferrell, J.E., Jr., and E.D. Sontag, 2004. Detection of multistability, bifurca-tions, and hysteresis in a large class of biological positive-feedback systems. Proc Natl Acad Sci U S A 101, 1822-1827. Bachellerie, J.P., Cavaille, J., and A. Huttenhofer, 2002. The expanding snoRNA world. Biochimie 84, 775-790.

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  Epigenetic Gene Expression and Regulation

  • Suming Huang, Michael D. Litt, C. Ann Blakey, Michael D Litt(Authors)
  • 2015(Publication Date)
  • Academic Press

    (Publisher)

  2] . These numbers vary, but reports indicate as much as 75% of the human genome is transcribed. The expansive transcriptome, as it can be referred, is also a fact for most commonly used model organisms throughout the biomedical research community. This pervasive transcription has led to a series of questions: do these RNAs code for a protein, what is the biological function of these RNAs, if any, and what is the molecular mechanism by which these RNAs execute that function? The majority of these newly discovered RNA molecules do not have any identifiable open reading frame, do not associate with the ribosomes, and many are nuclear localized. Thus, the consensus is that these represent noncoding RNAs (ncRNAs).

  In spite of the power of high-throughput sequencing to promote the discovery of newly identified biological molecules, the most well understood of these ncRNAs that affect chromatin structure were discovered without the aid of high-throughput DNA sequencing. These two very different ncRNAs are Xist and siRNAs. Xist was originally discovered in the early 1990s and is shown to be an ncRNA required for maintaining a silent X chromosome in mammals [3 –6] . This long ncRNA (17  kb in humans and 15  kb in mice) functions by coating the silent X chromosome and recruiting factors that promote heterochromatin.

  The other well-studied ncRNA was discovered using the model systems Arabidopsis thaliana and Caenorhabditis elegans . Using these genetic models, the observation was made that transgenes containing a high degree of homology to an endogenous gene were being transcriptionally silenced [7 –9] . Interestingly, this silencing extended to the endogenous counterpart of the transgene. The mechanism by which these genes were being silenced was ultimately shown to be due to the action of small RNAs, spanning 21–24 nucleotides in length. These were named small interfering RNAs (siRNAs), and the mechanism by which they silenced both the transgene and its endogenous counterpart in C. elegans was termed RNA interference (RNAi). The mechanism, as it was originally understood, acted to degrade the messenger RNA (mRNA) of these genes posttranscriptionally. This type of RNAi does not involve changes to chromatin structure. However, later work in another model organism, Schizosaccharomyces pombe , identified the RNAi machinery as being critical for the establishment and maintenance of heterochromatin at the centromere [10 ,11] . Over the past decade, the ability of the RNAi machinery to regulate chromatin structure has been extended to include regulation of genomic regions other than the centromere, and has also been extended to flies, mice, and humans [12]

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  Genome Organization And Function In The Cell Nucleus

  • Karsten Rippe(Author)
  • 2012(Publication Date)
  • Wiley-VCH

    (Publisher)

  Figure 13.6a ).

  2. The ncRNA targets the transcriptional machinery or recruits a regulatory factor (Figure 13.6b ).

  3. They may also affect downstream processes such as splicing, nuclear export and mRNA stability (Figure 13.6b ).

  4. The ncRNA regulates nucleosome structure (Figure 13.6c ).

  5. The ncRNA regulates the higher order chromatin organization and nuclear localization (Figure 13.6d ) of its target and thereby influences gene expression.

  Table 13.1 Mechanisms of gene regulation by small and long Non-Coding RNAs.

  ncRNA	Description of proposed mode of action	Reference
  Transcription itself has regulatory function
  Yeast PHO5 and SER3 upstream transcripts	Transcription of nc RNA changes chromatin plasticitiy	[183, 184]
  β-Globin region, Ig-heavy chain V region	DNA becomes accessible to binding proteins	[185, 186]
  Tsix-mediated Xist regulation	Readthrough of Xist gene/promoter leads to altered chromatin and Xist repression	[160–162]
  Hox genes	Continuous transcription prevents heterochromatin formation	[177, 178, 180]
  Imprinted genes	Transcription through regulatory region results in altered binding/activity of activating/repressing factors	[187]
  Yeast fbp1+locus upsteam transcript	Opening chromatin in fbp1+locus allowing accessibility	[188]
  Interaction with the transcription machinery or recruitment of regulatory factors
  Exogenous siRNAs to initiation sites	Inhibition of RNAP II binding to TATA box	[110–112]
  siRNAs	Inhibition of RNAP II elongation in C. elegans

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  Oncogene and Cancer

  From Bench to Clinic

  • Yahwardiah Siregar(Author)
  • 2013(Publication Date)
  • IntechOpen

    (Publisher)

  It has also been discovered that lincRNA-p21 interacts with hnRNPK and this binding is essential for the modulation of p53 activity. The final category of lncRNAs is represented by those molecules capable to generate the formation of compartmentalized nuclear organelles, subnuclear membraneless nuclear bodies whose funtion is relative unknown. One of them is represented by cell-cycle regulated nuclear foci, named paraspeckles. In addition to protein components, two lncRNAs, NEAT1 and Men epsilon, have been detected as essential part of the paraspeckles. While depletion of NEAT or Men epsilon disrupts the paraspeckles, their overexpression strongly increases their number. There is a number of different lncRNAs that localize to different nuclear regions [204]. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) localizes to the splicing speckles, Xist and Kcnq1ot1 both, localize to the perinucleolar region during the S phase of the cell cycle, a class of repeat-associated lncRNAs (es SatIII) are associated to nuclear stress bodies which are produced on specifc pericentromeric heterochromatic domains containing SatIII gene itself. 9. Conclusions Alterations in microRNAs and other short or long Non-Coding RNA (ncRNA) are involved in the initiation, progression, and metastasis of human cancer. Over the last decade, a growing number of non-coding transcripts have been found to have roles in gene regulation and RNA processing. The most well known small Non-Coding RNAs are the microRNAs, but the network of long and short non-coding transcripts is complex and is likely to contain as yet unidentified classes of molecules that form transcriptional regulatory networks. The field of small and long non coding RNAs is rapidly advancing toward in vivo delivery for therapeutic purposes. Advanced molecular therapies aimed at downmodulating or upmodulating the level of a given miRNA in model organisms have been successfully established.

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