Noncoding RNAs in Biology and Disease

Abstract

Regulatory noncoding ribonucleic acids (ncRNAs) play a pivotal role in the control of gene expression in all organisms. The molecular processes controlled by ncRNAs include virtually all steps of transmission of genetic information from deoxyribonucleic acid (DNA) to protein. They affect the structure of chromatin, activity of transcription factors, posttranscriptional modifications and the stabilty of RNA. In mammals, noncoding transcripts have been linked to regulation of many cellular mechanisms and their proper expression is crucial for normal development, growth differentiation and the maintenance of cells identity. Epigenetic and genetic aberrations disrupting ncRNA genes or changing their expression profiles often result in pathologies including developmental defects, neurobehavioural illness, cancer and other diseases. The progress in identification of novel RNA‚Äźdependent molecular mechanisms and their medical implications makes ncRNAs attractive targets for development of new diagnostic and therapeutic approaches.

Key Concepts

  • Noncoding RNAs (ncRNAs) constitute a significant fraction of a total transcription from the human genome.

  • NcRNAs are key factors in setting up and maintaining epigenetic marks that are crucial for correct expression of genetic information.

  • NcRNAs regulate expression of genes by influencing the activity of transcriptional machinery.

  • The stability and translation of numerous mRNAs involved in cells growth and proliferation is controlled by microRNAs.

  • Correct expression of imprinted gene clusters depends on chromatin modifications guided by ncRNAs.

  • Aberrant expression of ncRNAs is often associated with human diseases.

  • Expression profiles of ncRNAs provide valuable information for molecular diagnostics.

Keywords: noncoding RNAs; riboregulators; cancer; imprinting; epigenetics

Figure 1.

The flow of genetic information (black arrows) and the regulatory interactions with noncoding RNAs (red arrows).

close

References

Adams BD, Furneaux H and White BA (2007) The micro‐ribonucleic acid (miRNA) miR‐206 targets the human estrogen receptor‐alpha (ERα) and represses ERα messenger RNA and protein expression in breast cancer cell lines. Molecular Endocrinology 21: 1132–1147.

Barrandon C, Spiluttini B and Bensaude O (2008) Non‐coding RNAs regulating the transcriptional machinery. Biology of the Cell 100: 83–95.

Blenkiron C and Miska EA (2007) miRNAs in cancer: approaches, aetiology, diagnostics and therapy. Human Molecular Genetics 16(Spec no 1): R106–R113.

Cai X and Cullen BR (2007) The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA 13: 313–316.

Calin GA, Sevignani C, Dumitru CD et al. (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences of the USA 101: 2999–3004.

Callis TE and Wang DZ (2008) Taking microRNAs to heart. Trends in Molecular Medicine 14: 254–260.

Carninci P and Hayashizaki Y (2007) Noncoding RNA transcription beyond annotated genes. Current Opinion in Genet Development 17: 139–144.

Chen K and Rajewsky N (2007) The evolution of gene regulation by transcription factors and microRNAs. Nature Reviews. Genetics 8: 93–103.

Chendrimada TP, Finn KJ, Ji X et al. (2007) MicroRNA silencing through RISC recruitment of eIF6. Nature 447: 823–828.

Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ and Millar JK (2008) The DISC locus in psychiatric illness. Molecular Psychiatry 13: 36–64.

Cimmino A, Calin GA, Fabbri M et al. (2005) miR‐15 and miR‐16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the USA 102: 13944–13949.

Dahm R, Kiebler M and Macchi P (2007) RNA localisation in the nervous system. Seminars in Cell & Developmental Biology 18: 216–223.

Dieci G, Fiorino G, Castelnuovo M, Teichmann M and Pagano A (2007) The expanding RNA polymerase III transcriptome. Trends in Genetics 23: 614–622.

Fu X, Ravindranath L, Tran N, Petrovics G and Srivastava S (2006) Regulation of apoptosis by a prostate‐specific and prostate cancer‐associated noncoding gene, PCGEM1. DNA and Cell Biology 25: 135–141.

Hagan JP and Croce CM (2007) MicroRNAs in carcinogenesis. Cytogenetic and Genome Research 118: 252–259.

Hennessy E and O'Driscoll L (2008) Molecular medicine of microRNAs: structure, function and implications for diabetes. Expert Reviews in Molecular Medicine 10: e24.

Hon LS and Zhang Z (2007) The roles of binding site arrangement and combinatorial targeting in microRNA repression of gene expression. Genome Biology 8: R166.

Hutchinson JN, Ensminger AW, Clemson CM et al. (2007) A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 8: 39.

Imamura T, Yamamoto S, Ohgane J et al. (2004) Non‐coding RNA directed DNA demethylation of Sphk1 CpG island. Biochemical and Biophysical Research Communications 322: 593–600.

Ivanovska I, Ball AS, Diaz RL et al. (2008) MicroRNAs in the miR‐106b family regulate p21/CDKN1A and promote cell cycle progression. Molecular and Cellular Biology 28: 2167–2174.

Ji P, Diederichs S, Wang W et al. (2003) MALAT‐1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early stage non‐small cell lung cancer. Oncogene 22: 8031–8041.

Kaneko S, Aki I, Tsuda K et al. (2006) Origin and evolution of processed pseudogenes that stabilize functional Makorin1 mRNAs in mice, primates and other mammals. Genetics 172: 2421–2429.

Kent OA and Mendell JT (2006) A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 25: 6188–6196.

Kiriakidou M, Tan GS, Lamprinaki S et al. (2007) An mRNA m7G cap binding‐like motif within human Ago2 represses translation. Cell 129: 1141–1151.

Kumar MS, Lu J, Mercer KL, Golub TR and Jacks T (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nature Genetics 39: 673–677.

Kuwabara T, Hsieh J, Nakashima K, Taira K and Gage FH (2004) A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116: 779–793.

Lalande M and Calciano MA (2007) Molecular epigenetics of Angelman syndrome. Cellular and Molecular Life Sciences 64: 947–960.

Leygue E (2007) Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer. Nuclear Receptor Signaling 5: e006.

Lin R, Maeda S, Liu C, Karin M and Edgington TS (2007) A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 26: 851–858.

Linsley PS, Schelter J, Burchard J et al. (2007) Transcripts targeted by the microRNA‐16 family cooperatively regulate cell cycle progression. Molecular and Cellular Biology 27: 2240–2252.

Liu J (2008) Control of protein synthesis and mRNA degradation by microRNAs. Current Opinion in Cell Biology 20: 214–221.

Lu J, Getz G, Miska EA et al. (2005) MicroRNA expression profiles classify human cancers. Nature 435: 834–838.

Lu Z, Liu M, Stribinskis V et al. (2008) MicroRNA‐21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene 27: 4373–4379.

Mariner PD, Walters RD, Espinoza CA et al. (2008) Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock. Molecular Cell 29: 499–509.

Mattes J, Collison A and Foster PS (2008) Emerging role of microRNAs in disease pathogenesis and strategies for therapeutic modulation. Current Opinion in Molecular Therapy 10: 150–157.

Mattick JS and Makunin IV (2006) Non‐coding RNA. Human Molecular Genetics 15(Spec No 1): R17–R29.

Meng F, Henson R, Wehbe‐Janek H et al. (2007) MicroRNA‐21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133: 647–658.

Peterlin BM and Price DH (2006) Controlling the elongation phase of transcription with P‐TEFb. Molecular Cell 23: 297–305.

Pizzuti A, Novelli G, Ratti A et al. (1999) Isolation and characterization of a novel transcript embedded within HIRA, a gene deleted in DiGeorge syndrome. Molecular Genetics and Metabolism 67: 227–235.

Royo H and Cavaillé J (2008) Non‐coding RNAs in imprinted gene clusters. Biology of the Cell 100: 149–166.

Rump P, Zeegers MP and van Essen AJ (2005) Tumor risk in Beckwith‐Wiedemann syndrome: a review and meta‐analysis. American Journal of Medical Genetics Part A 136: 95–104.

Sasaki YT, Sano M, Ideue T et al. (2007) Identification and characterization of human non‐coding RNAs with tissue‐specific expression. Biochemical and Biophysical Research Communications 357: 991–996.

Sonkoly E, Ståhle M and Pivarcsi A (2008) MicroRNAs: novel regulators in skin inflammation. Clinical and Experimental Dermatology 33: 312–315.

Sutherland HF, Wadey R, McKie JM et al. (1996) Identification of a novel transcript disrupted by a balanced translocation associated with DiGeorge syndrome. American Journal of Human Genetics 59: 23–31.

Szymanski M, Barciszewska MZ, Erdmann VA and Barciszewski J (2005) A new frontier for molecular medicine: noncoding RNAs. Biochimica et Biophysica Acta 1756: 65–75.

Tsang WP, Wong TW, Cheung AH, Co CN and Kwok TT (2007) Induction of drug resistance and transformation in human cancer cells by the noncoding RNA CUDR. RNA 13: 890–898.

Vincent JB, Petek E, Thevarkunnel S et al. (2002) The RAY1/ST7 tumor‐suppressor locus on chromosome 7q31 represents a complex multi‐transcript system. Genomics 80: 283–294.

Walter J and Paulsen M (2003) Imprinting and disease. Seminars in Cell & Developmental Biology 14: 101–110.

Wang H, Iacoangeli A, Popp S et al. (2002) Dendritic BC1 RNA: functional role in regulation of translation initiation. Journal of Neuroscience 22: 10232–10241.

Wentzensen N, Coy JF, Knaebel HP et al. (2007) Expression of an endogenous retroviral sequence from the HERV‐H group in gastrointestinal cancers. International Journal of Cancer 121: 1417–1423.

Wu J, Qin Y, Li B, He WZ and Sun ZL (2008) Hypomethylated and hypermethylated profiles of H19DMR are associated with the aberrant imprinting of IGF2 and H19 in human hepatocellular carcinoma. Genomics 91: 443–450.

Zhu S, Si ML, Wu H and Mo YY (2007) MicroRNA‐21 targets the tumor suppressor gene tropomyosin 1 (TPM1). Journal of Biological Chemistry 282: 14328–14336.

Further Reading

Clark SJ (2007) Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis. Human Molecular Genetics 16(Spec No 1): R88–R95.

Costa FF (2008) Non‐coding RNAs, epigenetics and complexity. Gene 410: 9–17.

Liu J (2008) Control of protein synthesis and mRNA degradation by microRNAs. Current Opinion in Cell Biology 20: 214–221.

Mattick JS (2003) Introns and noncoding RNAs the hidden layer of eukaryotic complexity. In: Barciszewski J and Erdmann VA (eds), Noncoding RNAs: Molecular Biology and Molecular Medicine, pp. 12–33. Georgetown, TX: Landes Bioscience.

Papagiannakopoulos T and Kosik KS (2008) MicroRNAs: regulators of oncogenesis and stemness. BMC Medicine 6: 15.

Stenvang J and Kauppinen S (2008) MicroRNAs as targets for antisense‐based therapeutics. Expert Opinion on Biological Therapy 8: 59–81.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Szymański, Maciej, and Barciszewski, Jan(Mar 2009) Noncoding RNAs in Biology and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021437]