Translation of noncoding RNAs: Focus on lncRNAs, pri‐miRNAs, and circRNAs

Abstract Mammalian genome is pervasively transcribed, producing large number of noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), primary miRNAs (pri‐miRNA), and circular RNAs (circRNAs). The translation of these ncRNAs has long been overlooked. Increasing studies, however, based on ribosome profiling in various organisms provide important clues to unanticipated translation potential of lncRNAs. Moreover, a few functional peptides encoded by lncRNAs and pri‐miRNAs underline the significance of their translation. Recently, several novel researches also evidence the translation of endogenous circRNAs. Given the functional significance exemplified by peptides translated by some ncRNAs and their pervasive translation, it is not too far‐fetched to image that abnormal translation of ncRNAs may contribute to human diseases. Through challenging, deciphering ncRNA translation is required for comprehensive understanding of biology and medicine. In this review, we firstly present evidence concerning translation potential of lncRNAs and go on to introduce a few functional short peptides encoded by lncRNAs. Then, salient observations showing translation of pri‐miRNAs and circRNAs are described in detail. We end by discussing the impact of ncRNA translation beyond producing peptides and referring briefly to the potential role of abnormal ncRNA translation in human diseases. HighlightsMethods based on ribosome profiling highlight translation potential of lncRNAs.Peptides encoded lncRNAs and pri‐miRNAs display functional importance.Translation of endogenous circRNAs has recently been discovered.The role of abnormal translation of ncRNAs in human disorders merits further investigation.

[1]  A. Regev,et al.  Many lncRNAs, 5’UTRs, and pseudogenes are translated and some are likely to express functional proteins , 2015, eLife.

[2]  Sebastian D. Mackowiak,et al.  Circular RNAs are a large class of animal RNAs with regulatory potency , 2013, Nature.

[3]  Ying Chen Eyre-Walker,et al.  Extensive translation of small Open Reading Frames revealed by Poly-Ribo-Seq , 2014, eLife.

[4]  Nicholas T. Ingolia,et al.  Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity and Dynamics of Mammalian Proteomes , 2011, Cell.

[5]  J. Rinn,et al.  Modular regulatory principles of large non-coding RNAs , 2012, Nature.

[6]  Gideon Rechavi,et al.  Gene expression regulation mediated through reversible m6A RNA methylation , 2014, Nature Reviews Genetics.

[7]  John M. Shelton,et al.  A Micropeptide Encoded by a Putative Long Noncoding RNA Regulates Muscle Performance , 2015, Cell.

[8]  Michael T. Wolfinger,et al.  General and MicroRNA-Mediated mRNA Degradation Occurs on Ribosome Complexes in Drosophila Cells , 2015, Molecular and Cellular Biology.

[9]  V. Mootha,et al.  Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans , 2009, Proceedings of the National Academy of Sciences.

[10]  T. Girke,et al.  Translational dynamics revealed by genome-wide profiling of ribosome footprints in Arabidopsis , 2013, Proceedings of the National Academy of Sciences.

[11]  Michael R Brent,et al.  Genome annotation past, present, and future: how to define an ORF at each locus. , 2005, Genome research.

[12]  Nicholas T. Ingolia,et al.  Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling , 2009, Science.

[13]  D. Ye,et al.  Competitive endogenous RNA network: potential implication for systemic lupus erythematosus , 2017, Expert opinion on therapeutic targets.

[14]  P. Tak,et al.  MicroRNAs—novel regulators of systemic lupus erythematosus pathogenesis , 2012, Nature Reviews Rheumatology.

[15]  A. Schier,et al.  Identifying (non‐)coding RNAs and small peptides: Challenges and opportunities , 2015, BioEssays : news and reviews in molecular, cellular and developmental biology.

[16]  Frances M. G. Pearl,et al.  Conserved Regulation of Cardiac Calcium Uptake by Peptides Encoded in Small Open Reading Frames , 2013, Science.

[17]  M. Esteller.  Non-coding RNAs in human disease , 2011, Nature Reviews Genetics.

[18]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[19]  D. Ye,et al.  Comprehensive long non-coding RNA expression profiling reveals their potential roles in systemic lupus erythematosus. , 2017, Cellular immunology.

[20]  Joshua A. Arribere,et al.  Roles for transcript leaders in translation and mRNA decay revealed by transcript leader sequencing , 2013, Genome research.

[21]  N. Sonenberg,et al.  DAP5 associates with eIF2β and eIF4AI to promote Internal Ribosome Entry Site driven translation , 2015, Nucleic acids research.

[22]  Michael K. Slevin,et al.  Circular RNAs are abundant, conserved, and associated with ALU repeats. , 2013, RNA.

[23]  B. Barrell,et al.  Life with 6000 Genes , 1996, Science.

[24]  Shu-Bing Qian,et al.  Dynamic m6A mRNA methylation directs translational control of heat shock response , 2015, Nature.

[25]  N. Rajewsky,et al.  Translation of CircRNAs , 2017, Molecular cell.

[26]  A. Gramolini,et al.  Enhanced Ca2+ transport and muscle relaxation in skeletal muscle from sarcolipin-null mice. , 2011, American journal of physiology. Cell physiology.

[27]  S. Jaffrey,et al.  A mRNA methylation directs translational control of heat shock response , 2015 .

[28]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[29]  J. Kjems,et al.  Natural RNA circles function as efficient microRNA sponges , 2013, Nature.

[30]  Wu Guocui.  Immunoregulation function of long noncoding RNA in rheumatic diseases , 2016 .

[31]  Jef D Boeke,et al.  Functional genomics of genes with small open reading frames (sORFs) in S. cerevisiae. , 2006, Genome research.

[32]  Petar Glažar,et al.  Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. , 2015, Molecular cell.

[33]  M. Askarian-Amiri,et al.  ZFAS1: a long noncoding RNA associated with ribosomes in breast cancer cells , 2016, Biology Direct.

[34]  Yang Wang,et al.  Efficient backsplicing produces translatable circular mRNAs , 2015, RNA.

[35]  Roderic Guigó,et al.  Cytoplasmic long noncoding RNAs are frequently bound to and degraded at ribosomes in human cells , 2016, RNA.

[36]  Tim R. Mercer,et al.  Differentiating Protein-Coding and Noncoding RNA: Challenges and Ambiguities , 2008, PLoS Comput. Biol..

[37]  P. Sarnow,et al.  Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. , 1995, Science.

[38]  K. Shinozaki,et al.  Small open reading frames associated with morphogenesis are hidden in plant genomes , 2013, Proceedings of the National Academy of Sciences.

[39]  Gerben Menschaert,et al.  Combining in silico prediction and ribosome profiling in a genome-wide search for novel putatively coding sORFs , 2013, BMC Genomics.

[40]  J. Masel,et al.  Putatively Noncoding Transcripts Show Extensive Association with Ribosomes , 2011, Genome biology and evolution.

[41]  N. Rajewsky,et al.  circRNA biogenesis competes with pre-mRNA splicing. , 2014, Molecular cell.

[42]  P. Barbry,et al.  Pateamine A-sensitive ribosome profiling reveals the scope of translation in mouse embryonic stem cells , 2016, BMC Genomics.

[43]  Nikolaus Rajewsky,et al.  Identification of small ORFs in vertebrates using ribosome footprinting and evolutionary conservation , 2014, The EMBO journal.

[44]  B. Kuster,et al.  Mass-spectrometry-based draft of the human proteome , 2014, Nature.

[45]  J. Couso,et al.  Ribosomal profiling adds new coding sequences to the proteome. , 2015, Biochemical Society transactions.

[46]  J. Dolata,et al.  Posttranscriptional coordination of splicing and miRNA biogenesis in plants , 2017, Wiley interdisciplinary reviews. RNA.

[47]  O. Elemento,et al.  Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons , 2012, Cell.

[48]  Christophe Dunand,et al.  Primary transcripts of microRNAs encode regulatory peptides , 2015, Nature.

[49]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature reviews genetics.

[50]  Howard Y. Chang,et al.  Molecular mechanisms of long noncoding RNAs. , 2011, Molecular cell.

[51]  P. Cook,et al.  “Dark matter” worlds of unstable RNA and protein , 2014, Nucleus.

[52]  J. Rinn,et al.  Ribosome profiling reveals resemblance between long non-coding RNAs and 5′ leaders of coding RNAs , 2013, Development.

[53]  M. Kupiec,et al.  Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq , 2012, Nature.

[54]  Igor Ulitsky,et al.  Methods for distinguishing between protein-coding and long noncoding RNAs and the elusive biological purpose of translation of long noncoding RNAs , 2015, bioRxiv.

[55]  A. Eyre-Walker,et al.  Hundreds of putatively functional small open reading frames in Drosophila , 2011, Genome Biology.

[56]  Akinobu Matsumoto,et al.  mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide , 2016, Nature.

[57]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[58]  Yang Zhang,et al.  Extensive translation of circular RNAs driven by N6-methyladenosine , 2017, Cell Research.

[59]  Shanshan Zhu,et al.  Circular intronic long noncoding RNAs. , 2013, Molecular cell.

[60]  J. Rinn,et al.  Peptidomic discovery of short open reading frame-encoded peptides in human cells , 2012, Nature chemical biology.

[61]  D. Ye,et al.  Circular RNAs and systemic lupus erythematosus. , 2016, Experimental cell research.

[62]  Nicholas T. Ingolia,et al.  Ribosome Profiling Provides Evidence that Large Noncoding RNAs Do Not Encode Proteins , 2013, Cell.

[63]  Roger P. Hellens,et al.  Plant biology: Coding in non-coding RNAs , 2015, Nature.

[64]  Jennifer A. Mitchell,et al.  The Air Noncoding RNA Epigenetically Silences Transcription by Targeting G9a to Chromatin , 2008, Science.

[65]  J. Mattick,et al.  Long non-coding RNAs: insights into functions , 2009, Nature Reviews Genetics.

[66]  James B. Brown,et al.  Long noncoding RNAs are rarely translated in two human cell lines , 2012, Genome research.

[67]  R. Hajjar,et al.  Modulation of Cardiac Contractility by the Phopholamban/SERCA2a Regulatome , 2012, Circulation research.

[68]  M. Albà,et al.  Long non-coding RNAs as a source of new peptides , 2014, eLife.

[69]  Wenqian Hu,et al.  Translation of small open reading frames within unannotated RNA transcripts in Saccharomyces cerevisiae. , 2014, Cell reports.

[70]  Hui-Kuan Lin,et al.  Circular RNAs in cancer: novel insights into origins, properties, functions and implications. , 2015, American journal of cancer research.

[71]  Nicholas T Ingolia,et al.  Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. , 2014, Cell reports.

[72]  S Kobayashi,et al.  Small Peptides Switch the Transcriptional Activity of Shavenbaby During Drosophila Embryogenesis , 2010, Science.

[73]  Stefan L Ameres,et al.  Diversifying microRNA sequence and function , 2013, Nature Reviews Molecular Cell Biology.

[74]  E. Cuppen,et al.  Extensive localization of long noncoding RNAs to the cytosol and mono- and polyribosomal complexes , 2014, Genome Biology.

[75]  J. Lykke-Andersen,et al.  Execution of nonsense-mediated mRNA decay: what defines a substrate? , 2009, Current opinion in cell biology.

[76]  Joseph A. Rothnagel,et al.  Emerging evidence for functional peptides encoded by short open reading frames , 2014, Nature Reviews Genetics.

[77]  Stephen C. Cannon,et al.  A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle , 2016, Science.

[78]  Olivier Elemento,et al.  5′ UTR m6A Promotes Cap-Independent Translation , 2015, Cell.

[79]  Michael T. McManus,et al.  Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs , 2013, PLoS genetics.

[80]  Piero Carninci,et al.  Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat , 2012, Nature.

[81]  C. Ponting,et al.  Evolution and Functions of Long Noncoding RNAs , 2009, Cell.

[82]  N. Rajewsky,et al.  Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis , 2017, Molecular cell.

[83]  Minoru Yoshida,et al.  Rolling Circle Translation of Circular RNA in Living Human Cells , 2015, Scientific Reports.

[84]  J. Steitz,et al.  The Noncoding RNA Revolution—Trashing Old Rules to Forge New Ones , 2014, Cell.