Specific expression of long noncoding RNAs in the mouse brain

A major proportion of the mammalian transcriptome comprises long RNAs that have little or no protein-coding capacity (ncRNAs). Only a handful of such transcripts have been examined in detail, and it is unknown whether this class of transcript is generally functional or merely artifact. Using in situ hybridization data from the Allen Brain Atlas, we identified 849 ncRNAs (of 1,328 examined) that are expressed in the adult mouse brain and found that the majority were associated with specific neuroanatomical regions, cell types, or subcellular compartments. Examination of their genomic context revealed that the ncRNAs were expressed from diverse places including intergenic, intronic, and imprinted loci and that many overlap with, or are transcribed antisense to, protein-coding genes of neurological importance. Comparisons between the expression profiles of ncRNAs and their associated protein-coding genes revealed complex relationships that, in combination with the specific expression profiles exhibited at both regional and subcellular levels, are inconsistent with the notion that they are transcriptional noise or artifacts of chromatin remodeling. Our results show that the majority of ncRNAs are expressed in the brain and provide strong evidence that the majority of processed transcripts with no protein-coding capacity function intrinsically as RNAs.

[1]  AC Tose Cell , 1993, Cell.

[2]  J. Mattick,et al.  Introns: evolution and function. , 1994, Current opinion in genetics & development.

[3]  A. Mccarthy Development , 1996, Current Opinion in Neurobiology.

[4]  Carolyn J. Brown,et al.  Stabilization and Localization of Xist RNA are Controlled by Separate Mechanisms and are Not Sufficient for X Inactivation , 1998, The Journal of cell biology.

[5]  R. Quatrano Genomics , 1998, Plant Cell.

[6]  A. Ferguson-Smith,et al.  The mouse Gtl2 gene is differentially expressed during embryonic development, encodes multiple alternatively spliced transcripts, and may act as an RNA , 1998, Developmental dynamics : an official publication of the American Association of Anatomists.

[7]  G. Olsen,et al.  CRITICA: coding region identification tool invoking comparative analysis. , 1999, Molecular biology and evolution.

[8]  김삼묘,et al.  “Bioinformatics” 특집을 내면서 , 2000 .

[9]  Y. Hahn,et al.  Mit1/Lb9 and Copg2, new members of mouse imprinted genes closely linked to Peg1/Mest , 2000, FEBS letters.

[10]  M. Saraste,et al.  FEBS Lett , 2000 .

[11]  S. Morita,et al.  Identification of a new imprinted gene, Rian, on mouse chromosome 12 by fluorescent differential display screening. , 2001, Journal of biochemistry.

[12]  V. Tarabykin,et al.  Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. , 2001, Development.

[13]  W. J. Kent,et al.  BLAT--the BLAST-like alignment tool. , 2002, Genome research.

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

[15]  Michael Zuker,et al.  Mfold web server for nucleic acid folding and hybridization prediction , 2003, Nucleic Acids Res..

[16]  Yoshihide Hayashizaki,et al.  Discovery of imprinted transcripts in the mouse transcriptome using large-scale expression profiling. , 2003, Genome research.

[17]  Martina Paulsen,et al.  Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene , 2003, Nature Genetics.

[18]  C. Hayward,et al.  Mutations in SOX2 cause anophthalmia , 2003, Nature Genetics.

[19]  N. Niikawa,et al.  Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. , 2003, Human molecular genetics.

[20]  R. Myers,et al.  An abundance of bidirectional promoters in the human genome. , 2003, Genome research.

[21]  Ryan D. Morin,et al.  The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). , 2004, Genome research.

[22]  C. Kanduri,et al.  An Antisense RNA Regulates the Bidirectional Silencing Property of the Kcnq1 Imprinting Control Region , 2004, Molecular and Cellular Biology.

[23]  S. Batalov,et al.  A gene atlas of the mouse and human protein-encoding transcriptomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Jürgen Brosius,et al.  Waste not, want not--transcript excess in multicellular eukaryotes. , 2005, Trends in genetics : TIG.

[25]  Cameron S. Osborne,et al.  Replication and transcription: Shaping the landscape of the genome , 2005, Nature Reviews Genetics.

[26]  Michael Q. Zhang,et al.  Regulating Gene Expression through RNA Nuclear Retention , 2005, Cell.

[27]  S. Salzberg,et al.  The Transcriptional Landscape of the Mammalian Genome , 2005, Science.

[28]  R. Mcinnes,et al.  Natural antisense transcripts associated with genes involved in eye development. , 2005, Human molecular genetics.

[29]  Joaquín Dopazo,et al.  PupasView: a visual tool for selecting suitable SNPs, with putative pathological effect in genes, for genotyping purposes , 2005, Nucleic Acids Res..

[30]  N. Niikawa,et al.  Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air. , 2005, Human molecular genetics.

[31]  Masahiko Watanabe,et al.  Cbln1 is essential for synaptic integrity and plasticity in the cerebellum , 2005, Nature Neuroscience.

[32]  S. Batalov,et al.  A Strategy for Probing the Function of Noncoding RNAs Finds a Repressor of NFAT , 2005, Science.

[33]  L. Wilkinson,et al.  Imprinted gene expression in the brain , 2005, Neuroscience & Biobehavioral Reviews.

[34]  S. Batalov,et al.  Antisense Transcription in the Mammalian Transcriptome , 2005, Science.

[35]  P. Stadler,et al.  Mapping of conserved RNA secondary structures predicts thousands of functional noncoding RNAs in the human genome , 2005, Nature Biotechnology.

[36]  O. Britanova,et al.  Novel transcription factor Satb2 interacts with matrix attachment region DNA elements in a tissue‐specific manner and demonstrates cell‐type‐dependent expression in the developing mouse CNS , 2005, The European journal of neuroscience.

[37]  Jun Kawai,et al.  Clusters of Internally Primed Transcripts Reveal Novel Long Noncoding RNAs , 2006, PLoS genetics.

[38]  John S Mattick,et al.  Non‐coding RNAs in the nervous system , 2006, The Journal of physiology.

[39]  Sergio Verjovski-Almeida,et al.  Genome mapping and expression analyses of human intronic noncoding RNAs reveal tissue-specific patterns and enrichment in genes related to regulation of transcription , 2007, Genome Biology.

[40]  David Haussler,et al.  The UCSC Known Genes , 2006, Bioinform..

[41]  David Haussler,et al.  Forces Shaping the Fastest Evolving Regions in the Human Genome , 2006, PLoS genetics.

[42]  Brian S. Clark,et al.  The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. , 2006, Genes & development.

[43]  Yitzhak Pilpel,et al.  Genome‐wide natural antisense transcription: coupling its regulation to its different regulatory mechanisms , 2006, EMBO reports.

[44]  C. Bult,et al.  Discrimination of Non-Protein-Coding Transcripts from Protein-Coding mRNA , 2006, RNA biology.

[45]  Sin Lam Tan,et al.  Complex Loci in Human and Mouse Genomes , 2006, PLoS genetics.

[46]  Fred H. Gage,et al.  Generation of neuronal variability and complexity , 2006, Nature.

[47]  E. Nudler,et al.  Gene Control by Large Noncoding RNAs , 2006, Science's STKE.

[48]  J. Mattick,et al.  Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. , 2006, Trends in genetics : TIG.

[49]  A. Ferguson-Smith,et al.  High-resolution map and imprinting analysis of the Gtl2-Dnchc1 domain on mouse chromosome 12. , 2006, Genomics.

[50]  Jun Kawai,et al.  The Abundance of Short Proteins in the Mammalian Proteome , 2006, PLoS genetics.

[51]  M. Rijnkels,et al.  A noncoding RNA is a potential marker of cell fate during mammary gland development. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[52]  D. Gautheret,et al.  Beyond the 3′ end: experimental validation of extended transcript isoforms , 2007, Nucleic acids research.

[53]  C. Ponting,et al.  Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs. , 2007, Genome research.

[54]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

[55]  M. Takeichi,et al.  The mRNA-like noncoding RNA Gomafu constitutes a novel nuclear domain in a subset of neurons , 2007, Journal of Cell Science.

[56]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[57]  Ana Serra Barros,et al.  Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript , 2007, Nature.

[58]  J. Mattick,et al.  The relationship between non-protein-coding DNA and eukaryotic complexity. , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[59]  P. Tomançak,et al.  Global Analysis of mRNA Localization Reveals a Prominent Role in Organizing Cellular Architecture and Function , 2007, Cell.

[60]  D. Spector,et al.  Eukaryotic regulatory RNAs: an answer to the 'genome complexity' conundrum. , 2007, Genes & development.

[61]  S. Dey,et al.  MicroRNA regulation of cyclooxygenase-2 during embryo implantation , 2007, Proceedings of the National Academy of Sciences.

[62]  Tatiana Tatusova,et al.  NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins , 2004, Nucleic Acids Res..

[63]  K. Struhl Transcriptional noise and the fidelity of initiation by RNA polymerase II , 2007, Nature Structural &Molecular Biology.

[64]  Allen D. Delaney,et al.  Large-scale production of SAGE libraries from microdissected tissues, flow-sorted cells, and cell lines. , 2006, Genome research.

[65]  David Haussler,et al.  The UCSC genome browser database: update 2007 , 2006, Nucleic Acids Res..

[66]  F. Pauler,et al.  Silencing by imprinted noncoding RNAs: is transcription the answer? , 2007, Trends in genetics : TIG.

[67]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[68]  J. Guénet,et al.  Gtl2lacZ, an insertional mutation on mouse Chromosome 12 with parental origin-dependent phenotype , 2009, Mammalian Genome.

[69]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.