Investigating the link between tRNA and mRNA abundance PDF
Preview Investigating the link between tRNA and mRNA abundance
ThisdissertationissubmittedforthedegreeofDoctorofPhilosophy Investigating the link between tRNA and mRNA abundance in mammals Konrad Ludwig Moritz Rudolph May 2015 St Edmund’s College, University of Cambridge EMBL-EBI Thesourcecodeofthethesisisavailableathttps://github.com/klmr/thesis. LicensedunderCreativeCommonsAttribution(CCBY)3.0 Thisdissertationistheresultofmyownworkandincludesnothingwhichis theoutcomeofworkdoneincollaborationexceptasdeclaredinthePreface andspecifiedinthetext. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, isbeingconcurrentlysubmittedforanysuchdegree,diplomaorotherqual- ification at the University of Cambridge or any other University of similar institutionexceptasdeclaredinthePrefaceandspecifiedinthetext. ItdoesnotexceedtheprescribedwordlimitfortherelevantDegreeCom- mittee. 3 Contents Listofabbreviations 9 ListofFigures 11 ListofTables 15 Summary 17 Acknowledgements 19 1. Introduction 21 1.1. Thecentraldogma 21 1.1.1. dna 22 1.1.2. rna 24 1.1.3. Proteins 25 1.2. Transcription&translation 26 1.2.1. Transcription 26 1.2.2. Thegeneticcode 28 1.2.3. Transferrna 28 1.2.4. Translation 34 1.3. rnasequencingquantifiesprotein-codinggeneexpression 36 1.3.1. Thetranscriptomereflectsthestateofthecell 36 1.3.2. Microarrays 36 1.3.3. rna-seq 37 1.3.4. Expressionnormalisation 40 1.3.5. Differentialexpression 42 5 contents 1.4. PoliiiChip-sequencingquantifiestrnageneexpression 43 1.4.1. Chip-seqisadnabindingassay 43 1.4.2. Quantifyingexpressionoftrnagenes 44 1.5. Mouseliverdevelopment 47 1.6. Quantifyingcodonusageandanticodonabundance 49 1.7. Structureofthisthesis 54 2. Developmentalstabilityofthemrna–trnainterface 55 2.1. Protein-codinggeneexpressionchangesdynamically duringmousedevelopment 57 2.2. Dynamicchangesoftrnageneexpressionduringmouse development 61 2.3. Everymousemrnatranscriptomeencodesthesame distributionoftripletcodonsandaminoacids 64 2.4. Stableisoacceptoranticodonabundancethrough developmentindicatestightregulationoftrnagene expression 67 2.5. mrnatripletcodonusageishighlycorrelatedwithtrna anticodonisoacceptorabundanceduringdevelopment 67 2.6. Variablechromatinaccessibilitymayinfluencetrnagene transcription 70 2.7. trnaanticodonisoacceptorfamiliesaretranscriptionally compensatedacrossdevelopment 75 3. Implicationsofcodon–anticodoninteractionontheregulation oftranslation 81 3.1. “Adualprogramfortranslationregulationincellular proliferationanddifferentiation” 81 3.1.1. trnaanticodonschangeinabundanceintumour tissues 82 3.1.2. Codonusagediffersbetweengenesinvolvedincell proliferationandgenesinvolvedindifferentiation 82 6 contents 3.1.3. Differentialcodonusageincell-conditionspecific genesetsmatchestrnaanticodonabundancein correspondingcells 84 3.2. Aretrnaanticodonabundanceandcodonusagehighly adaptedtodifferentcellularconditions? 87 3.2.1. Theeffectofgenesetsizeoncodonusagebias 88 3.2.2. Theextentofanticodonadaptationtodistinct cellularconditions 90 3.2.3. Othergenomicfeaturesmaydrivetheperceived codonusagebias 95 3.3. Discussion 97 3.3.1. Codon–anticodonadaptationtodistinctcellular conditions 98 3.3.2. Evolutionaryconservationofcodon–anticodon adaptation 99 4. Thepoliiitranscriptomeconsistsofmorethanjusttrna 101 4.1. Aprofileofpoliiibindingacrossdifferentfeatures 101 4.1.1. sinesaretranscribedbypoliii 104 5. Conclusion 109 5.1. Discussion 110 5.1.1. Regulationoftrnageneexpression 110 5.1.2. Absenceofevidenceforcodonbias-dependent translationefficiencyinmammals 112 5.1.3. Theextendedpoliiitranscriptome 113 5.2. Futuredirections 114 5.2.1. Regulationoftrnatranscription 114 5.2.2. Codonusageadaptation 114 5.2.3. Poliiitranscriptionofsines 116 7 list of abbreviations APPENDIX A. Supplementarymaterialforchapter2 121 A.1. Code 121 A.2. Supplementaryfiguresandtables 121 B. Supplementarymaterialforchapter3 147 B.1. Code 147 B.2. Supplementarytables 147 C. Supplementarymaterialforchapter4 155 C.1. Code 155 C.2. Supplementaryfigures 155 Bibliography 159 8 List of abbreviations AAB anticodonabundancebias cDNA complementarydna ChIP chromatinimmunoprecipitation ChIP-seq chromatinimmunoprecipitationfollowedbysequencing CTCF CCCTC-bindingfactor CU codonusage CUB codonusagebias DE differentiallyexpressed DNA deoxyribonucleicacid FDR falsediscoveryrate FPKM fragmentsperkilobaseoftranscriptpermillionmappedreadpairs GEO GeneExpressionOmnibus GO GeneOntology GRCm38 GenomeReferenceConsortiumMouseBuild38 HIV-1 type-1humanimmunodeficiencyvirus HTS high-throughputsequencing LINE longinterspersednuclearelement lncRNA longnon-codingrna mRNA messengerrna NCBIM37 ncbimousegenomebuild37 9 list of abbreviations ncRNA non-codingrna PCA principalcomponentsanalysis PCR polymerasechainreaction Pol I dna-dependentrnapolymerasei Pol II dna-dependentrnapolymeraseii Pol III dna-dependentrnapolymeraseiii RAA relativeanticodonabundance RCU relativecodonusage RISC rna-inducedsilencingcomplex RNA ribonucleicacid RNA-seq rnasequencing RPKM readcountperkilobaseoftranscriptpermillionmappedreads rRNA ribosomalrna SINE shortinterspersednuclearelement tAI trnaadaptationindex TBP TATAbindingprotein TF transcriptionfactor TFIIIB transcriptionfactoriiiB TFIIIC transcriptionfactoriiiC TPM transcriptspermillion tRNA transferrna TSS transcriptionstartsite UTR untranslatedregion 10
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