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Integrative Systems Approaches to Study Innate Immunity

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Clinical Applications of Immunomics

Part of the book series: Immunomics Reviews ((IMMUN,volume 2))

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Abstract

Integrative Systems Biology has emerged as an exciting research approach in molecular biology and functional genomics that involves a systematic use of genomic, proteomic, and metabolomic technologies for the construction of network based models of biological processes. These endeavors, collectively referred to as systems biology establish a paradigm by which to systematically interrogate, model, and iteratively refine our knowledge of the regulatory events within a cell. Here we discuss the latest experimental and computational advances in Integrative Systems Biology, with particular emphasis in approaches specifically designed to identify transcriptional networks governing the macrophage immune response to Lipopolysaccaride (LPS). We show examples where using this approach we are not only able to infer a global macrophage transcriptional network, but also time-specific sub-networks that are dynamically active across the LPS response. Another exiting aspect of this new approach to molecular sciences is that can be applied virtually to any mammalian systems.

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References

  • Aderem, A.: Systems biology: its practice and challenges. Cell 121: 511–3, 2005

    Article  PubMed  CAS  Google Scholar 

  • Bar-Joseph, Z., Gerber, G. K., Lee, T. I., Rinaldi, N. J., Yoo, J. Y., Robert, F., Gordon, D. B., Fraenkel, E., Jaakkola, T. S., Young, R. A., and Gifford, D. K.: Computational discovery of gene modules and regulatory networks. Nat Biotechnol 21: 1337–42, 2003

    Article  PubMed  CAS  Google Scholar 

  • Beutler, B.: The Toll-like receptors: analysis by forward genetic methods. Immunogenetics 57: 385–92, 2005

    Article  PubMed  CAS  Google Scholar 

  • Beutler, B., Georgel, P., Rutschmann, S., Jiang, Z., Croker, B., and Crozat, K.: Genetic analysis of innate resistance to mouse cytomegalovirus (MCMV). Brief Funct Genomic Proteomic 4: 203–13, 2005

    Article  PubMed  CAS  Google Scholar 

  • Birney, E. and Stamatoyannopoulos, J. A. and Dutta, A. and Guigo, R. and Gingeras, T. R. and Margulies, E. H. and Weng, Z. and Snyder, M. and Dermitzakis, E. T. and Thurman, R. E. and Kuehn, M. S. and Taylor, C. M. and Neph, S. and Koch, C. M. and Asthana, S. and Malhotra, A. and Adzhubei, I. and Greenbaum, J. A. and Andrews, R. M. and Flicek, P. and Boyle, P. J. and Cao, H. and Carter, N. P. and Clelland, G. K. and Davis, S. and Day, N. and Dhami, P. and Dillon, S. C. and Dorschner, M. O. and Fiegler, H. and Giresi, P. G. and Goldy, J. and Hawrylycz, M. and Haydock, A. and Humbert, R. and James, K. D. and Johnson, B. E. and Johnson, E. M. and Frum, T. T. and Rosenzweig, E. R. and Karnani, N. and Lee, K. and Lefebvre, G. C. and Navas, P. A. and Neri, F. and Parker, S. C. and Sabo, P. J. and Sandstrom, R. and Shafer, A. and Vetrie, D. and Weaver, M. and Wilcox, S. and Yu, M. and Collins, F. S. and Dekker, J. and Lieb, J. D. and Tullius, T. D. and Crawford, G. E. and Sunyaev, S. and Noble, W. S. and Dunham, I. and Denoeud, F. and Reymond, A. and Kapranov, P. and Rozowsky, J. and Zheng, D. and Castelo, R. and Frankish, A. and Harrow, J. and Ghosh, S. and Sandelin, A. and Hofacker, I. L. and Baertsch, R. and Keefe, D. and Dike, S. and Cheng, J. and Hirsch, H. A. and Sekinger, E. A. and Lagarde, J. and Abril, J. F. and Shahab, A. and Flamm, C. and Fried, C. and Hackermuller, J. and Hertel, J. and Lindemeyer, M. and Missal, K. and Tanzer, A. and Washietl, S. and Korbel, J. and Emanuelsson, O. and Pedersen, J. S. and Holroyd, N. and Taylor, R. and Swarbreck, D. and Matthews, N. and Dickson, M. C. and Thomas, D. J. and Weirauch, M. T. and Gilbert, J., et al.: Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447: 799–816, 2007

    Article  PubMed  CAS  Google Scholar 

  • Calvano, S. E., Xiao, W., Richards, D. R., Felciano, R. M., Baker, H. V., Cho, R. J., Chen, R. O., Brownstein, B. H., Cobb, J. P., Tschoeke, S. K., Miller-Graziano, C., Moldawer, L. L., Mindrinos, M. N., Davis, R. W., Tompkins, R. G., and Lowry, S. F.: A network-based analysis of systemic inflammation in humans. Nature 437: 1032–7, 2005

    Article  PubMed  CAS  Google Scholar 

  • Carninci, P., Sandelin, T.A., Lenhard, B., Katayamal, S., Shimokawa, K., Ponjavic, P., Semple, C.A., Taylor, M.S., Engstrom, P., Frith, M., Forrest, A.R.R., Alkema, W.B., Tan, S.L., Plessy, C., Kodzius, K., Ravasi, T. et al. Genome-wide analysis of mammalian promoter architecture and evolution. Nat Genet. 38(6):626–35, 2006

    Google Scholar 

  • Challen, G., Gardiner, B., Caruana, G., Kostoulias, X., Martinez, G., Crowe, M., Taylor, D. F., Bertram, J., Little, M., and Grimmond, S. M.: Temporal and spatial transcriptional programs in murine kidney development. Physiol Genomics 23: 159–71, 2005

    Article  PubMed  CAS  Google Scholar 

  • Challen, G. A., Martinez, G., Davis, M. J., Taylor, D. F., Crowe, M., Teasdale, R. D., Grimmond, S. M., and Little, M. H.: Identifying the molecular phenotype of renal progenitor cells. J Am Soc Nephrol 15: 2344–57, 2004

    Article  PubMed  CAS  Google Scholar 

  • Dai, X. M., Ryan, G. R., Hapel, A. J., Dominguez, M. G., Russell, R. G., Kapp, S., Sylvestre, V., and Stanley, E. R.: Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99: 111–20, 2002

    Article  PubMed  CAS  Google Scholar 

  • de Lichtenberg, U., Jensen, L. J., Brunak, S., and Bork, P.: Dynamic complex formation during the yeast cell cycle. Science 307: 724–7, 2005

    Article  PubMed  Google Scholar 

  • di Bernardo, D., Thompson, M. J., Gardner, T. S., Chobot, S. E., Eastwood, E. L., Wojtovich, A. P., Elliott, S. J., Schaus, S. E., and Collins, J. J.: Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks. Nat Biotechnol 23: 377–83, 2005

    Article  PubMed  Google Scholar 

  • Duarte, N. C., Becker, S. A., Jamshidi, N., Thiele, I., Mo, M. L., Vo, T. D., Srivas, R., and Palsson, B. O.: Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci USA 104: 1777–82, 2007

    Article  PubMed  CAS  Google Scholar 

  • Fortier, A., Min-Oo, G., Forbes, J., Lam-Yuk-Tseung, S., and Gros, P.: Single gene effects in mouse models of host: pathogen interactions. J Leukoc Biol 77: 868–77, 2005

    Article  PubMed  CAS  Google Scholar 

  • Gao, F., Foat, B. C., and Bussemaker, H. J.: Defining transcriptional networks through integrative modeling of mRNA expression and transcription factor binding data. BMC Bioinformatics 5: 31, 2004

    Article  PubMed  Google Scholar 

  • Gardner, T. S., di Bernardo, D., Lorenz, D., and Collins, J. J.: Inferring genetic networks and identifying compound mode of action via expression profiling. Science 301: 102–5, 2003

    Article  PubMed  CAS  Google Scholar 

  • Harbison, C. T., Gordon, D. B., Lee, T. I., Rinaldi, N. J., Macisaac, K. D., Danford, T. W., Hannett, N. M., Tagne, J. B., Reynolds, D. B., Yoo, J., Jennings, E. G., Zeitlinger, J., Pokholok, D. K., Kellis, M., Rolfe, P. A., Takusagawa, K. T., Lander, E. S., Gifford, D. K., Fraenkel, E., and Young, R. A.: Transcriptional regulatory code of a eukaryotic genome. Nature 431: 99–104, 2004

    Article  PubMed  CAS  Google Scholar 

  • Hart, G. T., Ramani, A. K., and Marcotte, E. M.: How complete are current yeast and human protein-interaction networks? Genome Biol 7: 120, 2006

    Article  PubMed  Google Scholar 

  • Himes, S. R. and Hume, D. A.: Transcription factors that regulate macrophage development. Handb Exp Pharmacol 158: 11–40, 2003

    Article  Google Scholar 

  • Ho, Y., Gruhler, A., Heilbut, A., Bader, G. D., Moore, L., Adams, S. L., Millar, A., Taylor, P., Bennett, K., Boutilier, K., Yang, L., Wolting, C., Donaldson, I., Schandorff, S., Shewnarane, J., Vo, M., Taggart, J., Goudreault, M., Muskat, B., Alfarano, C., Dewar, D., Lin, Z., Michalickova, K., Willems, A. R., Sassi, H., Nielsen, P. A., Rasmussen, K. J., Andersen, J. R., Johansen, L. E., Hansen, L. H., Jespersen, H., Podtelejnikov, A., Nielsen, E., Crawford, J., Poulsen, V., Sorensen, B. D., Matthiesen, J., Hendrickson, R. C., Gleeson, F., Pawson, T., Moran, M. F., Durocher, D., Mann, M., Hogue, C. W., Figeys, D., and Tyers, M.: Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415: 180–3, 2002

    Article  PubMed  CAS  Google Scholar 

  • Hsing, M., Bellenson, J. L., Shankey, C., and Cherkasov, A.: Modeling of cell signaling pathways in macrophages by semantic networks. BMC Bioinformatics 5: 156, 2004

    Article  PubMed  Google Scholar 

  • Hume, D. A.: The mononuclear phagocyte system. Curr Opin Immunol 18: 49–53, 2006

    Article  PubMed  CAS  Google Scholar 

  • Hume, D. A., Ross, I. L., Himes, S. R., Sasmono, R. T., Wells, C. A., and Ravasi, T.: The mononuclear phagocyte system revisited. J Leukoc Biol 72: 621–7, 2002

    PubMed  CAS  Google Scholar 

  • Katayama, S., Tomaru, Y., Kasukawa, T., Waki, K., Nakanishi, M., Nakamura, M., Nishida, H., Yap, C. C., Suzuki, M., Kawai, J., Suzuki, H., Carninci, P., Hayashizaki, Y., Wells, C., Frith, M., Ravasi, T., Pang, K. C., Hallinan, J., Mattick, J., Hume, D. A., Lipovich, L., Batalov, S., Engstrom, P. G., Mizuno, Y., Faghihi, M. A., Sandelin, A., Chalk, A. M., Mottagui-Tabar, S., Liang, Z., Lenhard, B., and Wahlestedt, C.: Antisense transcription in the mammalian transcriptome. Science 309: 1564–6, 2005

    Article  PubMed  Google Scholar 

  • Kummerfeld, S.K. and Teichmann, S.A. DBD: a transcription factor prediction database. Nucleic Acids Res. 34, 2006

    Google Scholar 

  • Lee, T. I., Rinaldi, N. J., Robert, F., Odom, D. T., Bar-Joseph, Z., Gerber, G. K., Hannett, N. M., Harbison, C. T., Thompson, C. M., Simon, I., Zeitlinger, J., Jennings, E. G., Murray, H. L., Gordon, D. B., Ren, B., Wyrick, J. J., Tagne, J. B., Volkert, T. L., Fraenkel, E., Gifford, D. K., and Young, R. A.: Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298: 799–804, 2002

    Article  PubMed  CAS  Google Scholar 

  • Liao, J. C., Boscolo, R., Yang, Y. L., Tran, L. M., Sabatti, C., and Roychowdhury, V. P.: Network component analysis: reconstruction of regulatory signals in biological systems. Proc Natl Acad Sci U S A 100: 15522–7, 2003

    Google Scholar 

  • Lichanska, A. M. and Hume, D. A.: Origins and functions of phagocytes in the embryo. Exp Hematol 28: 601–11, 2000

    Article  PubMed  CAS  Google Scholar 

  • MacDonald, K. P., Rowe, V., Bofinger, H. M., Thomas, R., Sasmono, T., Hume, D. A., and Hill, G. R.: The colony-stimulating factor 1 receptor is expressed on dendritic cells during differentiation and regulates their expansion. J Immunol 175: 1399–405, 2005

    PubMed  CAS  Google Scholar 

  • Mann, M., Hendrickson, R. C., and Pandey, A.: Analysis of proteins and proteomes by mass spectrometry. Annu Rev Biochem 70: 437–73, 2001

    Article  PubMed  CAS  Google Scholar 

  • Nilsson, R., Bajic, V.B., Katayama, K., Suzuki, H., Reid, J.F., Sweet, M.J., Gariboldi, M., Carninici, P., Hayashizaki, Y., Hume, D.A., Tegner, J., and Ravasi, T.: Transcriptional network dynamics governing macrophage activation. Genomics 88(2): 133–42, 2006

    Google Scholar 

  • Ravasi, T., Huber, T., Zavolan, M., Forrest, A., Gaasterland, T., Grimmond, S., and Hume, D. A.: Systematic characterization of the zinc-finger-containing proteins in the mouse transcriptome. Genome Res 13: 1430–42, 2003

    Article  PubMed  CAS  Google Scholar 

  • Ravasi, T., Suzuki, H., Pang, K. C., Katayama, S., Furuno, M., Okunishi, R., Fukuda, S., Ru, K., Frith, M. C., Gongora, M. M., Grimmond, S. M., Hume, D. A., Hayashizaki, Y., and Mattick, J. S.: Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res 16: 11–9, 2006

    Article  PubMed  CAS  Google Scholar 

  • Rehli, M., Lichanska, A., Cassady, A. I., Ostrowski, M. C., and Hume, D. A.: TFEC is a macrophage-restricted member of the microphthalmia-TFE subfamily of basic helix-loop-helix leucine zipper transcription factors. J Immunol 162: 1559–65, 1999

    PubMed  CAS  Google Scholar 

  • Rehli, M., Sulzbacher, S., Pape, S., Ravasi, T., Wells, C. A., Heinz, S., Sollner, L., El Chartouni, C., Krause, S. W., Steingrimsson, E., Hume, D. A., and Andreesen, R.: Transcription factor Tfec contributes to the IL-4-inducible expression of a small group of genes in mouse macrophages including the granulocyte colony-stimulating factor receptor. J Immunol 174: 7111–22, 2005

    PubMed  CAS  Google Scholar 

  • Ren, B., Robert, F., Wyrick, J. J., Aparicio, O., Jennings, E. G., Simon, I., Zeitlinger, J., Schreiber, J., Hannett, N., Kanin, E., Volkert, T. L., Wilson, C. J., Bell, S. P., and Young, R. A.: Genome-wide location and function of DNA binding proteins. Science 290: 2306–9, 2000

    Article  PubMed  CAS  Google Scholar 

  • Ross, I. L., Yue, X., Ostrowski, M. C., and Hume, D. A.: Interaction between PU.1 and another Ets family transcription factor promotes macrophage-specific Basal transcription initiation. J Biol Chem 273: 6662–9, 1998

    Article  PubMed  CAS  Google Scholar 

  • Rual, J. F., Venkatesan, K., Hao, T., Hirozane-Kishikawa, T., Dricot, A., Li, N., Berriz, G. F., Gibbons, F. D., Dreze, M., Ayivi-Guedehoussou, N., Klitgord, N., Simon, C., Boxem, M., Milstein, S., Rosenberg, J., Goldberg, D. S., Zhang, L. V., Wong, S. L., Franklin, G., Li, S., Albala, J. S., Lim, J., Fraughton, C., Llamosas, E., Cevik, S., Bex, C., Lamesch, P., Sikorski, R. S., Vandenhaute, J., Zoghbi, H. Y., Smolyar, A., Bosak, S., Sequerra, R., Doucette-Stamm, L., Cusick, M. E., Hill, D. E., Roth, F. P., and Vidal, M.: Towards a proteome-scale map of the human protein-protein interaction network. Nature 437: 1173–8, 2005

    Article  PubMed  CAS  Google Scholar 

  • Sasmono, R. T., Oceandy, D., Pollard, J. W., Tong, W., Pavli, P., Wainwright, B. J., Ostrowski, M. C., Himes, S. R., and Hume, D. A.: A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood 101: 1155–63, 2003

    Article  PubMed  CAS  Google Scholar 

  • Schroder, K., Hertzog, P. J., Ravasi, T., and Hume, D. A.: Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75: 163–89, 2004

    Article  PubMed  CAS  Google Scholar 

  • Segal, E., Friedman, N., Kaminski, N., Regev, A., and Koller, D.: From signatures to models: understanding cancer using microarrays. Nat Genet 37 Suppl: S38–45, 2005

    Article  Google Scholar 

  • Sester, D. P., Trieu, A., Brion, K., Schroder, K., Ravasi, T., Robinson, J. A., McDonald, R. C., Ripoll, V., Wells, C. A., Suzuki, H., Hayashizaki, Y., Stacey, K. J., Hume, D. A., and Sweet, M. J.: LPS regulates a set of genes in primary murine macrophages by antagonising CSF-1 action. Immunobiology 210: 97–107, 2005

    Article  PubMed  CAS  Google Scholar 

  • Simonis, N., van Helden, J., Cohen, G. N., and Wodak, S. J.: Transcriptional regulation of protein complexes in yeast. Genome Biol 5: R33, 2004

    Article  PubMed  Google Scholar 

  • Su, A. I., Wiltshire, T., Batalov, S., Lapp, H., Ching, K. A., Block, D., Zhang, J., Soden, R., Hayakawa, M., Kreiman, G., Cooke, M. P., Walker, J. R., and Hogenesch, J. B.: A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101: 6062–7, 2004

    Article  PubMed  CAS  Google Scholar 

  • Suzuki, H., Saito, R., Kanamori, M., Kai, C., Schonbach, C., Nagashima, T., Hosaka, J., and Hayashizaki, Y.: The mammalian protein-protein interaction database and its viewing system that is linked to the main FANTOM2 viewer. Genome Res 13: 1534–41, 2003

    Article  PubMed  CAS  Google Scholar 

  • Sweet, M. J. and Hume, D. A.: CSF-1 as a regulator of macrophage activation and immune responses. Arch Immunol Ther Exp (Warsz) 51: 169–77, 2003

    CAS  Google Scholar 

  • Tagoh, H., Himes, R., Clarke, D., Leenen, P. J., Riggs, A. D., Hume, D., and Bonifer, C.: Transcription factor complex formation and chromatin fine structure alterations at the murine c-fms (CSF-1 receptor) locus during maturation of myeloid precursor cells. Genes Dev 16: 1721–37, 2002

    Article  PubMed  CAS  Google Scholar 

  • Tan, K., Shlomi, T., Feizi, H., Ideker, T., and Sharan, R.: Transcriptional regulation of protein complexes within and across species. Proc Natl Acad Sci USA 104: 1283–8, 2007

    Article  PubMed  CAS  Google Scholar 

  • Tegner, J. and Bjorkegren, J.: Perturbations to uncover gene networks. Trends Genet 23: 34–41, 2007

    Article  PubMed  CAS  Google Scholar 

  • Tegner, J., Nilsson, R., Bajic, V. B., Bjorkegren, J., and Ravasi, T.: Systems biology of innate immunity. Cell Immunol 244: 105–9, 2006

    Article  PubMed  CAS  Google Scholar 

  • Tomlins, S. A., Mehra, R., Rhodes, D. R., Cao, X., Wang, L., Dhanasekaran, S. M., Kalyana-Sundaram, S., Wei, J. T., Rubin, M. A., Pienta, K. J., Shah, R. B., and Chinnaiyan, A. M.: Integrative molecular concept modeling of prostate cancer progression. Nat Genet 39: 41–51, 2007

    Article  PubMed  CAS  Google Scholar 

  • Wells, C. A., Chalk, A., Forrest, A., Taylor, D., Waddell, N., Schroder, K., Himes, S. R., Faulkner, G., Lo, S., Kasukawa, T., Kawaji, H., Kai, C., Kawai, J., Katayama, S., Carninci, P., Hayashizaki, Y., Hume, D. A., and Grimmond, S. M.: Alternative transcription of the toll-like receptor signalling cascade. Genome Biol 7: R10, 2006

    Article  PubMed  Google Scholar 

  • Wells, C. A., Ravasi, T., Faulkner, G. J., Carninci, P., Okazaki, Y., Hayashizaki, Y., Sweet, M., Wainwright, B. J., and Hume, D. A.: Genetic control of the innate immune response. BMC Immunol 4: 5, 2003a

    Article  Google Scholar 

  • Wells, C. A., Ravasi, T., Sultana, R., Yagi, K., Carninci, P., Bono, H., Faulkner, G., Okazaki, Y., Quackenbush, J., Hume, D. A., and Lyons, P. A.: Continued discovery of transcriptional units expressed in cells of the mouse mononuclear phagocyte lineage. Genome Res 13: 1360–5, 2003b

    Article  CAS  Google Scholar 

  • Yu, H., Luscombe, N. M., Lu, H. X., Zhu, X., Xia, Y., Han, J. D., Bertin, N., Chung, S., Vidal, M., and Gerstein, M.: Annotation transfer between genomes: protein-protein interologs and protein-DNA regulogs. Genome Res 14: 1107–18, 2004

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Timothy Ravasi was supported by the National Institute of Mental Health (NIMH), grant 2P30MH062261-07.

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  1. Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

    Timothy Ravasi

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    Ravasi, T. (2009). Integrative Systems Approaches to Study Innate Immunity. In: Falus, A. (eds) Clinical Applications of Immunomics. Immunomics Reviews, vol 2. Springer, New York, NY. https://doi.org/10.1007/978-0-387-79208-8_1

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