Error message

No crossref credentials set for sci

Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling

Science, 4 July 2003
Vol. 301, Issue 5629, p. 102-105
DOI: 10.1126/science.1081900

Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling

  1. Timothy S. Gardner1,*,
  2. Diego di Bernardo1,2,*,
  3. David Lorenz1,
  4. James J. Collins1,
  1. 1Center for BioDynamics and Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA. 2Telethon Institute for Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131, Naples, Italy.
  1. To whom correspondence should be addressed. E-mail: jcollins{at}bu.edu
  • * These authors contributed equally to this work.

Abstract

The complexity of cellular gene, protein, and metabolite networks can hinder attempts to elucidate their structure and function. To address this problem, we used systematic transcriptional perturbations to construct a first-order model of regulatory interactions in a nine-gene subnetwork of the SOS pathway in Escherichia coli. The model correctly identified the major regulatory genes and the transcriptional targets of mitomycin C activity in the subnetwork. This approach, which is experimentally and computationally scalable, provides a framework for elucidating the functional properties of genetic networks and identifying molecular targets of pharmacological compounds.

    • Received for publication 24 December 2002.
    • Accepted for publication 3 June 2003.

    Citation:

    T. S. Gardner, D. di Bernardo, D. Lorenz, and J. J. Collins, Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling. Science 301, 102-105 (2003).

    Mechanistic Explanation in Systems Biology: Cellular Networks
    D. Matthiessen
    Br J Philos Sci 0, axv011v1-axv011 (9 April 2015)

    Conditional mutual inclusive information enables accurate quantification of associations in gene regulatory networks
    X. Zhang, J. Zhao, J.-K. Hao, X.-M. Zhao, and L. Chen
    Nucleic Acids Res 43, e31-e31 (11 March 2015)

    Variation and Genetic Control of Gene Expression in Primary Immunocytes across Inbred Mouse Strains
    S. Mostafavi, A. Ortiz-Lopez, M. A. Bogue, K. Hattori, C. Pop, D. Koller, D. Mathis, C. Benoist, and The Immunological Genome Consortium
    J. Immunol. 193, 4485-4496 (1 November 2014)

    Predicting dynamic signaling network response under unseen perturbations
    F. Zhu, and Y. Guan
    Bioinformatics 30, 2772-2778 (1 October 2014)

    Causal network inference using biochemical kinetics
    C. J. Oates, F. Dondelinger, N. Bayani, J. Korkola, J. W. Gray, and S. Mukherjee
    Bioinformatics 30, i468-i474 (1 September 2014)

    Size matters: network inference tackles the genome scale
    B. Hayete, T. S. Gardner, and J. J. Collins
    Mol Syst Biol 3, 77-77 (28 July 2014)

    A network biology approach to prostate cancer
    A. Ergun, C. A. Lawrence, M. A. Kohanski, T. A. Brennan, and J. J. Collins
    Mol Syst Biol 3, 82-82 (28 July 2014)

    Biological context networks: a mosaic view of the interactome
    J. Rachlin, D. D. Cohen, C. Cantor, and S. Kasif
    Mol Syst Biol 2, 66-66 (28 July 2014)

    Human disease classification in the postgenomic era: A complex systems approach to human pathobiology
    J. Loscalzo, I. Kohane, and A.-L. Barabasi
    Mol Syst Biol 3, 124-124 (28 July 2014)

    Monitoring dynamics of single-cell gene expression over multiple cell cycles
    S. Cookson, N. Ostroff, W. L. Pang, D. Volfson, and J. Hasty
    Mol Syst Biol 1, 2005.0024-2005.0024 (28 July 2014)

    A systems biology approach to prediction of oncogenes and molecular perturbation targets in B-cell lymphomas
    K. M. Mani, C. Lefebvre, K. Wang, W. K. Lim, K. Basso, R. Dalla-Favera, and A. Califano
    Mol Syst Biol 4, 169-169 (28 July 2014)

    How to infer gene networks from expression profiles
    M. Bansal, V. Belcastro, A. Ambesi-Impiombato, and D. di Bernardo
    Mol Syst Biol 3, 78-78 (28 July 2014)

    Elucidating regulatory mechanisms downstream of a signaling pathway using informative experiments
    E. Szczurek, I. Gat-Viks, J. Tiuryn, and M. Vingron
    Mol Syst Biol 5, 287-287 (28 July 2014)

    Reverse engineering a hierarchical regulatory network downstream of oncogenic KRAS
    I. Stelniec-Klotz, S. Legewie, O. Tchernitsa, F. Witzel, B. Klinger, C. Sers, H. Herzel, N. Bluthgen, and R. Schafer
    Mol Syst Biol 8, 601-601 (23 July 2014)

    Genome-scale bacterial transcriptional regulatory networks: reconstruction and integrated analysis with metabolic models
    J. P. Faria, R. Overbeek, F. Xia, M. Rocha, I. Rocha, and C. S. Henry
    Brief Bioinform 15, 592-611 (1 July 2014)

    Systems mapping: how to map genes for biomass allocation toward an ideotype
    W. Bo, G. Fu, Z. Wang, F. Xu, Y. Shen, J. Xu, Z. Huang, J. Gai, C. E. Vallejos, R. Wu et al.
    Brief Bioinform 15, 660-669 (1 July 2014)

    Unraveling the regulatory connections between two controllers of breast cancer cell fate
    J. Lee, A. Tiwari, V. Shum, G. B. Mills, M. A. Mancini, O. A. Igoshin, and G. Balazsi
    Nucleic Acids Res 42, 6839-6849 (17 June 2014)

    Functional association networks as priors for gene regulatory network inference
    M. E. Studham, A. Tjarnberg, T. E. M. Nordling, S. Nelander, and E. L. L. Sonnhammer
    Bioinformatics 30, i130-i138 (15 June 2014)

    Towards a comprehensive picture of the genetic landscape of complex traits
    Z. Wang, Y. Wang, N. Wang, J. Wang, Z. Wang, C. E. Vallejos, and R. Wu
    Brief Bioinform 15, 30-42 (1 January 2014)

    hARACNe: improving the accuracy of regulatory model reverse engineering via higher-order data processing inequality tests
    I. S. Jang, A. Margolin, and A. Califano
    Interface Focus 3, 20130011-20130011 (25 June 2013)

    Reverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia
    L. Vallat, C. A. Kemper, N. Jung, M. Maumy-Bertrand, F. Bertrand, N. Meyer, A. Pocheville, J. W. Fisher, J. G. Gribben, S. Bahram et al.
    Proc. Natl. Acad. Sci. USA 110, 459-464 (8 January 2013)

    NARROMI: a noise and redundancy reduction technique improves accuracy of gene regulatory network inference
    X. Zhang, K. Liu, Z.-P. Liu, B. Duval, J.-M. Richer, X.-M. Zhao, J.-K. Hao, and L. Chen
    Bioinformatics 29, 106-113 (1 January 2013)

    Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis
    Y. Liang, H. Wu, R. Lei, R. A. Chong, Y. Wei, X. Lu, I. Tagkopoulos, S.-Y. Kung, Q. Yang, G. Hu et al.
    J Biol Chem 287, 33533-33544 (28 September 2012)

    Computational design of genomic transcriptional networks with adaptation to varying environments
    J. Carrera, S. F. Elena, and A. Jaramillo
    Proc. Natl. Acad. Sci. USA 109, 15277-15282 (18 September 2012)

    Detection of transcriptional triggers in the dynamics of microbial growth: application to the respiratorily versatile bacterium Shewanella oneidensis
    Q. K. Beg, M. Zampieri, N. Klitgord, S. B. Collins, C. Altafini, M. H. Serres, and D. Segre
    Nucleic Acids Res 40, 7132-7149 (1 August 2012)

    The Emerging Paradigm of Network Medicine in the Study of Human Disease
    S. Y. Chan, and J. Loscalzo
    Circ. Res. 111, 359-374 (20 July 2012)

    Gene network inference and visualization tools for biologists: application to new human transcriptome datasets
    D. Hurley, H. Araki, Y. Tamada, B. Dunmore, D. Sanders, S. Humphreys, M. Affara, S. Imoto, K. Yasuda, Y. Tomiyasu et al.
    Nucleic Acids Res 40, 2377-2398 (1 March 2012)

    Inferring gene regulatory networks from gene expression data by path consistency algorithm based on conditional mutual information
    X. Zhang, X.-M. Zhao, K. He, L. Lu, Y. Cao, J. Liu, J.-K. Hao, Z.-P. Liu, and L. Chen
    Bioinformatics 28, 98-104 (1 January 2012)

    A system-level approach for deciphering the transcriptional response to prion infection
    M. Zampieri, G. Legname, D. Segre, and C. Altafini
    Bioinformatics 27, 3407-3414 (15 December 2011)

    How to infer gene networks from expression profiles, revisited
    C. A. Penfold, and D. L. Wild
    Interface Focus 1, 857-870 (6 December 2011)

    Transcriptional gene network inference from a massive dataset elucidates transcriptome organization and gene function
    V. Belcastro, V. Siciliano, F. Gregoretti, P. Mithbaokar, G. Dharmalingam, S. Berlingieri, F. Iorio, G. Oliva, R. Polishchuck, N. Brunetti-Pierri et al.
    Nucleic Acids Res 39, 8677-8688 (1 November 2011)

    Large-scale dynamic gene regulatory network inference combining differential equation models with local dynamic Bayesian network analysis
    Z. Li, P. Li, A. Krishnan, and J. Liu
    Bioinformatics 27, 2686-2691 (1 October 2011)

    Functional characterization of bacterial sRNAs using a network biology approach
    S. R. Modi, D. M. Camacho, M. A. Kohanski, G. C. Walker, and J. J. Collins
    Proc. Natl. Acad. Sci. USA 108, 15522-15527 (13 September 2011)

    Discovering the Targets of Drugs Via Computational Systems Biology
    H. N. Chua, and F. P. Roth
    J Biol Chem 286, 23653-23658 (8 July 2011)

    Inference of gene networks--application to Bifidobacterium
    D. Lai, X. Yang, G. Wu, Y. Liu, and C. Nardini
    Bioinformatics 27, 232-237 (15 January 2011)

    Discovery of drug mode of action and drug repositioning from transcriptional responses
    F. Iorio, R. Bosotti, E. Scacheri, V. Belcastro, P. Mithbaokar, R. Ferriero, L. Murino, R. Tagliaferri, N. Brunetti-Pierri, A. Isacchi et al.
    Proc. Natl. Acad. Sci. USA 107, 14621-14626 (17 August 2010)

    Causal relationship inference for a large-scale cellular network
    T. Zhou, and Y.-L. Wang
    Bioinformatics 26, 2020-2028 (15 August 2010)

    Identification of genetic network dynamics with unate structure
    R. Porreca, E. Cinquemani, J. Lygeros, and G. Ferrari-Trecate
    Bioinformatics 26, 1239-1245 (1 May 2010)

    Cell cycle-dependent variations in protein concentration
    N. A. Cookson, S. W. Cookson, L. S. Tsimring, and J. Hasty
    Nucleic Acids Res 38, 2676-2681 (1 May 2010)

    Revealing strengths and weaknesses of methods for gene network inference
    D. Marbach, R. J. Prill, T. Schaffter, C. Mattiussi, D. Floreano, and G. Stolovitzky
    Proc. Natl. Acad. Sci. USA 107, 6286-6291 (6 April 2010)

    Regulatory impact factors: unraveling the transcriptional regulation of complex traits from expression data
    A. Reverter, N. J. Hudson, S. H. Nagaraj, M. Perez-Enciso, and B. P. Dalrymple
    Bioinformatics 26, 896-904 (1 April 2010)

    Blueprint for antimicrobial hit discovery targeting metabolic networks
    Y. Shen, J. Liu, G. Estiu, B. Isin, Y.-Y. Ahn, D.-S. Lee, A.-L. Barabasi, V. Kapatral, O. Wiest, Z. N. Oltvai et al.
    Proc. Natl. Acad. Sci. USA 107, 1082-1087 (19 January 2010)

    Concurrent Quantification of Proteome and Phosphoproteome to Reveal System-wide Association of Protein Phosphorylation and Gene Expression
    Y.-B. Wu, J. Dai, X.-L. Yang, S.-J. Li, S.-L. Zhao, Q.-H. Sheng, J.-S. Tang, G.-Y. Zheng, Y.-X. Li, J.-R. Wu et al.
    MCP 8, 2809-2826 (1 December 2009)

    Reconstructing transcriptional regulatory networks through genomics data
    Ning Sun, and Hongyu Zhao
    Stat Methods Med Res 18, 595-617 (1 December 2009)

    Learning gene regulatory networks from gene expression measurements using non-parametric molecular kinetics
    T. Aijo, and H. Lahdesmaki
    Bioinformatics 25, 2937-2944 (15 November 2009)

    An overview of recent developments in genomics and associated statistical methods
    P. J. Bickel, J. B. Brown, H. Huang, and Q. Li
    Phil Trans R Soc A 367, 4313-4337 (13 November 2009)

    An efficient method for identifying statistical interactors in gene association networks
    A. Andrei, and C. Kendziorski
    Biostatistics 10, 706-718 (1 October 2009)

    New Connections, New Components, Real Dynamics
    J. S. Bader, and C. Kendziorski
    Sci Signal 2, pe48-pe48 (4 August 2009)

    Transcriptional Regulatory Circuits: Predicting Numbers from Alphabets
    H. D. Kim, T. Shay, E. K. O''Shea, and A. Regev
    Science 325, 429-432 (24 July 2009)

    List-decoding methods for inferring polynomials in finite dynamical gene network models
    J. Dingel, and O. Milenkovic
    Bioinformatics 25, 1686-1693 (1 July 2009)

    Linking high-resolution metabolic flux phenotypes and transcriptional regulation in yeast modulated by the global regulator Gcn4p
    J. F. Moxley, M. C. Jewett, M. R. Antoniewicz, S. G. Villas-Boas, H. Alper, R. T. Wheeler, L. Tong, A. G. Hinnebusch, T. Ideker, J. Nielsen et al.
    Proc. Natl. Acad. Sci. USA 106, 6477-6482 (21 April 2009)

    Genetic network inference as a series of discrimination tasks
    S. Kimura, S. Nakayama, and M. Hatakeyama
    Bioinformatics 25, 918-925 (1 April 2009)

    Model-based redesign of global transcription regulation
    J. Carrera, G. Rodrigo, and A. Jaramillo
    Nucleic Acids Res 37, e38-e38 (1 April 2009)

    Gene network reconstruction from transcriptional dynamics under kinetic model uncertainty: a case for the second derivative
    D. R. Bickel, Z. Montazeri, P.-C. Hsieh, M. Beatty, S. J. Lawit, and N. J. Bate
    Bioinformatics 25, 772-779 (15 March 2009)

    A network biology approach to aging in yeast
    D. R. Lorenz, C. R. Cantor, and J. J. Collins
    Proc. Natl. Acad. Sci. USA 106, 1145-1150 (27 January 2009)

    Models and computational strategies linking physiological response to molecular networks from large-scale data
    F. Ortega, K. Sameith, N. Turan, R. Compton, V. Trevino, M. Vannucci, and F. Falciani
    Phil Trans R Soc A 366, 3067-3089 (13 September 2008)

    SIRENE: supervised inference of regulatory networks
    F. Mordelet, and J.-P. Vert
    Bioinformatics 24, i76-i82 (15 August 2008)

    Computational approaches to study transcriptional regulation
    M. M. Babu, and J.-P. Vert
    Biochm. Soc. Trans. 36, 758-765 (1 August 2008)

    Direct targets of the TRP63 transcription factor revealed by a combination of gene expression profiling and reverse engineering
    G. Della Gatta, M. Bansal, A. Ambesi-Impiombato, D. Antonini, C. Missero, and D. di Bernardo
    Genome Res 18, 939-948 (1 June 2008)

    Ensemble learning of genetic networks from time-series expression data
    D. Nam, S. H. Yoon, and J. F. Kim
    Bioinformatics 23, 3225-3231 (1 December 2007)

    Refinement and expansion of signaling pathways: The osmotic response network in yeast
    I. Gat-Viks, and R. Shamir
    Genome Res 17, 358-367 (1 March 2007)

    Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Multi-organ whole-genome measurements and reverse engineering to uncover gene networks underlying complex traits
    J. Tegner, J. Skogsberg, and J. Bjorkegren
    J. Lipid Res. 48, 267-277 (1 February 2007)

    Building the power house: recent advances in mitochondrial studies through proteomics and systems biology
    T. D. Vo, and B. O. Palsson
    Am. J. Physiol. Cell Physiol. 292, C164-C177 (1 January 2007)

    Using the principle of entropy maximization to infer genetic interaction networks from gene expression patterns
    T. R. Lezon, J. R. Banavar, M. Cieplak, A. Maritan, and N. V. Fedoroff
    Proc. Natl. Acad. Sci. USA 103, 19033-19038 (12 December 2006)

    Reconstructing repressor protein levels from expression of gene targets in Escherichia coli
    R. Khanin, V. Vinciotti, and E. Wit
    Proc. Natl. Acad. Sci. USA 103, 18592-18596 (5 December 2006)

    Strategies for dealing with incomplete information in the modeling of molecular interaction networks
    H. de Jong, and D. Ropers
    Brief Bioinform 7, 354-363 (1 December 2006)

    Systems interface biology
    F. J Doyle, and J. Stelling
    J R Soc Interface 3, 603-616 (22 October 2006)

    Topology-based cancer classification and related pathway mining using microarray data
    C.-C. Liu, W.-S. E. Chen, C.-C. Lin, H.-C. Liu, H.-Y. Chen, P.-C. Yang, P.-C. Chang, and J. J.W. Chen
    Nucleic Acids Res 34, 4069-4080 (1 September 2006)

    Inference of gene regulatory networks and compound mode of action from time course gene expression profiles
    M. Bansal, G. D. Gatta, and D. di Bernardo
    Bioinformatics 22, 815-822 (1 April 2006)

    Gradient directed regularization for sparse Gaussian concentration graphs, with applications to inference of genetic networks
    H. Li, and J. Gui
    Biostatistics 7, 302-317 (1 April 2006)

    Bayesian sparse hidden components analysis for transcription regulation networks
    C. Sabatti, and G. M. James
    Bioinformatics 22, 739-746 (15 March 2006)

    Least absolute regression network analysis of the murine osteoblast differentiation network
    E. P. van Someren, B. L. T. Vaes, W. T. Steegenga, A. M. Sijbers, K. J. Dechering, and M. J. T. Reinders
    Bioinformatics 22, 477-484 (15 February 2006)

    Use of PMA1 as a Housekeeping Biomarker for Assessment of Toxicant-Induced Stress in Saccharomyces cerevisiae
    M. Schmitt, P. Schwanewilm, J. Ludwig, and H. Lichtenberg-Frate
    Appl. Environ. Microbiol. 72, 1515-1522 (1 February 2006)

    libSRES: a C library for stochastic ranking evolution strategy for parameter estimation
    X. Ji, and Y. Xu
    Bioinformatics 22, 124-126 (1 January 2006)

    Non-transcriptional pathway features reconstructed from secondary effects of RNA interference
    F. Markowetz, J. Bloch, and R. Spang
    Bioinformatics 21, 4026-4032 (1 November 2005)

    Transcriptional regulation and metabolism
    M. P. Brynildsen, W. W. Wong, and J. C. Liao
    Biochm. Soc. Trans. 33, 1423-1426 (26 October 2005)

    Inferring the connectivity of a regulatory network from mRNA quantification in Synechocystis PCC6803
    S. Lemeille, A. Latifi, and J. Geiselmann
    Nucleic Acids Res 33, 3381-3389 (8 June 2005)

    Intracellular Signaling: Spatial and Temporal Control
    I. I. Moraru, and L. M. Loew
    Physiology 20, 169-179 (1 June 2005)

    The use of oscillatory signals in the study of genetic networks
    O. Lipan, and W. H. Wong
    Proc. Natl. Acad. Sci. USA 102, 7063-7068 (17 May 2005)

    Validation of alternative methods of data normalization in gene co-expression studies
    A. Reverter, W. Barris, S. McWilliam, K. A. Byrne, Y. H. Wang, S. H. Tan, N. Hudson, and B. P. Dalrymple
    Bioinformatics 21, 1112-1120 (1 April 2005)

    CADLIVE dynamic simulator: Direct link of biochemical networks to dynamic models
    H. Kurata, K. Masaki, Y. Sumida, and R. Iwasaki
    Genome Res 15, 590-600 (1 April 2005)

    Sensitivity, principal component and flux analysis applied to signal transduction: the case of epidermal growth factor mediated signaling
    G. Liu, M. T. Swihart, and S. Neelamegham
    Bioinformatics 21, 1194-1202 (1 April 2005)

    Bayesian analysis of signaling networks governing embryonic stem cell fate decisions
    P. J. Woolf, W. Prudhomme, L. Daheron, G. Q. Daley, and D. A. Lauffenburger
    Bioinformatics 21, 741-753 (15 March 2005)

    Reconstructing biological networks using conditional correlation analysis
    J. J. Rice, Y. Tu, and G. Stolovitzky
    Bioinformatics 21, 765-773 (15 March 2005)

    Dynamics of cellular level function and regulation derived from murine expression array data
    B. de Bivort, S. Huang, and Y. Bar-Yam
    Proc. Natl. Acad. Sci. USA 101, 17687-17692 (21 December 2004)

    Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882