MicroRNA-Mediated Obstruction of Stem-loop Alternative Splicing (MIMOSAS): a global mechanism for the regulation of alternative splicing

While RNA secondary structures are critical to regulate alternative splicing of long-range pre-mRNA, the factors that modulate RNA structure and interfere with the recognition of the splice sites are largely unknown. Previously, we identified a small, non-coding microRNA that sufficiently affects stable stem structure formation of Nmnat pre-mRNA to regulate the outcomes of alternative splicing. However, the fundamental question remains whether such microRNA-mediated interference with RNA secondary structures is a global molecular mechanism for regulating mRNA splicing. We designed and refined a bioinformatic pipeline to predict candidate microRNAs that potentially interfere with pre-mRNA stem-loop structures, and experimentally verified splicing predictions of three different long-range pre-mRNAs in the Drosophila model system. Specifically, we observed that microRNAs can either disrupt or stabilize stem-loop structures to influence splicing outcomes. Our study suggests that MicroRNA-Mediated Obstruction of Stem-loop Alternative Splicing (MIMOSAS) is a novel regulatory mechanism for the transcriptome-wide regulation of alternative splicing, increases the repertoire of microRNA function and further indicates cellular complexity of post-transcriptional regulation. One-Sentence Summary MicroRNA-Mediated Obstruction of Stem-loop Alternative Splicing (MIMOSAS) is a novel regulatory mechanism for the transcriptome-wide regulation of alternative splicing.

[1]  M. Ladomery,et al.  Epigenetic Regulation of Alternative Splicing: How LncRNAs Tailor the Message , 2021, Non-coding RNA.

[2]  Changwei Lin,et al.  Noncoding RNAs regulate alternative splicing in Cancer , 2021, Journal of experimental & clinical cancer research : CR.

[3]  Dmitri D. Pervouchine,et al.  Conserved long-range base pairings are associated with pre-mRNA processing of human genes , 2020, Nature Communications.

[4]  S. Wuchty,et al.  MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing , 2019, bioRxiv.

[5]  I. MacRae,et al.  Regulation of microRNA function in animals , 2018, Nature Reviews Molecular Cell Biology.

[6]  C. Peng,et al.  Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation , 2018, Front. Endocrinol..

[7]  Hyoung-Kyu kim,et al.  Alternative splicing isoforms in health and disease , 2018, Pflügers Archiv - European Journal of Physiology.

[8]  Sunantha Sethuraman,et al.  Modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH) Identifies Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Targets in Endothelial Cells , 2018, Journal of Virology.

[9]  K. Neugebauer,et al.  Splicing and transcription touch base: co-transcriptional spliceosome assembly and function , 2017, Nature Reviews Molecular Cell Biology.

[10]  Anne-Claude Gingras,et al.  Regulatory Expansion in Mammals of Multivalent hnRNP Assemblies that Globally Control Alternative Splicing , 2017, Cell.

[11]  M. Leonetti,et al.  Improved split fluorescent proteins for endogenous protein labeling , 2017, bioRxiv.

[12]  Ritika Giri,et al.  MicroRNA function in Drosophila melanogaster. , 2017, Seminars in cell & developmental biology.

[13]  Araxi O. Urrutia,et al.  Alternative splicing and the evolution of phenotypic novelty , 2016, Philosophical Transactions of the Royal Society B: Biological Sciences.

[14]  P. Stadler,et al.  RNA folding with hard and soft constraints , 2016, Algorithms for Molecular Biology.

[15]  R. Zhai,et al.  Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress , 2015, Nature Communications.

[16]  D. Corey,et al.  Modulation of Splicing by Single-Stranded Silencing RNAs. , 2015, Nucleic acid therapeutics.

[17]  R. F. Luco,et al.  A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature , 2015, Nature Structural &Molecular Biology.

[18]  Araxi O. Urrutia,et al.  Correcting for Differential Transcript Coverage Reveals a Strong Relationship between Alternative Splicing and Organism Complexity , 2014, Molecular biology and evolution.

[19]  D. Tollervey,et al.  Mapping the Human miRNA Interactome by CLASH Reveals Frequent Noncanonical Binding , 2013, Cell.

[20]  Annick Harel-Bellan,et al.  Argonaute proteins couple chromatin silencing to alternative splicing , 2012, Nature Structural &Molecular Biology.

[21]  P. Stadler,et al.  ViennaRNA Package 2.0 , 2011, Algorithms for Molecular Biology : AMB.

[22]  D. Cooper,et al.  Loss of exon identity is a common mechanism of human inherited disease. , 2011, Genome research.

[23]  D. Corey,et al.  Expanding the action of duplex RNAs into the nucleus: redirecting alternative splicing , 2011, Nucleic acids research.

[24]  Benjamin J. Raphael,et al.  Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes , 2011, Proceedings of the National Academy of Sciences.

[25]  J. Steitz,et al.  Posttranscriptional activation of gene expression in Xenopus laevis oocytes by microRNA–protein complexes (microRNPs) , 2011, Proceedings of the National Academy of Sciences.

[26]  Yongfeng Jin,et al.  New insights into RNA secondary structure in the alternative splicing of pre-mRNAs , 2011, RNA biology.

[27]  S. Cook,et al.  MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. , 2010, Cardiovascular research.

[28]  A. Riggs,et al.  CRM1 mediates nuclear-cytoplasmic shuttling of mature microRNAs , 2009, Proceedings of the National Academy of Sciences.

[29]  Li-Na Wei,et al.  MicroRNA mir-346 targets the 5'-untranslated region of receptor-interacting protein 140 (RIP140) mRNA and up-regulates its protein expression. , 2009, The Biochemical journal.

[30]  J. Rubio,et al.  Splicing, cis genetic variation and disease. , 2009, Biochemical Society transactions.

[31]  Karsten König,et al.  Trafficking of mature miRNA-122 into the nucleus of live liver cells. , 2009, Current pharmaceutical biotechnology.

[32]  P. Tam.  Faculty Opinions recommendation of miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. , 2009 .

[33]  Manuel de la Mata,et al.  Control of alternative splicing through siRNA-mediated transcriptional gene silencing , 2009, Nature Structural &Molecular Biology.

[34]  Mikhail S. Gelfand,et al.  Modulation of alternative splicing by long-range RNA structures in Drosophila , 2009, Nucleic acids research.

[35]  Petra Schwille,et al.  Importin 8 Is a Gene Silencing Factor that Targets Argonaute Proteins to Distinct mRNAs , 2009, Cell.

[36]  V. Scaria,et al.  MicroRNA-mediated up-regulation of an alternatively polyadenylated variant of the mouse cytoplasmic β-actin gene , 2008, Nucleic acids research.

[37]  U. A. Ørom,et al.  MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation. , 2008, Molecular cell.

[38]  Ronny Lorenz,et al.  The Vienna RNA Websuite , 2008, Nucleic Acids Res..

[39]  J. Steitz,et al.  Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation , 2007, Science.

[40]  M. Hentze,et al.  A conserved motif in Argonaute-interacting proteins mediates functional interactions through the Argonaute PIWI domain , 2007, Nature Structural &Molecular Biology.

[41]  Peter F. Stadler,et al.  Thermodynamics of RNA-RNA Binding , 2006, German Conference on Bioinformatics.

[42]  S. Stamm,et al.  The snoRNA HBII-52 Regulates Alternative Splicing of the Serotonin Receptor 2C , 2006, Science.

[43]  P. Sarnow,et al.  Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA , 2005, Science.

[44]  J. McCaskill.  The equilibrium partition function and base pair binding probabilities for RNA secondary structure , 1990, Biopolymers.

[45]  G. Chawla,et al.  Analysis of MicroRNA Function in Drosophila. , 2016, Methods in molecular biology.

[46]  Dmitri D. Pervouchine,et al.  conserved long-range RNA structures Evidence for widespread association of mammalian splicing and Material Supplemental , 2011 .

[47]  A. Kornblihtt.  Chromatin, transcript elongation and alternative splicing , 2006, Nature Structural &Molecular Biology.