Rapid Turnover of Long Noncoding RNAs and the Evolution of Gene Expression

A large proportion of functional sequence within mammalian genomes falls outside protein-coding exons and can be transcribed into long RNAs. However, the roles in mammalian biology of long noncoding RNA (lncRNA) are not well understood. Few lncRNAs have experimentally determined roles, with some of these being lineage-specific. Determining the extent by which transcription of lncRNA loci is retained or lost across multiple evolutionary lineages is essential if we are to understand their contribution to mammalian biology and to lineage-specific traits. Here, we experimentally investigated the conservation of lncRNA expression among closely related rodent species, allowing the evolution of DNA sequence to be uncoupled from evolution of transcript expression. We generated total RNA (RNAseq) and H3K4me3-bound (ChIPseq) DNA data, and combined both to construct catalogues of transcripts expressed in the adult liver of Mus musculus domesticus (C57BL/6J), Mus musculus castaneus, and Rattus norvegicus. We estimated the rate of transcriptional turnover of lncRNAs and investigated the effects of their lineage-specific birth or death. LncRNA transcription showed considerably greater gain and loss during rodent evolution, compared with protein-coding genes. Nucleotide substitution rates were found to mirror the in vivo transcriptional conservation of intergenic lncRNAs between rodents: only the sequences of noncoding loci with conserved transcription were constrained. Finally, we found that lineage-specific intergenic lncRNAs appear to be associated with modestly elevated expression of genomically neighbouring protein-coding genes. Our findings show that nearly half of intergenic lncRNA loci have been gained or lost since the last common ancestor of mouse and rat, and they predict that such rapid transcriptional turnover contributes to the evolution of tissue- and lineage-specific gene expression.

[1]  T. Borodina,et al.  Transcriptome analysis by strand-specific sequencing of complementary DNA , 2009, Nucleic acids research.

[2]  R. Durbin,et al.  Mapping Quality Scores Mapping Short Dna Sequencing Reads and Calling Variants Using P

, 2022 .

[3]  Peter A. Meric,et al.  Lineage-Specific Biology Revealed by a Finished Genome Assembly of the Mouse , 2009, PLoS biology.

[4]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[5]  J. Rinn,et al.  Ab initio reconstruction of transcriptomes of pluripotent and lineage committed cells reveals gene structures of thousands of lincRNAs , 2010, Nature Biotechnology.

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

[7]  Esther T. Chan,et al.  Conservation of core gene expression in vertebrate tissues , 2009, Journal of biology.

[8]  Michael D. Wilson,et al.  ChIP-seq: using high-throughput sequencing to discover protein-DNA interactions. , 2009, Methods.

[9]  J. Rinn,et al.  Ab initio reconstruction of transcriptomes of pluripotent and lineage committed cells reveals gene structures of thousands of lincRNAs , 2010, Nature biotechnology.

[10]  T. Derrien,et al.  Long Noncoding RNAs with Enhancer-like Function in Human Cells , 2010, Cell.

[11]  Daniel J. Blankenberg,et al.  Galaxy: a platform for interactive large-scale genome analysis. , 2005, Genome research.

[12]  G. Bourque,et al.  Transposable elements have rewired the core regulatory network of human embryonic stem cells , 2010, Nature Genetics.

[13]  Webb Miller,et al.  Using genomic data to unravel the root of the placental mammal phylogeny. , 2007, Genome research.

[14]  J. Rinn,et al.  Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression , 2009, Proceedings of the National Academy of Sciences.

[15]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[16]  D. Haussler,et al.  Human-mouse alignments with BLASTZ. , 2003, Genome research.

[17]  Daniel Rios,et al.  Ensembl 2011 , 2010, Nucleic Acids Res..

[18]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

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

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

[21]  M. Robinson,et al.  A scaling normalization method for differential expression analysis of RNA-seq data , 2010, Genome Biology.

[22]  H. Kimura,et al.  The organization of histone H3 modifications as revealed by a panel of specific monoclonal antibodies. , 2008, Cell structure and function.

[23]  L. Steinmetz,et al.  Functional consequences of bidirectional promoters. , 2011, Trends in genetics : TIG.

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

[25]  Alvis Brazma,et al.  Pol Iii Binding in Six Mammalian Genomes Shows High Conservation among Amino Acid Isotypes, despite Divergence in Trna Gene Usage Ukpmc Funders Group Author Manuscript Introduction , 2022 .

[26]  E. Birney,et al.  Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs , 2002, Nature.

[27]  Leighton J. Core,et al.  Nascent RNA Sequencing Reveals Widespread Pausing and Divergent Initiation at Human Promoters , 2008, Science.

[28]  J. Rinn,et al.  Non-coding RNAs as regulators of embryogenesis , 2011, Nature Reviews Genetics.

[29]  Cole Trapnell,et al.  Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. , 2010, Nature biotechnology.

[30]  Francesca Chiaromonte,et al.  Scoring Pairwise Genomic Sequence Alignments , 2001, Pacific Symposium on Biocomputing.

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

[32]  J. Rinn,et al.  A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response , 2010, Cell.

[33]  S. Bergmann,et al.  The evolution of gene expression levels in mammalian organs , 2011, Nature.

[34]  Miki Ebisuya,et al.  Ripples from neighbouring transcription , 2008, Nature Cell Biology.

[35]  Chris P. Ponting,et al.  Genome-Wide Identification of Human Functional DNA Using a Neutral Indel Model , 2005, PLoS Comput. Biol..

[36]  W. Kamps,et al.  Evidence Based Selection of Housekeeping Genes , 2007, PloS one.

[37]  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.

[38]  S. Ranade,et al.  Stem cell transcriptome profiling via massive-scale mRNA sequencing , 2008, Nature Methods.

[39]  Daniel E. Newburger,et al.  Variation in Homeodomain DNA Binding Revealed by High-Resolution Analysis of Sequence Preferences , 2008, Cell.

[40]  Yong Zhang,et al.  CPC: assess the protein-coding potential of transcripts using sequence features and support vector machine , 2007, Nucleic Acids Res..

[41]  Martin J. Lercher,et al.  Clustering of housekeeping genes provides a unified model of gene order in the human genome , 2002, Nature Genetics.

[42]  C. Ponting,et al.  Long noncoding RNA genes: conservation of sequence and brain expression among diverse amniotes , 2010, Genome Biology.

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

[44]  E. Liu,et al.  Evolution of the mammalian transcription factor binding repertoire via transposable elements. , 2008, Genome research.

[45]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[46]  P. Sorensen,et al.  The majority of total nuclear-encoded non-ribosomal RNA in a human cell is 'dark matter' un-annotated RNA , 2010, BMC Biology.

[47]  M. Stanhope,et al.  Local Molecular Clocks in Three Nuclear Genes: Divergence Times for Rodents and Other Mammals and Incompatibility Among Fossil Calibrations , 2003, Journal of Molecular Evolution.

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

[49]  C. Ponting,et al.  Genomic and Transcriptional Co-Localization of Protein-Coding and Long Non-Coding RNA Pairs in the Developing Brain , 2009, PLoS genetics.

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

[51]  Ziheng Yang,et al.  PAML: a program package for phylogenetic analysis by maximum likelihood , 1997, Comput. Appl. Biosci..

[52]  Michael Q. Zhang,et al.  Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development. , 2009, Genomics.

[53]  C. Ponting,et al.  Massive turnover of functional sequence in human and other mammalian genomes. , 2010, Genome research.

[54]  C. Ponting,et al.  Catalogues of mammalian long noncoding RNAs: modest conservation and incompleteness , 2009, Genome Biology.

[55]  Ernest Fraenkel,et al.  Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression , 2010, Molecular and Cellular Biology.

[56]  Stuart L. Schreiber,et al.  Active genes are tri-methylated at K4 of histone H3 , 2002, Nature.

[57]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[58]  Tao Ye,et al.  seqMINER: an integrated ChIP-seq data interpretation platform , 2010, Nucleic acids research.

[59]  H. Hoekstra,et al.  Molecular spandrels: tests of adaptation at the genetic level , 2011, Nature Reviews Genetics.

[60]  Thomas E. Royce,et al.  Global Identification of Human Transcribed Sequences with Genome Tiling Arrays , 2004, Science.

[61]  J. Rinn,et al.  lincRNAs act in the circuitry controlling pluripotency and differentiation , 2011, Nature.

[62]  Jeannie T. Lee,et al.  Tsix, a gene antisense to Xist at the X-inactivation centre , 1999, Nature Genetics.

[63]  Cole Trapnell,et al.  Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. , 2011, Genes & development.

[64]  Michael D. Wilson,et al.  Five-Vertebrate ChIP-seq Reveals the Evolutionary Dynamics of Transcription Factor Binding , 2010, Science.

[65]  E R Weibel,et al.  Distribution of Organelles and Membranes between Hepatocytes and Nonhepatocytes in a Stereological Study , 2022 .

[66]  Michael D. Wilson,et al.  Waves of Retrotransposon Expansion Remodel Genome Organization and CTCF Binding in Multiple Mammalian Lineages , 2012, Cell.

[67]  Howard Y. Chang,et al.  A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression , 2011, Nature.