Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements

There is now compelling evidence that the complexity of higher organisms correlates with the relative amount of non-coding RNA rather than the number of protein-coding genes. Previously dismissed as “junk DNA”, it is the non-coding regions of the genome that are responsible for regulation, facilitating complex temporal and spatial gene expression through the combinatorial effect of numerous mechanisms and interactions working together to fine-tune gene expression. The major regions involved in regulation of a particular gene are the 5′ and 3′ untranslated regions and introns. In addition, pervasive transcription of complex genomes produces a variety of non-coding transcripts that interact with these regions and contribute to regulation. This review discusses recent insights into the regulatory roles of the untranslated gene regions and non-coding RNAs in the control of complex gene expression, as well as the implications of this in terms of organism complexity and evolution.

[1]  Yong Huang,et al.  Biological functions of microRNAs: a review , 2011, Journal of Physiology and Biochemistry.

[2]  J. Bähler,et al.  Rapidly regulated genes are intron poor. , 2008, Trends in genetics : TIG.

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

[4]  Robert S. Illingworth,et al.  Orphan CpG Islands Identify Numerous Conserved Promoters in the Mammalian Genome , 2010, PLoS genetics.

[5]  I. Gérin,et al.  Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* , 2010, The Journal of Biological Chemistry.

[6]  H. Pelham,et al.  An efficient mRNA-dependent translation system from reticulocyte lysates. , 1976, European journal of biochemistry.

[7]  Christopher J. Ott,et al.  Intronic enhancers coordinate epithelial-specific looping of the active CFTR locus , 2009, Proceedings of the National Academy of Sciences.

[8]  Zhiping Weng,et al.  Transcription factor binding and modified histones in human bidirectional promoters. , 2007, Genome research.

[9]  B. Tian,et al.  Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development , 2009, Proceedings of the National Academy of Sciences.

[10]  Yang Liu,et al.  Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis , 2009, Nature Genetics.

[11]  Brian D Athey,et al.  New class of microRNA targets containing simultaneous 5'-UTR and 3'-UTR interaction sites. , 2009, Genome research.

[12]  N. Maizels,et al.  Conserved elements with potential to form polymorphic G-quadruplex structures in the first intron of human genes , 2008, Nucleic acids research.

[13]  Q. Cao,et al.  Dissolution of the maskin–eIF4E complex by cytoplasmic polyadenylation and poly(A)‐binding protein controls cyclin B1 mRNA translation and oocyte maturation , 2002, The EMBO journal.

[14]  Eugene Bolotin,et al.  Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters. , 2007, Gene.

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

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

[17]  Francisco Martinez-Murillo,et al.  Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise , 2004, Nature Genetics.

[18]  R. Cohen,et al.  Thy-1 mRNA destabilization by norepinephrine a 3′ UTR cAMP responsive decay element and involves RNA binding proteins , 2010, Brain, Behavior, and Immunity.

[19]  M. Waterman,et al.  Diversity of LEF/TCF action in development and disease , 2006, Oncogene.

[20]  S. Schweiger,et al.  Alternative polyadenylation signals and promoters act in concert to control tissue-specific expression of the Opitz Syndrome gene MID1 , 2007, BMC Molecular Biology.

[21]  C. Gissi,et al.  Untranslated regions of mRNAs , 2002, Genome Biology.

[22]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[23]  J. Hauber,et al.  A minimal uORF within the HIV-1 vpu leader allows efficient translation initiation at the downstream env AUG. , 2007, Virology.

[24]  M. Esteller,et al.  Intronic RNAs mediate EZH2 regulation of epigenetic targets , 2012, Nature Structural &Molecular Biology.

[25]  K. Lilley,et al.  Identification of Internal Ribosome Entry Segment (IRES)-trans-Acting Factors for the Myc Family of IRESs , 2007, Molecular and Cellular Biology.

[26]  R. Sciot,et al.  HMGA2 Regulates Transcription of the Imp2 Gene via an Intronic Regulatory Element in Cooperation with Nuclear Factor-κB , 2007, Molecular Cancer Research.

[27]  E. M. Muro,et al.  Functional evidence of post-transcriptional regulation by pseudogenes. , 2011, Biochimie.

[28]  Robert L. Tanguay,et al.  Translational efficiency is regulated by the length of the 3' untranslated region , 1996, Molecular and cellular biology.

[29]  D. Heo,et al.  MicroRNA-146a Downregulates NFκB Activity via Targeting TRAF6 and Functions as a Tumor Suppressor Having Strong Prognostic Implications in NK/T Cell Lymphoma , 2011, Clinical Cancer Research.

[30]  A. Visel,et al.  Response to Comment on "Human-Specific Gain of Function in a Developmental Enhancer" , 2009, Science.

[31]  R. Tjian,et al.  Unexpected roles for core promoter recognition factors in cell-type-specific transcription and gene regulation , 2010, Nature Reviews Genetics.

[32]  J. Pal,et al.  Role of 5′‐ and 3′‐untranslated regions of mRNAs in human diseases , 2009, Biology of the cell.

[33]  Yong Zhao,et al.  A developmental view of microRNA function. , 2007, Trends in biochemical sciences.

[34]  R. Elkon,et al.  Major role for mRNA stability in shaping the kinetics of gene induction , 2010, BMC Genomics.

[35]  B. Montanini,et al.  Eukaryotic snoRNAs: a paradigm for gene expression flexibility. , 2009, Genomics.

[36]  Z. Shah,et al.  The bidirectional promoter of two genes for the mitochondrial translational apparatus in mouse is regulated by an array of CCAAT boxes interacting with the transcription factor NF-Y , 2006, Nucleic acids research.

[37]  Jing-Yuan Fang,et al.  Natural antisense transcripts regulate gene expression in an epigenetic manner. , 2010, Biochemical and biophysical research communications.

[38]  R. Roeder,et al.  Core promoter-specific function of a mutant transcription factor TFIID defective in TATA-box binding. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[39]  O. Elroy-Stein,et al.  Translational Control of Protein Kinase Cη by Two Upstream Open Reading Frames , 2009, Molecular and Cellular Biology.

[40]  Michael T. McManus,et al.  Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2 , 2007, Cell.

[41]  K. Morris RNA-directed transcriptional gene silencing and activation in human cells. , 2009, Oligonucleotides.

[42]  A B Rose,et al.  Intron-mediated regulation of gene expression. , 2008, Current topics in microbiology and immunology.

[43]  C. Wahlestedt,et al.  Regulatory roles of natural antisense transcripts , 2009, Nature Reviews Molecular Cell Biology.

[44]  W. Gilbert,et al.  Alternative Ways to Think about Cellular Internal Ribosome Entry* , 2010, The Journal of Biological Chemistry.

[45]  A. Ansari Riboactivators: transcription activation by noncoding RNA. , 2009, Critical reviews in biochemistry and molecular biology.

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

[47]  E. Olson,et al.  MicroRNA control of muscle development and disease. , 2009, Current opinion in cell biology.

[48]  Shawn McClelland,et al.  Regulation of Translational Efficiency by Disparate 5′ UTRs of PPARγ Splice Variants , 2009, PPAR research.

[49]  P. Kelly,et al.  Evidence for generation of the growth hormone-binding protein through proteolysis of the growth hormone membrane receptor. , 1993, Endocrinology.

[50]  R. Roeder,et al.  TATA‐binding protein‐associated factor(s) in TFIID function through the initiator to direct basal transcription from a TATA‐less class II promoter. , 1994, The EMBO journal.

[51]  Karthikeyan Kandasamy,et al.  The 3′-untranslated region length and AU-rich RNA location modulate RNA–protein interaction and translational control of β2-adrenergic receptor mRNA , 2011, Molecular and Cellular Biochemistry.

[52]  Jörg Hackermüller,et al.  mRNA Openers and Closers: Modulating AU‐Rich Element‐Controlled mRNA Stability by a Molecular Switch in mRNA Secondary Structure , 2004, Chembiochem : a European journal of chemical biology.

[53]  Sumio Sugano,et al.  Diversity of Translation Start Sites May Define Increased Complexity of the Human Short ORFeome*S , 2007, Molecular & Cellular Proteomics.

[54]  S K Burley,et al.  TATA element recognition by the TATA box-binding protein has been conserved throughout evolution. , 1999, Genes & development.

[55]  Markus Ringnér,et al.  Folding Free Energies of 5′-UTRs Impact Post-Transcriptional Regulation on a Genomic Scale in Yeast , 2005, PLoS Comput. Biol..

[56]  Nicholas G Martin,et al.  A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. , 2008, American journal of human genetics.

[57]  A. Jacobson,et al.  Poly(A)-binding proteins: multifunctional scaffolds for the post-transcriptional control of gene expression , 2003, Genome Biology.

[58]  V. Speirs,et al.  Differential regulation of oestrogen receptor β isoforms by 5′ untranslated regions in cancer , 2009, Journal of cellular and molecular medicine.

[59]  F. Talamantes,et al.  Growth hormone (GH) receptor and GH-binding protein messenger ribonucleic acids with alternative 5'-untranslated regions are differentially expressed in mouse liver and placenta. , 1995, Endocrinology.

[60]  R. Jackson,et al.  The mechanism of eukaryotic translation initiation and principles of its regulation , 2010, Nature Reviews Molecular Cell Biology.

[61]  K. Ekwall,et al.  Epigenetics: heterochromatin meets RNAi , 2009, Cell Research.

[62]  G. T. Bowden,et al.  Nucleolin stabilizes Bcl-X L messenger RNA in response to UVA irradiation. , 2008, Cancer research.

[63]  Ajit Varki,et al.  Human uniqueness: genome interactions with environment, behaviour and culture , 2008, Nature Reviews Genetics.

[64]  D. Kaye,et al.  Mechanistic insights into the link between a polymorphism of the 3′UTR of the SLC7A1 gene and hypertension , 2009, Human mutation.

[65]  Y. Sakaki,et al.  Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes , 2008, Nature.

[66]  S. Balasubramanian,et al.  Position and stability are determining factors for translation repression by an RNA G-quadruplex-forming sequence within the 5' UTR of the NRAS proto-oncogene. , 2008, Biochemistry.

[67]  M. Kastan,et al.  5'-3'-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA damage. , 2010, Genes & development.

[68]  Michael R. Green,et al.  Transcriptional regulatory elements in the human genome. , 2006, Annual review of genomics and human genetics.

[69]  Ivan N. Shatsky,et al.  Efficient Translation Initiation Directed by the 900-Nucleotide-Long and GC-Rich 5′ Untranslated Region of the Human Retrotransposon LINE-1 mRNA Is Strictly Cap Dependent Rather than Internal Ribosome Entry Site Mediated , 2007, Molecular and Cellular Biology.

[70]  A. Willis,et al.  The implications of structured 5' untranslated regions on translation and disease. , 2005, Seminars in cell & developmental biology.

[71]  Alexei Fedorov,et al.  Introns in Gene Evolution , 2004, Genetica.

[72]  P. Pandolfi,et al.  A coding-independent function of gene and pseudogene mRNAs regulates tumour biology , 2010, Nature.

[73]  C. D. Krause,et al.  Chaperone Hsp27 Modulates AUF1 Proteolysis and AU-Rich Element-Mediated mRNA Degradation , 2011, Molecular and Cellular Biology.

[74]  Sergio Verjovski-Almeida,et al.  Long intronic noncoding RNA transcription: expression noise or expression choice? , 2009, Genomics.

[75]  Sarah E. Walker,et al.  The 5'-7-methylguanosine cap on eukaryotic mRNAs serves both to stimulate canonical translation initiation and to block an alternative pathway. , 2010, Molecular cell.

[76]  Vasudevan Seshadri,et al.  Translational control by the 3'-UTR: the ends specify the means. , 2003, Trends in biochemical sciences.

[77]  R. Tjian,et al.  Transcription regulation and animal diversity , 2003, Nature.

[78]  M. Tsuda,et al.  Involvement of the 3′‐untranslated region of the brain‐derived neurotrophic factor gene in activity‐dependent mRNA stabilization , 2010, Journal of neurochemistry.

[79]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[80]  R. K. Karuturi,et al.  The role of post-transcriptional RNA processing and plasmid vector sequences on transient transgene expression in zebrafish , 2010, Transgenic Research.

[81]  M. Holcik,et al.  Distinct 5′ UTRs regulate XIAP expression under normal growth conditions and during cellular stress , 2010, Nucleic acids research.

[82]  J. Wilusz,et al.  Polyadenylation: alternative lifestyles of the A‐rich (and famous?) , 2010, The EMBO journal.

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

[84]  A. Riccio,et al.  To localize or not to localize: mRNA fate is in 3'UTR ends. , 2009, Trends in cell biology.

[85]  J. T. Kadonaga,et al.  The RNA polymerase II core promoter. , 2003, Annual review of biochemistry.

[86]  J. Steitz,et al.  Interactions of small nuclear RNA's with precursor messenger RNA during in vitro splicing. , 1992, Science.

[87]  R. Young,et al.  Ronin/Hcf-1 binds to a hyperconserved enhancer element and regulates genes involved in the growth of embryonic stem cells. , 2010, Genes & development.

[88]  E. Nevo,et al.  Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates , 2010, Proceedings of the National Academy of Sciences.

[89]  D. Hogness,et al.  The organization of the histone genes in Drosophila melanogaster: functional and evolutionary implications. , 1978, Cold Spring Harbor symposia on quantitative biology.

[90]  W. Filipowicz,et al.  Regulation of mRNA translation and stability by microRNAs. , 2010, Annual review of biochemistry.

[91]  Laura Smith Post-transcriptional regulation of gene expression by alternative 5'-untranslated regions in carcinogenesis. , 2008, Biochemical Society transactions.

[92]  H. Kaessmann,et al.  Evolutionary origin and functions of retrogene introns. , 2009, Molecular biology and evolution.

[93]  F. Ayala,et al.  Origins and evolution of spliceosomal introns. , 2006, Annual review of genetics.

[94]  Chong-Jian Chen,et al.  Differential genome-wide profiling of tandem 3' UTRs among human breast cancer and normal cells by high-throughput sequencing. , 2011, Genome research.

[95]  M. King,et al.  Evolution at two levels in humans and chimpanzees. , 1975, Science.

[96]  J. Mergny,et al.  A G-quadruplex structure within the 5′-UTR of TRF2 mRNA represses translation in human cells , 2010, Nucleic acids research.

[97]  M. Esteller,et al.  Aberrant Regulation of Messenger RNA 3′-Untranslated Region in Human Cancer , 2007, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[98]  D. Goss,et al.  Poly(A) binding proteins: are they all created equal? , 2013, Wiley interdisciplinary reviews. RNA.

[99]  E. Punch,et al.  Pseudogenes: pseudo-functional or key regulators in health and disease? , 2011, RNA.

[100]  V. Corces,et al.  Enhancer function: new insights into the regulation of tissue-specific gene expression , 2011, Nature Reviews Genetics.

[101]  P. Sharp,et al.  Proliferating Cells Express mRNAs with Shortened 3' Untranslated Regions and Fewer MicroRNA Target Sites , 2008, Science.

[102]  Lan Jin,et al.  Biological basis for restriction of microRNA targets to the 3' untranslated region in mammalian mRNAs. , 2009, Nature structural & molecular biology.

[103]  O. Mühlemann,et al.  Posttranscriptional Gene Regulation by Spatial Rearrangement of the 3′ Untranslated Region , 2008, PLoS biology.

[104]  L. Ovchinnikov,et al.  Interplay between Y-box-binding protein 1 (YB-1) and poly(A) binding protein (PABP) in specific regulation of YB-1 mRNA translation , 2011, RNA biology.

[105]  R. Sachidanandam,et al.  Post-transcriptional processing generates a diversity of 5′-modified long and short RNAs , 2009, Nature.

[106]  I. Korf,et al.  Longer First Introns Are a General Property of Eukaryotic Gene Structure , 2008, PloS one.

[107]  R. Russell,et al.  Animal MicroRNAs Confer Robustness to Gene Expression and Have a Significant Impact on 3′UTR Evolution , 2005, Cell.

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

[109]  J. Mattick,et al.  Nucleosomes are preferentially positioned at exons in somatic and sperm cells , 2009, Cell cycle.

[110]  Bo Song,et al.  miR-192 Regulates Dihydrofolate Reductase and Cellular Proliferation through the p53-microRNA Circuit , 2008, Clinical Cancer Research.

[111]  Wei Chen,et al.  A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. , 2007, American journal of human genetics.

[112]  K. Lindblad-Toh,et al.  Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals , 2005, Nature.

[113]  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.

[114]  G. Karypis,et al.  Conserved GU-rich elements mediate mRNA decay by binding to CUG-binding protein 1. , 2008, Molecular cell.

[115]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[116]  David Hogg,et al.  Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma , 1999, Nature Genetics.

[117]  Eugene V Koonin,et al.  Evolution of alternative and constitutive regions of mammalian 5'UTRs , 2009, BMC Genomics.

[118]  Dimitris Thanos,et al.  Transcription factors mediate long-range enhancer–promoter interactions , 2009, Proceedings of the National Academy of Sciences.

[119]  T. Hughes,et al.  Regulation of gene expression by alternative untranslated regions. , 2006, Trends in genetics : TIG.

[120]  D. Spector,et al.  Long noncoding RNAs: functional surprises from the RNA world. , 2009, Genes & development.

[121]  M. Kozak The scanning model for translation: an update , 1989, The Journal of cell biology.

[122]  B. Tian,et al.  Reprogramming of 3′ Untranslated Regions of mRNAs by Alternative Polyadenylation in Generation of Pluripotent Stem Cells from Different Cell Types , 2009, PloS one.

[123]  C. Mayr,et al.  Widespread Shortening of 3′UTRs by Alternative Cleavage and Polyadenylation Activates Oncogenes in Cancer Cells , 2009, Cell.

[124]  J. Mattick,et al.  Non‐coding RNAs: regulators of disease , 2010, The Journal of pathology.

[125]  Takaya Saito,et al.  MicroRNAs--targeting and target prediction. , 2010, New biotechnology.

[126]  J. Mattick,et al.  Small regulatory RNAs in mammals. , 2005, Human molecular genetics.

[127]  J. Beaudoin,et al.  5′-UTR G-quadruplex structures acting as translational repressors , 2010, Nucleic acids research.

[128]  D. Cane,et al.  The nonsense-mediated decay RNA surveillance pathway. , 2007, Annual review of biochemistry.

[129]  C. Gissi,et al.  Structural and functional features of eukaryotic mRNA untranslated regions. , 2001, Gene.

[130]  Haifan Lin,et al.  piRNAs in the Germ Line , 2007, Science.

[131]  T. Chow,et al.  A new internal-ribosome-entry-site motif potentiates XIAP- mediated cytoprotection , 1999, Nature Cell Biology.

[132]  D. Cacchiarelli,et al.  A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA , 2011, Cell.

[133]  R. Mantovani,et al.  A survey of 178 NF-Y binding CCAAT boxes. , 1998, Nucleic acids research.

[134]  J. T. Kadonaga,et al.  The RNA polymerase II core promoter - the gateway to transcription. , 2008, Current opinion in cell biology.

[135]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[136]  Paulo P. Amaral,et al.  The Eukaryotic Genome as an RNA Machine , 2008, Science.

[137]  John S Mattick,et al.  Long noncoding RNAs in cell biology. , 2011, Seminars in cell & developmental biology.

[138]  Shankar Balasubramanian,et al.  An RNA G-quadruplex in the 5' UTR of the NRAS proto-oncogene modulates translation. , 2007, Nature chemical biology.

[139]  Can Cenik,et al.  Genome-wide functional analysis of human 5' untranslated region introns , 2010, Genome Biology.

[140]  Xuexiu Zheng,et al.  Chimeric RNAs as potential biomarkers for tumor diagnosis. , 2012, BMB reports.

[141]  Ferdinando Di Cunto,et al.  Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs , 2011, Cell.

[142]  M. Mehler,et al.  Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease , 2012, Nature Reviews Neuroscience.

[143]  G. Helt,et al.  Transcriptional Maps of 10 Human Chromosomes at 5-Nucleotide Resolution , 2005, Science.

[144]  Daehyun Baek,et al.  Characterization and predictive discovery of evolutionarily conserved mammalian alternative promoters. , 2007, Genome research.

[145]  Cory Y. McLean,et al.  Human-specific loss of regulatory DNA and the evolution of human-specific traits , 2011, Nature.

[146]  N A Kolchanov,et al.  Eukaryotic mRNAs encoding abundant and scarce proteins are statistically dissimilar in many structural features , 1998, FEBS letters.

[147]  Terrence S. Furey,et al.  Both Noncoding and Protein-Coding RNAs Contribute to Gene Expression Evolution in the Primate Brain , 2010, Genome biology and evolution.

[148]  P. Pandolfi,et al.  In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma , 2011, Cell.

[149]  B. Hall,et al.  Human cell type diversity, evolution, development, and classification with special reference to cells derived from the neural crest , 2006, Biological reviews of the Cambridge Philosophical Society.

[150]  I. Terenin,et al.  [Efficient cap-dependent in vitro and in vivo translation of mammalian mRNAs with long and highly structured 5'-untranslated regions]. , 2009, Molekuliarnaia biologiia.

[151]  Klaus Wethmar,et al.  Upstream open reading frames: Molecular switches in (patho)physiology , 2010, BioEssays : news and reviews in molecular, cellular and developmental biology.

[152]  Masaru Taniguchi Tomio Tada 1934–2010 , 2010, Nature Immunology.

[153]  D. Perkins,et al.  Additional layers of gene regulatory complexity from recently discovered microRNA mechanisms. , 2010, The international journal of biochemistry & cell biology.

[154]  Josef Pánek,et al.  Translation Reinitiation Relies on the Interaction between eIF3a/TIF32 and Progressively Folded cis-Acting mRNA Elements Preceding Short uORFs , 2011, PLoS genetics.

[155]  J. Mattick Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[156]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[157]  I. Terenin,et al.  Cap- and IRES-independent scanning mechanism of translation initiation as an alternative to the concept of cellular IRESs , 2010, Molecules and cells.

[158]  C. Y. Chen,et al.  AU-rich elements: characterization and importance in mRNA degradation. , 1995, Trends in biochemical sciences.

[159]  Eric C. Lai,et al.  Endogenous small interfering RNAs in animals , 2008, Nature Reviews Molecular Cell Biology.

[160]  Wenfang Liu,et al.  Alternative promoter use in eye development: the complex role and regulation of the transcription factor MITF , 2008, Development.

[161]  D. Gallie The cap and poly(A) tail function synergistically to regulate mRNA translational efficiency. , 1991, Genes & development.

[162]  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.

[163]  W. L. Ruzzo,et al.  Comparative genomics beyond sequence-based alignments: RNA structures in the ENCODE regions. , 2008, Genome research.

[164]  Paulo P. Amaral,et al.  RNA regulation of epigenetic processes , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[165]  Peter Saffrey,et al.  Complex Exon-Intron Marking by Histone Modifications Is Not Determined Solely by Nucleosome Distribution , 2010, PloS one.

[166]  D. Morris,et al.  Upstream Open Reading Frames as Regulators of mRNA Translation , 2000, Molecular and Cellular Biology.

[167]  A. K. Banerjee 5'-terminal cap structure in eucaryotic messenger ribonucleic acids. , 1980, Microbiological reviews.

[168]  J. Mattick The central role of RNA in human development and cognition , 2011, FEBS letters.

[169]  Nancy A. Monteiro-Riviere,et al.  Structure and Function of Skin , 2010 .

[170]  J. Mattick,et al.  RNAs as extracellular signaling molecules. , 2008, Journal of molecular endocrinology.

[171]  Sheng Tan,et al.  Retained introns increase putative microRNA targets within 3′ UTRs of human mRNA , 2007, FEBS letters.

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

[173]  W. Filipowicz,et al.  The widespread regulation of microRNA biogenesis, function and decay , 2010, Nature Reviews Genetics.

[174]  J. Raymond,et al.  Translational Control of β2-Adrenergic Receptor mRNA by T-cell-restricted Intracellular Antigen-related Protein* , 2005, Journal of Biological Chemistry.

[175]  T. Elton,et al.  Trisomy-21 gene dosage over-expression of miRNAs results in the haploinsufficiency of specific target proteins , 2010, RNA biology.

[176]  Kaushal Kumar,et al.  Comparative analysis of chromatin landscape in regulatory regions of human housekeeping and tissue specific genes , 2005, BMC Bioinformatics.

[177]  A. Sandelin,et al.  PROMoter uPstream Transcripts share characteristics with mRNAs and are produced upstream of all three major types of mammalian promoters , 2011, Nucleic acids research.

[178]  Mikkel H. Schierup,et al.  RNA Exosome Depletion Reveals Transcription Upstream of Active Human Promoters , 2008, Science.

[179]  J. Gorodkin,et al.  Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure. , 2006, Genome research.

[180]  J. Pfeilschifter,et al.  Modulation of mRNA stability as a novel therapeutic approach. , 2007, Pharmacology & therapeutics.

[181]  D. Bartel,et al.  MicroRNA-Directed Cleavage of HOXB8 mRNA , 2004, Science.

[182]  J. Mattick The central role of RNA in the genetic programming of complex organisms. , 2010, Anais da Academia Brasileira de Ciencias.

[183]  J. Mattick Non‐coding RNAs: the architects of eukaryotic complexity , 2001, EMBO reports.

[184]  L. Steinmetz,et al.  Bidirectional promoters generate pervasive transcription in yeast , 2009, Nature.

[185]  K. Morris,et al.  RNA and transcriptional modulation of gene expression , 2008, Cell cycle.

[186]  J. Mattick,et al.  RNA editing, DNA recoding and the evolution of human cognition , 2008, Trends in Neurosciences.

[187]  G. Dreyfuss,et al.  General RNA binding proteins render translation cap dependent. , 1996, The EMBO journal.

[188]  D. Cooper,et al.  A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants , 2006, Human Genetics.

[189]  J. Steitz,et al.  AU-Rich-Element-Mediated Upregulation of Translation by FXR1 and Argonaute 2 , 2007, Cell.

[190]  Françoise Bono,et al.  Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells , 2011, Molecular biology of the cell.

[191]  Sumio Sugano,et al.  The functional consequences of alternative promoter use in mammalian genomes. , 2008, Trends in genetics : TIG.

[192]  C. Wahlestedt,et al.  Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation , 2012, Nature Biotechnology.

[193]  William A. Richardson,et al.  Poly(A)-binding proteins are functionally distinct and have essential roles during vertebrate development , 2011, Proceedings of the National Academy of Sciences.

[194]  Elmar Wahle,et al.  Messenger RNA Turnover in Eukaryotes: Pathways and Enzymes , 2004, Critical reviews in biochemistry and molecular biology.

[195]  R. Myers,et al.  Comprehensive analysis of transcriptional promoter structure and function in 1% of the human genome. , 2005, Genome research.

[196]  G. Stamatoyannopoulos,et al.  Developmental specificity of recruitment of TBP to the TATA box of the human gamma-globin gene. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[197]  J. Lykke-Andersen,et al.  Regulated and quality-control mRNA turnover pathways in eukaryotes. , 2010, Biochemical Society transactions.

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

[199]  John C Mathers,et al.  Induction of epigenetic alterations by dietary and other environmental factors. , 2010, Advances in genetics.

[200]  J. Mattick,et al.  A global view of genomic information--moving beyond the gene and the master regulator. , 2010, Trends in genetics : TIG.

[201]  A. Prats,et al.  Generation of protein isoform diversity by alternative initiation of translation at non‐AUG codons , 2003, Biology of the cell.

[202]  K. Khabar,et al.  Alternative polyadenylation variants of the RNA binding protein, HuR: abundance, role of AU-rich elements and auto-Regulation , 2009, Nucleic acids research.

[203]  J. Mattick RNA regulation: a new genetics? , 2004, Nature Reviews Genetics.

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

[205]  N. Gray,et al.  The roles of cytoplasmic poly(A)-binding proteins in regulating gene expression: a developmental perspective. , 2004, Briefings in functional genomics & proteomics.

[206]  Philipp Kapranov,et al.  Pseudogenes in the ENCODE regions: consensus annotation, analysis of transcription, and evolution. , 2007, Genome research.

[207]  B. Tian,et al.  Systematic Analysis of Cis-Elements in Unstable mRNAs Demonstrates that CUGBP1 Is a Key Regulator of mRNA Decay in Muscle Cells , 2010, PloS one.

[208]  W. Theurkauf,et al.  Biogenesis and germline functions of piRNAs , 2007, Development.

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

[210]  H. Meijer,et al.  Control of eukaryotic protein synthesis by upstream open reading frames in the 5'-untranslated region of an mRNA. , 2002, The Biochemical journal.

[211]  M. Kozak,et al.  Effects of intercistronic length on the efficiency of reinitiation by eucaryotic ribosomes. , 1987, Molecular and cellular biology.

[212]  Peter J. Lukavsky,et al.  Structure and function of HCV IRES domains , 2009, Virus research.

[213]  V. Speirs,et al.  Expression of oestrogen receptor beta isoforms is regulated by transcriptional and post-transcriptional mechanisms. , 2010, The Biochemical journal.

[214]  K. Kinzler,et al.  The Antisense Transcriptomes of Human Cells , 2008, Science.

[215]  G. Stamatoyannopoulos,et al.  Developmental specificity of recruitment of TBP to the TATA box of the human γ-globin gene , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[216]  Martin S. Taylor,et al.  Genome-wide analysis of mammalian promoter architecture and evolution , 2006, Nature Genetics.

[217]  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.

[218]  I. Terenin,et al.  Efficient cap-dependent translation of mammalian mRNAs with long and highly structured 5′-untranslated regions in vitro and in vivo , 2009, Molecular Biology.

[219]  C. Wahlestedt Natural antisense and noncoding RNA transcripts as potential drug targets. , 2006, Drug discovery today.

[220]  A. Komar,et al.  Internal Ribosome Entry Sites in Cellular mRNAs: Mystery of Their Existence* , 2005, Journal of Biological Chemistry.

[221]  C. Cremers,et al.  Novel coding‐region polymorphisms in mitochondrial seryl‐tRNA synthetase (SARSM) and mitoribosomal protein S12 (RPMS12) genes in DFNA4 autosomal dominant deafness families , 2001, Human mutation.

[222]  Howard Y. Chang,et al.  Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis , 2010, Nature.

[223]  J. F. Atkins,et al.  uORFs with unusual translational start codons autoregulate expression of eukaryotic ornithine decarboxylase homologs , 2008, Proceedings of the National Academy of Sciences.

[224]  Tsutomu Suzuki,et al.  Characterization and tRNA Recognition of Mammalian Mitochondrial Seryl-tRNA Synthetase* , 2000, The Journal of Biological Chemistry.

[225]  G. M. Wilson,et al.  A Hairpin-like Structure within an AU-rich mRNA-destabilizing Element Regulates trans-Factor Binding Selectivity and mRNA Decay Kinetics* , 2005, Journal of Biological Chemistry.

[226]  Bing Su,et al.  Small but influential: the role of microRNAs on gene regulatory network and 3'UTR evolution. , 2009, Journal of genetics and genomics = Yi chuan xue bao.

[227]  David Baltimore,et al.  MicroRNA-155 is induced during the macrophage inflammatory response , 2007, Proceedings of the National Academy of Sciences.

[228]  J. Kieft,et al.  Toward a structural understanding of IRES RNA function. , 2009, Current opinion in structural biology.

[229]  S. Abu-Ghanem,et al.  PKCeta confers protection against apoptosis by inhibiting the pro-apoptotic JNK activity in MCF-7 cells. , 2009, Experimental cell research.

[230]  C. Meristoudis,et al.  The structure of the 5′-untranslated region of mammalian poly(A) polymerase-α mRNA suggests a mechanism of translational regulation , 2010, Molecular and Cellular Biochemistry.

[231]  Tim R. Mercer,et al.  Expression of distinct RNAs from 3′ untranslated regions , 2010, Nucleic acids research.

[232]  Jon R Lorsch,et al.  The molecular mechanics of eukaryotic translation. , 2003, Annual review of biochemistry.

[233]  D. Peabody,et al.  Translation initiation at non-AUG triplets in mammalian cells. , 1989, The Journal of biological chemistry.

[234]  M. Minczuk,et al.  An Upstream Open Reading Frame and the Context of the Two AUG Codons Affect the Abundance of Mitochondrial and Nuclear RNase H1 , 2010, Molecular and Cellular Biology.

[235]  D. Haussler,et al.  Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. , 2005, Genome research.

[236]  M. Magnani,et al.  A potent enhancer element in the 5'-UTR intron is crucial for transcriptional regulation of the human ubiquitin C gene. , 2009, Gene.

[237]  G. Rappold,et al.  Transcriptional and Translational Regulation of the Léri-Weill and Turner Syndrome Homeobox Gene SHOX* , 2003, Journal of Biological Chemistry.

[238]  Sumio Sugano,et al.  Analysis of small human proteins reveals the translation of upstream open reading frames of mRNAs. , 2004, Genome research.

[239]  L. Paillard,et al.  Protein expression is increased by a class III AU-rich element and tethered CUG-BP1. , 2006, Biochemical and biophysical research communications.

[240]  E. Wahle,et al.  Poly(A) Tail Length Is Controlled by the Nuclear Poly(A)-binding Protein Regulating the Interaction between Poly(A) Polymerase and the Cleavage and Polyadenylation Specificity Factor* , 2009, The Journal of Biological Chemistry.

[241]  Reuven Agami,et al.  RNA-Binding Protein Dnd1 Inhibits MicroRNA Access to Target mRNA , 2007, Cell.