Small noncoding RNAs: Biogenesis, function, and emerging significance in toxicology

In recent years, the discovery of small ncRNAs (noncoding RNAs) has unveiled a slew of powerful riboregulators of gene expression. So far, many different types of small ncRNAs have been described. Of these, miRNAs (microRNAs), siRNAs (small interfering RNAs), and piRNAs (Piwi‐interacting RNAs) have been studied in more detail. A significant fraction of genes in most organisms and tissues is targets of these small ncRNAs. Because these tiny RNAs are turning out to be important regulators of gene and genome expression, their aberrant expression profiles are expected to be associated with cellular dysfunction and disease. In fact, an ever‐increasing number of studies have implicated miRNAs and siRNAs in human health and disease ranging from metabolic disorders to diseases of various organ systems as well as various forms of cancer. Nevertheless, despite the flurry of research on these small ncRNAs, many aspects of their biology still remain to be understood. The following discussion focuses on some aspects of the biogenesis and function of small ncRNAs with major emphasis on miRNAs since these are the most widespread endogenous small ncRNAs that have been called “micromanagers” of gene expression. Their emerging significance in toxicology is also discussed. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:195–216, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20325

[1]  S. Choudhuri,et al.  Usefulness of studies on the molecular mechanism of action of herbals/botanicals: The case of St. John's wort , 2005, Journal of biochemical and molecular toxicology.

[2]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Jef D. Boeke,et al.  Mighty Piwis Defend the Germline against Genome Intruders , 2007, Cell.

[4]  C. Croce,et al.  MiR-15a and miR-16-1 cluster functions in human leukemia , 2008, Proceedings of the National Academy of Sciences.

[5]  T. Du,et al.  Asymmetry in the Assembly of the RNAi Enzyme Complex , 2003, Cell.

[6]  A. Pasquinelli,et al.  Genes and Mechanisms Related to RNA Interference Regulate Expression of the Small Temporal RNAs that Control C. elegans Developmental Timing , 2001, Cell.

[7]  Byoung-Tak Zhang,et al.  Molecular Basis for the Recognition of Primary microRNAs by the Drosha-DGCR8 Complex , 2006, Cell.

[8]  Carola Berking,et al.  Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer , 2008, Cell cycle.

[9]  E. Conti,et al.  Dicer measures up , 2006, Nature Structural &Molecular Biology.

[10]  R. Lehmann,et al.  Targeted mRNA degradation by double-stranded RNA in vitro. , 1999, Genes & development.

[11]  C. Napoli,et al.  Introduction of a Chimeric Chalcone Synthase Gene into Petunia Results in Reversible Co-Suppression of Homologous Genes in trans. , 1990, The Plant cell.

[12]  Kevin J Luebke,et al.  Faculty Opinions recommendation of The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. , 2009 .

[13]  A. Pasquinelli,et al.  A Cellular Function for the RNA-Interference Enzyme Dicer in the Maturation of the let-7 Small Temporal RNA , 2001, Science.

[14]  Tariq M Rana,et al.  Small RNAs: Regulators and guardians of the genome , 2007, Journal of cellular physiology.

[15]  T. Tuschl,et al.  Identification of Novel Genes Coding for Small Expressed RNAs , 2001, Science.

[16]  Cheng Zhu,et al.  The role of microRNAs in copper and cadmium homeostasis. , 2009, Biochemical and biophysical research communications.

[17]  Isabelle Behm-Ansmant,et al.  P-Body Formation Is a Consequence, Not the Cause, of RNA-Mediated Gene Silencing , 2007, Molecular and Cellular Biology.

[18]  E. Sontheimer,et al.  Distinct Roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA Silencing Pathways , 2004, Cell.

[19]  O. Kovalchuk,et al.  Induction of microRNAome deregulation in rat liver by long-term tamoxifen exposure. , 2007, Mutation research.

[20]  N. Grishin,et al.  C3PO, an Endoribonuclease That Promotes RNAi by Facilitating RISC Activation , 2009, Science.

[21]  Eric Westhof,et al.  Single Processing Center Models for Human Dicer and Bacterial RNase III , 2004, Cell.

[22]  Lin He,et al.  The guardian's little helper: microRNAs in the p53 tumor suppressor network. , 2007, Cancer research.

[23]  H. Yamada,et al.  Changes of micro-RNA expression in rat liver treated by acetaminophen or carbon tetrachloride--regulating role of micro-RNA for RNA expression. , 2007, The Journal of toxicological sciences.

[24]  Thomas Tuschl,et al.  The growing catalog of small RNAs and their association with distinct Argonaute/Piwi family members , 2008, Development.

[25]  Katsutomo Okamura,et al.  The evolution and functional diversification of animal microRNA genes , 2008, Cell Research.

[26]  A. Hudder,et al.  miRNAs: effectors of environmental influences on gene expression and disease. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[27]  R. Firth Function , 1955, Yearbook of Anthropology.

[28]  Julius Brennecke,et al.  Specialized piRNA Pathways Act in Germline and Somatic Tissues of the Drosophila Ovary , 2009, Cell.

[29]  A. Armugam,et al.  MicroRNAs: biogenesis, function and applications. , 2009, Current opinion in molecular therapeutics.

[30]  N. Lau,et al.  Characterization of the piRNA Complex from Rat Testes , 2006, Science.

[31]  E. Lai,et al.  The Mirtron Pathway Generates microRNA-Class Regulatory RNAs in Drosophila , 2007, Cell.

[32]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[33]  J. Mol,et al.  Flavonoid genes in petunia: addition of a limited number of gene copies may lead to a suppression of gene expression. , 1990, The Plant cell.

[34]  Phillip D Zamore,et al.  Perspective: machines for RNAi. , 2005, Genes & development.

[35]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

[36]  D. Tollervey,et al.  Function and synthesis of small nucleolar RNAs. , 1997, Current opinion in cell biology.

[37]  Augustine E. Souza,et al.  The guide RNA database , 1998, Nucleic Acids Res..

[38]  D. Barlow,et al.  Quantitative genetics: Turning up the heat on QTL mapping , 2002, Nature Reviews Genetics.

[39]  T. Gant,et al.  Emerging fundamental roles for non-coding RNA species in toxicology. , 2008, Toxicology.

[40]  R. Weinberg,et al.  Micromanagers of malignancy: role of microRNAs in regulating metastasis. , 2008, Trends in genetics : TIG.

[41]  T. Tuschl,et al.  Mechanisms of gene silencing by double-stranded RNA , 2004, Nature.

[42]  D. Marks,et al.  The small RNA profile during Drosophila melanogaster development. , 2003, Developmental cell.

[43]  V. Ambros,et al.  An Extensive Class of Small RNAs in Caenorhabditis elegans , 2001, Science.

[44]  B. Cullen,et al.  The imprinted H19 noncoding RNA is a primary microRNA precursor. , 2007, RNA.

[45]  Kathryn A. O’Donnell,et al.  Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model , 2009, Cell.

[46]  H. Lodish,et al.  MicroRNA-125b is a novel negative regulator of p53. , 2009, Genes & development.

[47]  John G Doench,et al.  Specificity of microRNA target selection in translational repression. , 2004, Genes & development.

[48]  Kuniaki Saito,et al.  A Slicer-Mediated Mechanism for Repeat-Associated siRNA 5' End Formation in Drosophila , 2007, Science.

[49]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[50]  V. Kim,et al.  Biogenesis of small RNAs in animals , 2009, Nature Reviews Molecular Cell Biology.

[51]  Akira Ishizuka,et al.  Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. , 2004, Genes & development.

[52]  Karl T Kelsey,et al.  MicroRNA responses to cellular stress. , 2006, Cancer research.

[53]  S. Hammond,et al.  An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells , 2000, Nature.

[54]  Shingo Takagi,et al.  Post-transcriptional Regulation of Human Pregnane X Receptor by Micro-RNA Affects the Expression of Cytochrome P450 3A4* , 2008, Journal of Biological Chemistry.

[55]  Theresa A. Storm,et al.  Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways , 2006, Nature.

[56]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[57]  Vladimir Gvozdev,et al.  A Distinct Small RNA Pathway Silences Selfish Genetic Elements in the Germline , 2006, Science.

[58]  D. Bartel,et al.  Intronic microRNA precursors that bypass Drosha processing , 2007, Nature.

[59]  Olivier Voinnet,et al.  The diversity of RNA silencing pathways in plants. , 2006, Trends in genetics : TIG.

[60]  Yukihide Tomari,et al.  piRNAs--the ancient hunters of genome invaders. , 2007, Genes & development.

[61]  Chang-Zheng Chen,et al.  MicroRNAs as oncogenes and tumor suppressors. , 2005, The New England journal of medicine.

[62]  R. Miranda,et al.  Competing Interactions between Micro-RNAs Determine Neural Progenitor Survival and Proliferation after Ethanol Exposure: Evidence from an Ex Vivo Model of the Fetal Cerebral Cortical Neuroepithelium , 2007, The Journal of Neuroscience.

[63]  Thomas Tuschl,et al.  Identification and characterization of small RNAs involved in RNA silencing , 2005, FEBS letters.

[64]  T. Tuschl,et al.  RNA interference is mediated by 21- and 22-nucleotide RNAs. , 2001, Genes & development.

[65]  G. Macino,et al.  Post-transcriptional gene silencing across kingdoms. , 2000, Current opinion in genetics & development.

[66]  G. Hannon,et al.  The Piwi-piRNA Pathway Provides an Adaptive Defense in the Transposon Arms Race , 2007, Science.

[67]  Kuniaki Saito,et al.  Pimet, the Drosophila homolog of HEN1, mediates 2'-O-methylation of Piwi- interacting RNAs at their 3' ends. , 2007, Genes & development.

[68]  Baohong Zhang,et al.  RDX Induces Aberrant Expression of MicroRNAs in Mouse Brain and Liver , 2008, Environmental health perspectives.

[69]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[70]  G. Dreyfuss,et al.  Ribonucleoprotein particles in cellular processes , 1988, The Journal of cell biology.

[71]  B. Davidson,et al.  RNA polymerase III transcribes human microRNAs , 2006, Nature Structural &Molecular Biology.

[72]  Wei Yan,et al.  Tissue-dependent paired expression of miRNAs , 2007, Nucleic acids research.

[73]  F. Guo,et al.  MicroRNA biogenesis: there's more than one way to skin a cat. , 2008, Biochimica et biophysica acta.

[74]  U. Bhadra,et al.  MicroRNAs – micro in size but macro in function , 2008, The FEBS journal.

[75]  K. Morimura,et al.  Peroxisome Proliferator-Activated Receptor α Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation , 2007, Molecular and Cellular Biology.

[76]  E. Memili,et al.  Murine Xist RNA isoforms are different at their 3' ends: a role for differential polyadenylation. , 2001, Gene.

[77]  Zissimos Mourelatos,et al.  An mRNA m 7 G Cap Binding-like Motif withinHumanAgo2RepressesTranslation , 2007 .

[78]  Shingo Takagi,et al.  MicroRNA regulates the expression of human cytochrome P450 1B1. , 2006, Cancer research.

[79]  Anastasia Khvorova,et al.  Off-target effects by siRNA can induce toxic phenotype. , 2006, RNA.

[80]  A. Caudy,et al.  Role for a bidentate ribonuclease in the initiation step of RNA interference , 2001 .

[81]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[82]  P. Boutros,et al.  microRNAs in adult rodent liver are refractory to dioxin treatment. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[83]  R. Carthew,et al.  Use of dsRNA-Mediated Genetic Interference to Demonstrate that frizzled and frizzled 2 Act in the Wingless Pathway , 1998, Cell.

[84]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[85]  P. Zamore,et al.  Small silencing RNAs: an expanding universe , 2009, Nature Reviews Genetics.

[86]  E. Izaurralde,et al.  A C-terminal silencing domain in GW182 is essential for miRNA function. , 2009, RNA.

[87]  T. Tuschl,et al.  Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells , 2001, Nature.

[88]  Mikiko C. Siomi,et al.  The Discovery of Rna Interference (rnai) Biogenesis of Small Rnas on the Road to Reading the Rna-interference Code Insight Review , 2022 .

[89]  E. Sontheimer,et al.  Origins and Mechanisms of miRNAs and siRNAs , 2009, Cell.

[90]  C. Sander,et al.  A novel class of small RNAs bind to MILI protein in mouse testes , 2006, Nature.

[91]  C. Guthrie,et al.  Spliceosomal snRNAs. , 1988, Annual review of genetics.

[92]  M. Zavolan,et al.  miRNA in situ hybridization in formaldehyde and EDC–fixed tissues , 2009, Nature Methods.

[93]  M. Kiriakidou,et al.  An mRNA m7G Cap Binding-like Motif within Human Ago2 Represses Translation , 2007, Cell.

[94]  A. Reynolds,et al.  Rational siRNA design for RNA interference , 2004, Nature Biotechnology.

[95]  L. Lim,et al.  An Abundant Class of Tiny RNAs with Probable Regulatory Roles in Caenorhabditis elegans , 2001, Science.

[96]  B. Reinhart,et al.  Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA , 2000, Nature.

[97]  Z. Weng,et al.  Collapse of Germline piRNAs in the Absence of Argonaute3 Reveals Somatic piRNAs in Flies , 2009, Cell.

[98]  P. Sharp,et al.  RNAi Double-Stranded RNA Directs the ATP-Dependent Cleavage of mRNA at 21 to 23 Nucleotide Intervals , 2000, Cell.

[99]  Eugene Berezikov,et al.  Mammalian mirtron genes. , 2007, Molecular cell.

[100]  Manolis Kellis,et al.  Discrete Small RNA-Generating Loci as Master Regulators of Transposon Activity in Drosophila , 2007, Cell.

[101]  Gunter Meister,et al.  miRNAs Get an Early Start on Translational Silencing , 2007, Cell.

[102]  M. Carmell,et al.  Posttranscriptional Gene Silencing in Plants , 2006 .

[103]  Peng Li,et al.  Teratogenic effects of sodium thiosulfate on developing zebrafish embryos. , 2009, Frontiers in bioscience.

[104]  Hiroshi I. Suzuki,et al.  Modulation of microRNA processing by p53 , 2009, Nature.