Systems Microbiology: Gaining Insights in Transcriptional Networks

  • Riet De Smet
  • Karen Lemmens
  • Ana Carolina Fierro
  • Kathleen Marchal


Bacteria are able to adapt to continuously changing environmental conditions. This complex cellular behavior is mediated by the underlying transcriptional network. The advent of high-throughput techniques has allowed large-scale identification of the different cellular entities, their expression patterns, and their biochemical and genetic interactions. Because different “omics” data such as transcription, regulatory motif, or ChIP-chip data unveil distinct aspects of the transcriptional network, their integration leads to a more complete insight into the biological system. Systems microbiology exploits these heterogeneous genome-wide data to obtain global insight into how different biological entities function and interact under various conditions. Several methods for the reconstruction of the corresponding transcriptional networks will be discussed in this chapter. We will also show how their application can contribute to our understanding of biological systems and lead to an improved management of bacterial infections and drug target discovery.


Regulatory Program Transcriptional Network Network Inference Transcriptional Regulatory Network Module Inference 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ackermann M, Stecher B, Freed NE et al (2008) Self-destructive cooperation mediated by phenotypic noise. Nature 454:987–990CrossRefPubMedGoogle Scholar
  2. Andre J, Godelle B (2005) Multicellular organization in bacteria as a target for drug therapy. Ecol Lett 8:800–810CrossRefGoogle Scholar
  3. Arifuzzaman M, Maeda M, Itoh A et al (2006) Large-scale identification of protein–protein interaction of Escherichia coli K-12. Genome Res 16:686–691CrossRefPubMedGoogle Scholar
  4. Baba T, Ara T, Hasegawa M et al (2006) Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol 2:2006CrossRefGoogle Scholar
  5. Babu MM, Teichmann SA (2003) Evolution of transcription factors and the gene regulatory network in Escherichia coli. Nucleic Acids Res 31:1234–1244CrossRefGoogle Scholar
  6. Balaban NQ, Merrin J, Chait R et al (2004) Bacterial persistence as a phenotypic switch. Science 305:1622–1625CrossRefPubMedGoogle Scholar
  7. Bammler T, Beyer RP, Bhattacharya S et al (2005) Standardizing global gene expression analysis between laboratories and across platforms. Nat Methods 2:351–356CrossRefPubMedGoogle Scholar
  8. Barrett T, Troup DB, Wilhite SE et al (2007) NCBI GEO: mining tens of millions of expression profiles – database and tools update. Nucleic Acids Res 35:D760–D765CrossRefPubMedGoogle Scholar
  9. Ben Yehuda S, Fujita M, Liu XS et al (2005) Defining a centromere-like element in Bacillus subtilis by identifying the binding sites for the chromosome-anchoring protein RacA. Mol Cell 17:773–782CrossRefPubMedGoogle Scholar
  10. Bergmann S, Ihmels J, Barkai N (2003) Iterative signature algorithm for the analysis of large-scale gene expression data. Phys Rev E Stat Nonlinear Soft Matter Phys 67:031902Google Scholar
  11. Blot N, Mavathur R, Geertz M et al (2006) Homeostatic regulation of supercoiling sensitivity coordinates transcription of the bacterial genome. EMBO Rep 7:710–715CrossRefPubMedGoogle Scholar
  12. Bochner BR, Gadzinski P, Panomitros E (2001) Phenotype microarrays for high-throughput phenotypic testing and assay of gene function. Genome Res 11:1246–1255CrossRefPubMedGoogle Scholar
  13. Bonneau R, Reiss DJ, Shannon P et al (2006) The Inferelator: an algorithm for learning parsimonious regulatory networks from systems-biology data sets de novo. Genome Biol 7:R36CrossRefPubMedGoogle Scholar
  14. Bonneau R, Facciotti MT, Reiss DJ et al (2007) A predictive model for transcriptional control of physiology in a free living cell. Cell 131:1354–1365CrossRefPubMedGoogle Scholar
  15. Brazma A, Hingamp P, Quackenbush J et al (2001) Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet 29:365–371CrossRefPubMedGoogle Scholar
  16. Brenner S, Johnson M, Bridgham J et al (2000) Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays. Nat Biotechnol 18:630–634CrossRefPubMedGoogle Scholar
  17. Bruggeman FJ, Westerhoff HV (2007) The nature of systems biology. Trends Microbiol 15:45–50CrossRefPubMedGoogle Scholar
  18. Bumann D (2008) Has nature already identified all useful antibacterial targets? Curr Opin Microbiol 11:387–392CrossRefPubMedGoogle Scholar
  19. Butland G, Peregrin-Alvarez JM, Li J et al (2005) Interaction network containing conserved and essential protein complexes in Escherichia coli. Nature 433:531–537CrossRefPubMedGoogle Scholar
  20. Butland G, Babu M, Diaz-Mejia JJ et al (2008) eSGA: E. coli synthetic genetic array analysis. Nat Methods 5:789–795CrossRefPubMedGoogle Scholar
  21. Cegelski L, Marshall GR, Eldridge GR et al (2008) The biology and future prospects of antivirulence therapies. Nat Rev Microbiol 6:17–27CrossRefPubMedGoogle Scholar
  22. Cheng Y, Church GM (2000) Biclustering of expression data. Proc Int Conf Intell Syst Mol Biol 8:93–103PubMedGoogle Scholar
  23. Cho BK, Knight EM, Barrett CL et al (2008a) Genome-wide analysis of Fis binding in Escherichia coli indicates a causative role for A-/AT-tracts. Genome Res 18:900–910CrossRefPubMedGoogle Scholar
  24. Cho BK, Barrett CL, Knight EM et al (2008b) Genome-scale reconstruction of the Lrp regulatory network in Escherichia coli. Proc Natl Acad Sci USA 105:19462–19467CrossRefPubMedGoogle Scholar
  25. de Hoon MJ, Makita Y, Imoto S et al (2004) Predicting gene regulation by sigma factors in Bacillus subtilis from genome-wide data. Bioinform 20(Suppl 1):i101–i108CrossRefGoogle Scholar
  26. De Keersmaecker SC, Thijs IM, Vanderleyden J et al (2006) Integration of omics data: how well does it work for bacteria? Mol Microbiol 62:1239–1250CrossRefPubMedGoogle Scholar
  27. Demeter J, Beauheim C, Gollub J et al (2007) The Stanford Microarray Database: implementation of new analysis tools and open source release of software. Nucleic Acids Res 35:D766–D770CrossRefPubMedGoogle Scholar
  28. Dhollander T, Sheng Q, Lemmens K et al (2007) Query-driven module discovery in microarray data. Bioinformatics 23:2573–2580CrossRefPubMedGoogle Scholar
  29. Dwyer DJ, Kohanski MA, Collins JJ (2008) Networking opportunities for bacteria. Cell 135:1153–1156CrossRefPubMedGoogle Scholar
  30. Eriksson S, Lucchini S, Thompson A et al (2003) Unravelling the biology of macrophage infection by gene expression profiling of intracellular Salmonella enterica. Mol Microbiol 47:103–118CrossRefPubMedGoogle Scholar
  31. Ernst J, Beg QK, Kay KA et al (2008) A semi-supervised method for predicting transcription factor–gene interactions in Escherichia coli. PLoS Comput Biol 4:e1000044CrossRefPubMedGoogle Scholar
  32. Faith JJ, Hayete B, Thaden JT et al (2007) Large-scale mapping and validation of Escherichia coli transcriptional regulation from a compendium of expression profiles. PLoS Biol 5:e8CrossRefPubMedGoogle Scholar
  33. Freiberg C, Brotz-Oesterhelt H (2005) Functional genomics in antibacterial drug discovery. Drug Discov Today 10:927–935CrossRefPubMedGoogle Scholar
  34. Freiberg C, Brotz-Oesterhelt H, Labischinski H (2004) The impact of transcriptome and proteome analyses on antibiotic drug discovery. Curr Opin Microbiol 7:451–459CrossRefPubMedGoogle Scholar
  35. Gama-Castro S, Jimenez-Jacinto V, Peralta-Gil M et al (2008) RegulonDB (version 6.0): gene regulation model of Escherichia coli K-12 beyond transcription, active (experimental) annotated promoters and Textpresso navigation. Nucleic Acids Res 36:D120–D124CrossRefPubMedGoogle Scholar
  36. Gao F, Foat BC, Bussemaker HJ (2004) Defining transcriptional networks through integrative modeling of mRNA expression and transcription factor binding data. BMC Bioinform 5:31CrossRefGoogle Scholar
  37. Getz G, Levine E, Domany E (2000) Coupled two-way clustering analysis of gene microarray data. Proc Natl Acad Sci USA 97:12079–12084CrossRefPubMedGoogle Scholar
  38. Grainger DC, Hurd D, Harrison M et al (2005) Studies of the distribution of Escherichia coli cAMP-receptor protein and RNA polymerase along the E. coli chromosome. Proc Natl Acad Sci USA 102:17693–17698CrossRefPubMedGoogle Scholar
  39. Grainger DC, Hurd D, Goldberg MD et al (2006) Association of nucleoid proteins with coding and non-coding segments of the Escherichia coli genome. Nucleic Acids Res 34:4642–4652CrossRefPubMedGoogle Scholar
  40. Grainger DC, Aiba H, Hurd D et al (2007) Transcription factor distribution in Escherichia coli: studies with FNR protein. Nucleic Acids Res 35:269–278CrossRefPubMedGoogle Scholar
  41. Grifantini R, Bartolini E, Muzzi A et al (2002) Previously unrecognized vaccine candidates against group B meningococcus identified by DNA microarrays. Nat Biotechnol 20:914–921CrossRefPubMedGoogle Scholar
  42. Grote A, Klein J, Retter I et al (2009) PRODORIC (release 2009): a database and tool platform for the analysis of gene regulation in prokaryotes. Nucleic Acids Res 37:D61-–D65CrossRefPubMedGoogle Scholar
  43. Hartwell LH, Hopfield JJ, Leibler S et al (1999) From molecular to modular cell biology. Nature 402:C47–C52CrossRefPubMedGoogle Scholar
  44. Herrgard MJ, Covert MW, Palsson BO (2003) Reconciling gene expression data with known genome-scale regulatory network structures. Genome Res 13(11):2423–2434; Epub (14 Oct 12003) 13:2423–2434CrossRefPubMedGoogle Scholar
  45. Hertzberg L, Zuk O, Getz G et al (2005) Finding motifs in promoter regions. J Comput Biol 12:314–330CrossRefPubMedGoogle Scholar
  46. Hibbs MA, Hess DC, Myers CL et al (2007) Exploring the functional landscape of gene expression: directed search of large microarray compendia. Bioinformatics 23:2692–2699CrossRefPubMedGoogle Scholar
  47. Hutter B, Schaab C, Albrecht S et al (2004) Prediction of mechanisms of action of antibacterial compounds by gene expression profiling. Antimicrob Agents Chemother 48:2838–2844CrossRefPubMedGoogle Scholar
  48. Ihmels J, Bergmann S, Barkai N (2004) Defining transcription modules using large-scale gene expression data. Bioinformatics 20:1993–2003CrossRefPubMedGoogle Scholar
  49. Irizarry RA, Warren D, Spencer F et al (2005) Multiple-laboratory comparison of microarray platforms. Nat Methods 2:345–350CrossRefPubMedGoogle Scholar
  50. Johnson DS, Mortazavi A, Myers RM et al (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316:1497–1502CrossRefPubMedGoogle Scholar
  51. Joshi A, De SR, Marchal K et al (2009) Module networks revisited: computational assessment and prioritization of model predictions. Bioinform 25:490–496CrossRefGoogle Scholar
  52. Kaern M, Elston TC, Blake WJ et al (2005) Stochasticity in gene expression: from theories to phenotypes. Nat Rev Genet 6:451–464CrossRefPubMedGoogle Scholar
  53. Kaushik DK, Sehgal D (2008) Developing antibacterial vaccines in genomics and proteomics era. Scand J Immunol 67:544–552CrossRefPubMedGoogle Scholar
  54. Keseler IM, Bonavides-Martinez C, Collado-Vides J et al (2009) EcoCyc: a comprehensive view of Escherichia coli biology. Nucleic Acids Res 37:D464–D470CrossRefPubMedGoogle Scholar
  55. Kitano H (2002) Computational systems biology. Nature 420:206–210CrossRefPubMedGoogle Scholar
  56. Laub MT, Chen SL, Shapiro L et al (2002) Genes directly controlled by CtrA, a master regulator of the Caulobacter cell cycle. Proc Natl Acad Sci USA 99:4632–4637CrossRefPubMedGoogle Scholar
  57. Lazzeroni L, Owen A (2002) Plaid models for gene expression data. Statist Sinica 2:61–86Google Scholar
  58. Lemmens K, De Bie T, Dhollander T et al (2009) DISTILLER: a data integration framework to reveal condition dependency of complex regulons in Escherichia coli. Genome Biol 10:R27CrossRefPubMedGoogle Scholar
  59. Lucchini S, Rowley G, Goldberg MD et al (2006) H-NS mediates the silencing of laterally acquired genes in bacteria. PLoS Pathog 2:e81CrossRefPubMedGoogle Scholar
  60. Luscombe NM, Babu MM, Yu H et al (2004) Genomic analysis of regulatory network dynamics reveals large topological changes. Nature 431:308–312CrossRefPubMedGoogle Scholar
  61. Madeira SC, Oliveira AL (2004) Biclustering algorithms for biological data analysis: a survey. IEEE/ACM Trans Comput Biol Bioinform 1:24–45CrossRefPubMedGoogle Scholar
  62. Marchal K, De Keersmaecker S, Monsieurs P et al (2004) In silico identification and experimental validation of PmrAB targets in Salmonella typhimurium by regulatory motif detection. Genome Biol 5:R9CrossRefPubMedGoogle Scholar
  63. Margolin AA, Nemenman I, Basso K et al (2006) ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context. BMC Bioinform 7(1):S7CrossRefGoogle Scholar
  64. Matys V, Kel-Margoulis OV, Fricke E et al (2006) TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res 34:D108–D110CrossRefPubMedGoogle Scholar
  65. Merrell DS, Butler SM, Qadri F et al (2002) Host-induced epidemic spread of the cholera bacterium. Nature 417:642–645CrossRefPubMedGoogle Scholar
  66. Michoel T, De Smet R, Joshi A et al (2009) Comparative analysis of module-based versus direct methods for reverse-engineering transcriptional regulatory networks BMC Syst Biol 3:49Google Scholar
  67. Molle V, Fujita M, Jensen ST et al (2003a) The Spo0A regulon of Bacillus subtilis. Mol Microbiol 50:1683–1701CrossRefPubMedGoogle Scholar
  68. Molle V, Nakaura Y, Shivers RP et al (2003b) Additional targets of the Bacillus subtilis global regulator CodY identified by chromatin immunoprecipitation and genome-wide transcript analysis. J Bacteriol 185:1911–1922CrossRefPubMedGoogle Scholar
  69. Mordelet F, Vert JP (2008) SIRENE: supervised inference of regulatory networks. Bioinform 24:i76–i82CrossRefGoogle Scholar
  70. Murali TM, Kasif S (2003) Extracting conserved gene expression motifs from gene expression data. Pacific Symp Biocomput 8:77–88Google Scholar
  71. Navarre WW, Porwollik S, Wang Y et al (2006) Selective silencing of foreign DNA with low GC content by the H-NS protein in Salmonella. Science 313:236–238CrossRefPubMedGoogle Scholar
  72. Orlando V (2000) Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation. Trends Biochem Sci 25:99–104CrossRefPubMedGoogle Scholar
  73. Parkinson H, Kapushesky M, Shojatalab M et al (2007) ArrayExpress – a public database of microarray experiments and gene expression profiles. Nucleic Acids Res 35:D747–D750CrossRefPubMedGoogle Scholar
  74. Perez AG, Angarica VE, Vasconcelos AT et al (2007) Tractor_DB (version 2.0): a database of regulatory interactions in gamma-proteobacterial genomes. Nucleic Acids Res 35:D132–D136CrossRefPubMedGoogle Scholar
  75. Qi Y, Ge H (2006) Modularity and dynamics of cellular networks. PLoS Comput Biol 2:e174CrossRefPubMedGoogle Scholar
  76. Quackenbush J (2001) Computational analysis of microarray data. Nat Rev Genet 2:418–427CrossRefPubMedGoogle Scholar
  77. Reiss DJ, Baliga NS, Bonneau R (2006) Integrated biclustering of heterogeneous genome-wide datasets for the inference of global regulatory networks. BMC Bioinform 7:280CrossRefGoogle Scholar
  78. Ren B, Robert F, Wyrick JJ et al (2000) Genome-wide location and function of DNA binding proteins. Science 290:2306–2309CrossRefPubMedGoogle Scholar
  79. Robertson G, Hirst M, Bainbridge M et al (2007) Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4:651–657CrossRefPubMedGoogle Scholar
  80. Sasik R, Woelk CH, Corbeil J (2004) Microarray truths and consequences. J Mol Endocrinol 33:1–9CrossRefPubMedGoogle Scholar
  81. Segal E, Shapira M, Regev A et al (2003) Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat Genet 34:166–176CrossRefPubMedGoogle Scholar
  82. Sheng Q, Moreau Y, De Moor B (2003) Biclustering microarray data by Gibbs sampling. Bioinform 19(Suppl 2):ii196–ii205Google Scholar
  83. Shi Y, Shi Y (2004) Metabolic enzymes and coenzymes in transcription – a direct link between metabolism and transcription? Trends Genet 20:445–452CrossRefPubMedGoogle Scholar
  84. Sierro N, Makita Y, de Hoon M et al (2008) DBTBS: a database of transcriptional regulation in Bacillus subtilis containing upstream intergenic conservation information. Nucleic Acids Res 36:D93–D96CrossRefPubMedGoogle Scholar
  85. Stickler D (1999) Biofilms. Curr Opin Microbiol 2:270–275CrossRefPubMedGoogle Scholar
  86. Stolovitzky G, Monroe D, Califano A (2007) Dialogue on reverse-engineering assessment and methods: the DREAM of high-throughput pathway inference. Ann N Y Acad Sci 1115:1–22CrossRefPubMedGoogle Scholar
  87. Tanay A, Sharan R, Shamir R (2002) Discovering statistically significant biclusters in gene expression data. Bioinformatics 18(Suppl 1):S136–S144Google Scholar
  88. Thieffry D, Huerta AM, Perez-Rueda E et al (1998) From specific gene regulation to genomic networks: a global analysis of transcriptional regulation in Escherichia coli. Bioessays 20:433–440CrossRefPubMedGoogle Scholar
  89. Thijs IM, De Keersmaecker SC, Fadda A et al (2007) Delineation of the Salmonella enterica serovar Typhimurium HilA regulon through genome-wide location and transcript analysis. J Bacteriol 189:4587–4596CrossRefPubMedGoogle Scholar
  90. Tompa M, Li N, Bailey TL et al (2005) Assessing computational tools for the discovery of transcription factor binding sites. Nat Biotechnol 23:137–144CrossRefPubMedGoogle Scholar
  91. Typas A, Nichols RJ, Siegele DA et al (2008) High-throughput, quantitative analyses of genetic interactions in E. coli. Nat Methods 5:781–787CrossRefPubMedGoogle Scholar
  92. Van den Bulcke T, Lemmens K, Van de Peer Y et al (2006a) Inferring transcriptional networks by mining omics data. Curr Bioinform 1:301–313CrossRefGoogle Scholar
  93. Van den Bulcke T, Van LK, Naudts B et al (2006b) SynTReN: a generator of synthetic gene expression data for design and analysis of structure learning algorithms. BMC Bioinform 7:43CrossRefGoogle Scholar
  94. Voyich JM, Sturdevant DE, Braughton KR et al (2003) Genome-wide protective response used by group A Streptococcus to evade destruction by human polymorphonuclear leukocytes. Proc Natl Acad Sci USA 100:1996–2001CrossRefPubMedGoogle Scholar
  95. Waters LS, Storz G (2009) Regulatory RNAs in bacteria. Cell 136:615–628CrossRefPubMedGoogle Scholar
  96. Yang HL, Zhu YZ, Qin JH et al (2006) In silico and microarray-based genomic approaches to identifying potential vaccine candidates against Leptospira interrogans. BMC Genom 7:293CrossRefGoogle Scholar
  97. Yue H, Eastman PS, Wang BB et al (2001) An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression. Nucleic Acids Res 29:E41CrossRefPubMedGoogle Scholar
  98. Zaki MJ, Hsiao C (2002) CHARM: an efficient algorithm for closed itemset mining. In: Grossman R, Han J, Kumar V, Mannila H, Motwani R (eds) Proc Second SIAM International Conference on Data Mining (SDM ‘02)Google Scholar
  99. Zhou L, Lei XH, Bochner BR et al (2003) Phenotype microarray analysis of Escherichia coli K-12 mutants with deletions of all two-component systems. J Bacteriol 185:4956–4972CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Riet De Smet
    • 1
  • Karen Lemmens
    • 1
  • Ana Carolina Fierro
    • 1
  • Kathleen Marchal
    • 1
  1. 1.Department of Microbial and Molecular SystemsKU LeuvenHeverleeBelgium

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