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From the Sequence to Cell Modeling: Comprehensive Functional Genomics in Escherichia coli

  • Mori, Hirotada (Research and Education Center of Genetic Information, Nara Institute of Science and Technology, Institute of Advanced Biosciences, Keio University)
  • Published : 2004.01.31
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Abstract

As a result of the enormous amount of information that has been collected with E. coli over the past half century (e.g. genome sequence, mutant phenotypes, metabolic and regulatory networks, etc.), we now have detailed knowledge about gene regulation, protein activity, several hundred enzyme reactions, metabolic pathways, macromolecular machines, and regulatory interactions for this model organism. However, understanding how all these processes interact to form a living cell will require further characterization, quantification, data integration, and mathematical modeling, systems biology. No organism can rival E. coli with respect to the amount of available basic information and experimental tractability for the technologies needed for this undertaking. A focused, systematic effort to understand the E. coli cell will accelerate the development of new post-genomic technologies, including both experimental and computational tools. It will also lead to new technologies that will be applicable to other organisms, from microbes to plants, animals, and humans. E. coli is not only the best studied free-living model organism, but is also an extensively used microbe for industrial applications, especially for the production of small molecules of interest. It is an excellent representative of Gram-negative commensal bacteria. E. coli may represent a perfect model organism for systems biology that is aimed at elucidating both its free-living and commensal life-styles, which should open the door to whole-cell modeling and simulation.

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References

  1. Aiba, H., Baba, T., Hayashi, K., Inada, T., Isono, K., Itoh, T., Kasai, H., Kashimoto, K., Kimura, S., Kitakawa, M. et al. (1996) A 570-kb DNA sequence of the Escherichia coli K-12 genome corresponding to the 28.0-40.1 min region on the linkage map. DNA Res. 3, 363-377. https://doi.org/10.1093/dnares/3.6.363
  2. Allen, T. E., Herrgard, M. J., Liu, M., Qiu, Y., Glasner, J. D., Blattner, F. R. and Palsson, B. O. (2003) Genome-scale analysis of the uses of the Escherichia coli genome: modeldriven analysis of heterogeneous data sets. J. Bacteriol. 185, 6392-6399. https://doi.org/10.1128/JB.185.21.6392-6399.2003
  3. Arifuzzaman, M. (in preparation).
  4. Baba, T. (in preparation).
  5. Baudin, A., Ozier-Kalogeropoulos, O., Denouel, A., Lacroute, F. and Cullin, C. (1993) A simple and efficient method for direct gene deletion in Saccharomyces cerevisiae. Nucleic Acids Res. 21, 3329-3330. https://doi.org/10.1093/nar/21.14.3329
  6. Bergler, H., Hogenauer, G. and Turnowsky, F. (1992) Sequences of the envM gene and of two mutated alleles in Escherichia coli. J. Gen. Microbiol. 138, 2093-2100. https://doi.org/10.1099/00221287-138-10-2093
  7. Blattner, F. R., Plunkett, G., 3rd, Bloch, C. A., Perna, N. T., Burland, V., Riley, M., Collado-Vides, J., Glasner, J. D., Rode, C. K., Mayhew, G. F. et al. (1997) The complete genome sequence of Escherichia coli K-12. Science 277, 1453-1474. https://doi.org/10.1126/science.277.5331.1453
  8. Corbin, R. W., Paliy, O., Yang, F., Shabanowitz, J., Platt, M., Lyons, C. E., Jr, Root, K., McAuliffe, J., Jordan, M. I., Kustu, S., Soupene, E. and Hunt, D. F. (2003) Toward a protein profile of Escherichia coli: comparison to its transcription profile. Proc. Natl. Acad. Sci. USA 100, 9232-9237. https://doi.org/10.1073/pnas.1533294100
  9. Datsenko, K. A. and Wanner, B. L. (2000) One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl. Acad. Sci. USA 97, 6640-6645. https://doi.org/10.1073/pnas.120163297
  10. Edwards, J. S. and Palsson, B. O. (2000) The Escherichia coli MG1655 in silico metabolic genotype: its definition, characteristics, and capabilities. Proc. Natl. Acad. Sci. USA 97, 5528-5533. https://doi.org/10.1073/pnas.97.10.5528
  11. Ehrenberg, M., Elf, J., Aurell, E., Sandberg, R. and Tegner, J. (2003) Systems biology is taking off. Genome Res. 13, 2377-2380. https://doi.org/10.1101/gr.1763203
  12. Fiehn, O. (2002) Metabolomics--the link between genotypes and phenotypes. Plant Mol. Biol. 48, 155-171. https://doi.org/10.1023/A:1013713905833
  13. Fiehn, O., Kopka, J., Dormann, P., Altmann, T., Trethewey, R. N. and Willmitzer, L. (2000) Metabolite profiling for plant functional genomics. Nat. Biotechnol. 18, 1157-1161. https://doi.org/10.1038/81137
  14. Figeys, D., Gygi, S. P., Zhang, Y., Watts, J., Gu, M. and Aebersold, R. (1998) Electrophoresis combined with novel mass spectrometry techniques: powerful tools for the analysis of proteins and proteomes. Electrophoresis 19, 1811-1818. https://doi.org/10.1002/elps.1150191045
  15. Forster, J., Famili, I., Fu, P., Palsson, B. O. and Nielsen, J. (2003) Genome-scale reconstruction of the Saccharomyces cerevisiae metabolic network. Genome Res. 13, 244-253. https://doi.org/10.1101/gr.234503
  16. Fromont-Racine, M., Rain, J. C. and Legrain, P. (1997) Toward a functional analysis of the yeast genome through exhaustive two-hybrid screens. Nat. Genet. 16, 277-282. https://doi.org/10.1038/ng0797-277
  17. Gavin, A. C., Bosche, M., Krause, R., Grandi, P., Marzioch, M., Bauer, A., Schultz, J., Rick, J. M., Michon, A. M., Cruciat, C. M. et al. (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141-147. https://doi.org/10.1038/415141a
  18. Goryanin, I., Hodgman, T. C. and Selkov, E. (1999) Mathematical simulation and analysis of cellular metabolism and regulation. Bioinformatics 15, 749-758. https://doi.org/10.1093/bioinformatics/15.9.749
  19. Gutierrez-Rios, R. M., Rosenblueth, D. A., Loza, J. A., Huerta, A. M., Glasner, J. D., Blattner, F. R. and Collado-Vides, J. (2003) Regulatory network of Escherichia coli: consistency between literature knowledge and microarray profiles. Genome Res. 13, 2435-2443. https://doi.org/10.1101/gr.1387003
  20. Gygi, S. P., Rist, B. and Aebersold, R. (2000) Measuring gene expression by quantitative proteome analysis. Curr. Opin. Biotechnol. 11, 396-401. https://doi.org/10.1016/S0958-1669(00)00116-6
  21. Hayashi, T., Makino, K., Ohnishi, M., Kurokawa, K., Ishii, K., Yokoyama, K., Han, C. G., Ohtsubo, E., Nakayama, K., Murata, T. et al. (2001) Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7 and genomic comparison with a laboratory strain K-12. DNA Res. 8, 11-22. https://doi.org/10.1093/dnares/8.1.11
  22. Herrgard, M. J., Covert, M. W. and Palsson, B. O. (2003) Reconciling gene expression data with known genome-scale regulatory network structures. Genome Res. 13, 2423-2434. https://doi.org/10.1101/gr.1330003
  23. Hill, C. W. and Harnish, B. W. (1981) Inversions between ribosomal RNA genes of Escherichia coli. Proc. Natl. Acad. Sci. USA 78, 7069-7072.
  24. Hill, T. M. (1996) in Escherichia coli and Salmonella: Cellular and Molecular Biology. Neidhart. F. C. (ed.), ASM Press, Washington, USA.
  25. Horiuchi, T. (in preparation).
  26. Hucka, M., Finney, A., Sauro, H. M., Bolouri, H., Doyle, J. C., Kitano, H., Arkin, A. P., Bornstein, B. J., Bray, D., Cornish-Bowden, A. et al. (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19, 524-531. https://doi.org/10.1093/bioinformatics/btg015
  27. Ishino, Y., Shinagawa, H., Makino, K., Amemura, M. and Nakata, A. (1987) Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. J. Bacteriol. 169, 5429-5433.
  28. Ito, T., Chiba, T., Ozawa, R., Yoshida, M., Hattori, M. and Sakaki, Y. (2001) A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc. Natl. Acad. Sci. USA 98, 4569-4574. https://doi.org/10.1073/pnas.061034498
  29. Itoh, T., Aiba, H., Baba, T., Hayashi, K., Inada, T., Isono, K., Kasai, H., Kimura, S., Kitakawa, M., Kitagawa, M. et al. (1996) A 460-kb DNA sequence of the Escherichia coli K-12 genome corresponding to the 40.1-50.0 min region on the linkage map. DNA Res. 3, 379-392. https://doi.org/10.1093/dnares/3.6.379
  30. Itoh, T., Okayama, T., Hashimoto, H., Takeda, J., Davis, R. W., Mori, H. and Gojobori, T. (1999) A low rate of nucleotide changes in Escherichia coli K-12 estimated from a comparison of the genome sequences between two different substrains. FEBS Lett. 450, 72-76. https://doi.org/10.1016/S0014-5793(99)00481-0
  31. Kanehisa, M., Goto, S., Kawashima, S. and Nakaya, A. (2002) The KEGG databases at GenomeNet. Nucleic Acids Res. 30, 42-46. https://doi.org/10.1093/nar/30.1.42
  32. Kitagawa, M. M. H. (in preparation).
  33. Kolisnychenko, V., Plunkett, G., 3rd, Herring, C. D., Feher, T., Posfai, J., Blattner, F. R. and Posfai, G. (2002) Engineering a reduced Escherichia coli genome. Genome Res. 12, 640-647. https://doi.org/10.1101/gr.217202
  34. Koonin, E. V., Tatusov, R. L. and Rudd, K. E. (1995) Sequence similarity analysis of Escherichia coli proteins: functional and evolutionary implications. Proc. Natl. Acad. Sci. USA 92, 11921-11925. https://doi.org/10.1073/pnas.92.25.11921
  35. Kumar, A., Agarwal, S., Heyman, J. A., Matson, S., Heidtman, M., Piccirillo, S., Umansky, L., Drawid, A., Jansen, R., Liu, Y., Cheung, K. H., Miller, P., Gerstein, M., Roeder, G. S. and Snyder, M. (2002) Subcellular localization of the yeast proteome. Genes Dev. 16, 707-719. https://doi.org/10.1101/gad.970902
  36. Lockhart, D. J., Dong, H., Byrne, M. C., Follettie, M. T., Gallo, M. V., Chee, M. S., Mittmann, M., Wang, C., Kobayashi, M., Horton, H. and Brown, E. L. (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat. Biotechnol. 14, 1675-1680. https://doi.org/10.1038/nbt1296-1675
  37. Maharjan, R. P. and Ferenci, T. (2003) Global metabolite analysis: the influence of extraction methodology on metabolome profiles of Escherichia coli. Anal. Biochem. 313, 145-154. https://doi.org/10.1016/S0003-2697(02)00536-5
  38. Mahillon, J. and Chandler, M. (1998) Insertion sequences. Microbiol. Mol. Biol. Rev. 62, 725-774.
  39. Mahillon, J., Leonard, C. and Chandler, M. (1999) IS elements as constituents of bacterial genomes. Res. Microbiol. 150, 675-687. https://doi.org/10.1016/S0923-2508(99)00124-2
  40. Masuda, N. and Church, G. M. (2003) Regulatory network of acid resistance genes in Escherichia coli. Mol. Microbiol. 48, 699-712. https://doi.org/10.1046/j.1365-2958.2003.03477.x
  41. Mendes, P. and Kell, D. B. (2001) MEG (Model Extender for Gepasi): a program for the modellingmodeling of complex, heterogeneous, cellular systems. Bioinformatics 17, 288-289. https://doi.org/10.1093/bioinformatics/17.3.288
  42. Mori, H., Isono, K., Horiuchi, T. and Miki, T. (2000) Functional genomics of Escherichia coli in Japan. Res Microbiol. 151, 121-128. https://doi.org/10.1016/S0923-2508(00)00119-4
  43. Nakata, A., Amemura, M. and Makino, K. (1989) Unusual nucleotide arrangement with repeated sequences in the Escherichia coli K-12 chromosome. J. Bacteriol. 171, 3553-3556.
  44. O'Farrell, P. H. (1975) High resolution two-dimensional electrophoresis of proteins. J. Biol. Chem. 250, 4007-4021.
  45. Oshima, T., Aiba, H., Baba, T., Fujita, K., Hayashi, K., Honjo, A., Ikemoto, K., Inada, T., Itoh, T., Kajihara, M. et al. (1996) A 718-kb DNA sequence of the Escherichia coli K-12 genome corresponding to the 12.7-28.0 min region on the linkage map. DNA Res. 3, 137-155. https://doi.org/10.1093/dnares/3.3.137
  46. Oshima, T., Aiba, H., Masuda, Y., Kanaya, S., Sugiura, M., Wanner, B. L., Mori, H. and Mizuno, T. (2002) Transcriptome analysis of all two-component regulatory system mutants of Escherichia coli K-12. Mol. Microbiol. 46, 281-291. https://doi.org/10.1046/j.1365-2958.2002.03170.x
  47. Perna, N. T., Plunkett, G., 3rd, Burland, V., Mau, B., Glasner, J. D., Rose, D. J., Mayhew, G. F., Evans, P. S., Gregor, J., Kirkpatrick, H. A. et al. (2001) Genome sequence of enterohaemorrhagic Escherichia coli O157:H7. Nature 409, 529-533. https://doi.org/10.1038/35054089
  48. Raamsdonk, L. M., Teusink, B., Broadhurst, D., Zhang, N., Hayes, A., Walsh, M. C., Berden, J. A., Brindle, K. M., Kell, D. B., Rowland, J. J., Westerhoff, H. V., van Dam, K. and Oliver, S. G. (2001) A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations. Nat. Biotechnol. 19, 45-50. https://doi.org/10.1038/83496
  49. Reed, J. L. and Palsson, B. O. (2003) Thirteen years of building constraint-based in silico models of Escherichia coli. J. Bacteriol. 185, 2692-2699. https://doi.org/10.1128/JB.185.9.2692-2699.2003
  50. Reed, J. L., Vo, T. D., Schilling, C. H. and Palsson, B. O. (2003) An expanded genome-scale model of Escherichia coli K-12 (iJR904 GSM/GPR). Genome Biol. 4, R54. https://doi.org/10.1186/gb-2003-4-9-r54
  51. Rigaut, G., Shevchenko, A., Rutz, B., Wilm, M., Mann, M. and Seraphin, B. (1999) A generic protein purification method for protein complex characterization and proteome exploration. Nat. Biotechnol. 17, 1030-1032. https://doi.org/10.1038/13732
  52. Riley, M. and Labedan, B. (1997) Protein evolution viewed through Escherichia coli protein sequences: introducing the notion of a structural segment of homology, the module. J. Mol. Biol. 268, 857-868. https://doi.org/10.1006/jmbi.1997.1003
  53. Ross-Macdonald, P., Coelho, P. S., Roemer, T., Agarwal, S., Kumar, A., Jansen, R., Cheung, K. H., Sheehan, A., Symoniatis, D., Umansky, L. et al. (1999) Large-scale analysis of the yeast genome by transposon tagging and gene disruption. Nature 402, 413-418. https://doi.org/10.1038/46558
  54. Rudd, K. E. (1999) Novel intergenic repeats of Escherichia coli K-12. Res. Microbiol. 150, 653-664. https://doi.org/10.1016/S0923-2508(99)00126-6
  55. Sabatti, C., Rohlin, L., Oh, M. K. and Liao, J. C. (2002) Coexpression pattern from DNA microarray experiments as a tool for operon prediction. Nucleic Acids Res. 30, 2886-2893. https://doi.org/10.1093/nar/gkf388
  56. Sharples, G. J. and Lloyd, R. G. (1990) A novel repeated DNA sequence located in the intergenic regions of bacterial chromosomes. Nucleic Acids Res. 18, 6503-6508. https://doi.org/10.1093/nar/18.22.6503
  57. Shen-Orr, S. S., Milo, R., Mangan, S. and Alon, U. (2002) Network motifs in the transcriptional regulation network of Escherichia coli. Nat. Genet. 31, 64-68. https://doi.org/10.1038/ng881
  58. Smith, G. R. (1988) Homologous recombination in procaryotes. Microbiol. Rev. 52, 1-28.
  59. Soga, T., Ohashi, Y., Ueno, Y., Naraoka, H., Tomita, M. and Nishioka, T. (2003) Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J. Proteome Res. 2, 488-494. https://doi.org/10.1021/pr034020m
  60. Soga, T., Ueno, Y., Naraoka, H., Matsuda, K., Tomita, M. and Nishioka, T. (2002a) Pressure-assisted capillary electrophoresis electrospray ionization mass spectrometry for analysis of multivalent anions. Anal. Chem. 74, 6224-6229. https://doi.org/10.1021/ac0202684
  61. Soga, T., Ueno, Y., Naraoka, H., Ohashi, Y., Tomita, M. and Nishioka, T. (2002b) Simultaneous determination of anionic intermediates for Bacillus subtilis metabolic pathways by capillary electrophoresis electrospray ionization mass spectrometry. Anal. Chem. 74, 2233-2239. https://doi.org/10.1021/ac020064n
  62. Storz, G. (2002) An expanding universe of noncoding RNAs. Science 296, 1260-1263.
  63. Tao, H., Bausch, C., Richmond, C., Blattner, F. R. and Conway, T. (1999) Functional genomics: expression analysis of Escherichia coli growing on minimal and rich media. J. Bacteriol. 181, 6425-6440.
  64. Tatusov, R. L., Koonin, E. V. and Lipman, D. J. (1997) A genomic perspective on protein families. Science 278, 631-637. https://doi.org/10.1126/science.278.5338.631
  65. Tomita, M., Hashimoto, K., Takahashi, K., Shimizu, T. S., Matsuzaki, Y., Miyoshi, F., Saito, K., Tanida, S., Yugi, K., Venter, J. C. and Hutchison, C. A., 3rd. (1999) E-CELL: software environment for whole-cell simulation. Bioinformatics 15, 72-84. https://doi.org/10.1093/bioinformatics/15.1.72
  66. Tweeddale, H., Notley-McRobb, L. and Ferenci, T. (1998) Effect of slow growth on metabolism of Escherichia coli, as revealed by global metabolite pool ('metabolome') analysis. J. Bacteriol. 180, 5109-5116.
  67. Uetz, P., Giot, L., Cagney, G., Mansfield, T. A., Judson, R. S., Knight, J. R., Lockshon, D., Narayan, V., Srinivasan, M., Pochart, P. et al. (2000) A comprehensive analysis of proteinprotein interactions in Saccharomyces cerevisiae. Nature 403, 623-627. https://doi.org/10.1038/35001009
  68. Van Dyk, T. K., Wei, Y., Hanafey, M. K., Dolan, M., Reeve, M. J., Rafalski, J. A., Rothman-Denes, L. B. and LaRossa, R. A. (2001) A genomic approach to gene fusion technology. Proc. Natl. Acad. Sci. USA 98, 2555-2560. https://doi.org/10.1073/pnas.041620498
  69. Vanbogelen, R. A. (1996) in Escherichia coli and Salmonella: Cellular and Molecular Biology. ed. Neidhart. F. C.
  70. Wada, A., Koyama, K., Maki, Y., Shimoi, Y., Tanaka, A. and Tsuji, H. (1993) A 5 kDa protein (SCS23) from the 30S subunit of the spinach chloroplast ribosome. FEBS Lett. 319, 115-118. https://doi.org/10.1016/0014-5793(93)80048-Y
  71. Yamamoto, Y., Aiba, H., Baba, T., Hayashi, K., Inada, T., Isono, K., Itoh, T., Kimura, S., Kitagawa, M., Makino, K. et al. (1997) Construction of a contiguous 874-kb sequence of the Escherichia coli-K12 genome corresponding to 50.0-68.8 min on the linkage map and analysis of its sequence features. DNA Res. 4, 91-113. https://doi.org/10.1093/dnares/4.2.91
  72. Yu, B. J., Sung, B. H., Koob, M. D., Lee, C. H., Lee, J. H., Lee, W. S., Kim, M. S. and Kim, S. C. (2002) Minimization of the Escherichia coli genome using a Tn5-targeted Cre/loxP excision system. Nat. Biotechnol. 20, 1018-1023. https://doi.org/10.1038/nbt740
  73. Zhu, H., Bilgin, M., Bangham, R., Hall, D., Casamayor, A., Bertone, P., Lan, N., Jansen, R., Bidlingmaier, S., Houfek, T., Mitchell, T., Miller, P., Dean, R. A., Gerstein, M. and Snyder, M. (2001) Global analysis of protein activities using proteome chips. Science 293, 2101-2105. https://doi.org/10.1126/science.1062191

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