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A computational study of bacterial gene regulation and adaptation on a genomic scaleAswin Sai Narain SeshasayeePhD ThesisA computational study of bacterial gene regulationand adaptation on a genomic scaleAswin Sai Narain SeshasayeeSummaryBacteria make up the simplest form of free-living life known to man. They are single-celledand vulnerable to adverse and dynamic environmental forces and yet, they have coloniseddiverse niches. Many bacteria can thrive in multiple habitats, each with its own distinct set ofnutrients. Much of their adaptive capabilities can be attributed to precise and rapid regulationof protein production and activity in response to prevailing environmental signals. Regulationof protein production and activity is achieved by a range of mechanisms involving smallmolecules, DNA, RNA and proteins. Making use of publicly-available genomic andfunctional genomic data, this thesis examines the following aspects of regulatory mechanismsutilised by bacteria:DNA sequence, 3D topology and trans-acting proteins in bacterialtranscriptional controlRegions involving transcriptional initiation in bacteria have a high AT-content. This enablesbinding of transcription factors to the DNA, and also allows easier unwinding of the DNA inorder to facilitate transcriptional initiation. Further, DNA supercoiling, a 3D topologicalproperty of the DNA, could complement or supersede the above in tightening or furtherunwinding the DNA, thus influencing transcriptional initiation. Using genome sequence andfunctional genomic data for E. coli, we investigate the balance between these two propertiesof DNA in controlling transcription.Small-molecules and regulation of metabolismNearly half of all transcription factors in the model bacterium Escherichia coli, unlike ineukaryotes, contain a domain that can potentially bind to a small-molecule. Thesepreferentially regulate enzymes of small-molecule metabolism, thus establishing a directinteraction between metabolism and its transcriptional regulation. In addition, small-
molecules also bind to enzymes directly and influence their activity. These two functionallyand kinetically complementary control mechanisms orchestrate genome-scale control ofsmall-molecule metabolism in E. coli. We make use of publicly available functional andgenomic data to understand general principles that underly the deployment of these tworegulatory mechanisms.A computational study of bacterial gene regulation and adaptation on a genomic scaleAswin Sai Narain SeshasayeePhD ThesisSecond messenger signalling by small-moleculesCyclic nucleotides are a class of small-molecules which act as ‘second messengers’ incontrolling diverse cellular processes. One such ubiquitous bacterial second messenger iscyclic-di-GMP, which controls complex processes including motility, adhesion and virulence.Using comparative genomics, we examine the phylogenetic distribution of proteins involvedin the turnover of this molecule across bacteria; how the numerous proteins, per bacterialgenome, involved in its synthesis are regulated; and enumerate the various scenarios that areapplicable to the activity of the unique class of proteins that contain domains involved in boththe synthesis and the hydrolysis of this molecule.One- and two-component signalling mechanisms in bacteriaIn this study, we perform a comparative genomic study to assess the prevalence of twocomponentregulatory mechanisms in genomes and metagenomes in an attempt to answerquestions related to (a) the balance between transcriptional and non-transcriptional outputs oftwo-component systems; (b) the balance between the sensing of internal and external signalsby two-component systems; (c) how small-molecule sensing systems are distributed betweenone- and two-component signalling systems; and (d) how the above might contribute to ourunderstanding of why bacteria have evolved complex, multi-component signalling systems.Conclusions and future directionsThis thesis presents a largely computational analysis of various bacterial regulatorymechanisms, significantly adding to existing body of academic research in this field.Mechanisms involving small regulatory RNAs, though important, are not studied here. Onefuture direction is to make use of this accrued knowledge in understanding the evolution ofbacterial pathogens as an adaptive phenomenon.
Page 3: Statement of lengthThis thesis does
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Chapter 1: Global regulators of bac
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Chapter 1: Global regulators of bac
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Chapter 2: Transcriptional control
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Chapter 4: Comparative genomics of
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two-domain architectures wherethese
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(A)60% of genomes from class4530150
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Discussion and conclusionsDiscussio
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Discussion and conclusionsD1.1.3. C
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Discussion and conclusionsD2. Futur
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BibliographyAmikam, D., Steinberger
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BibliographyBlattner, F.R., Plunket
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BibliographyChen, S.L., Hung, C.S.,
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BibliographyEchols, N., Harrison, P
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Bibliographysystem level analysis o
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BibliographyHerring, C.D., Raghunat
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BibliographyJenal, U., and Malone,
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BibliographyKeseler, I.M., Collado-
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BibliographyLee, S.H., Angelichio,
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BibliographyMcClelland, M., Sanders
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BibliographyO Croinin, T., Carroll,
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BibliographyPrice, M.N., Dehal, P.S
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BibliographySatriano, J., and Schlo
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BibliographySteinberger, O., Lapido
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BibliographyUssery, D.W., Wassenaar
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BibliographyYanofsky, C. 1981. Atte
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Appendix 1Appendix 1.1: Differences
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Appendix 1Appendix 1.5: Gene expres
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Appendix 2Appendix 2.1: Differences
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Appendix 2Appendix 2.3: Co-regulati
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Appendix 2Appendix 2.5: Flux coupli
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Appendix 2Appendix 2.7: Co-regulati
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Appendix 2Appendix 2.8B: Connectivi
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Appendix 2Appendix 2.10: Correlatio
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Appendix 2Appendix 2.12A: Robustnes
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Appendix 3Appendix 3Supplementary m
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Reaction ID Regulatory metabolite I
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Appendix 3Appendix 3.3B: Direct reg
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Appendix 3Appendix 3.4B: Direct reg
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Appendix 4Appendix 4Supplementary m
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Appendix 4Motile organisms are rich
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Appendix 4We can expand the analysi
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Appendix 5Appendix 5.1A: PFAMs for
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Appendix 5Appendix 5.1C: PFAMs for
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Appendix 5Appendix 5.2B: Small-mole
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Appendix 5Appendix 5.3: Organisms s
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Appendix 5Appendix 5.5: Partner dom
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Appendix 5fraction of SDRRs would a
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Appendix 5Appendix 5.6C: Non-hybrid
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Appendix 5Appendix 5.8: List of org
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Appendix 6Appendix 6List of genomes
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Appendix 648. Mycobacterium tubercu
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Appendix 6144. Bacillus cereus ATCC
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Appendix 6240. Nitrobacter winograd
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Appendix 6336. Cytophaga hutchinson
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Appendix 6432. Acinetobacter bauman
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Appendix 6528. Enterobacter sakazak
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Appendix 6624. Polynucleobacter nec
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Appendix 7Appendix 7List of genomes
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Appendix 748. Bordetella parapertus
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Appendix 7144. Haemophilus somnus14
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Appendix 7240. Prochlorococcus mari
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Appendix 7336. Synechococcus sp. CC
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Downloaded from genome.cshlp.org on
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JOURNAL OF BACTERIOLOGY, June 2008,
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VOL. 190, 2008 P. MIRABILIS GENOME
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2 Nucleic Acids Research, 2008PCR a
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4 Nucleic Acids Research, 2008Table
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8 Nucleic Acids Research, 2008solve
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An Assessment of the Role of DNA Ad
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DAM and Transcriptionpotential of s
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