Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 301 (5629): 102-105

Copyright © 2003 by the American Association for the Advancement of Science

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

Timothy S. Gardner,1* Diego di Bernardo,1,2* David Lorenz,1 James J. Collins1{dagger}

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.

1 Center for BioDynamics and Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA. 2 Telethon Institute for Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131, Naples, Italy.

Back to Top

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: jcollins{at}bu.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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, and R. Wu (2013)
Brief Bioinform
   Abstract »    Full Text »    PDF »
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 (2013)
Brief Bioinform
   Abstract »    Full Text »    PDF »
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 III, J. G. Gribben, and S. Bahram (2013)
PNAS 110, 459-464
   Abstract »    Full Text »    PDF »
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 (2013)
Bioinformatics 29, 106-113
   Abstract »    Full Text »    PDF »
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. (2012)
J. Biol. Chem. 287, 33533-33544
   Abstract »    Full Text »    PDF »
Computational design of genomic transcriptional networks with adaptation to varying environments.
J. Carrera, S. F. Elena, and A. Jaramillo (2012)
PNAS 109, 15277-15282
   Abstract »    Full Text »    PDF »
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 (2012)
Brief Bioinform
   Abstract »    Full Text »    PDF »
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 (2012)
Nucleic Acids Res. 40, 7132-7149
   Abstract »    Full Text »    PDF »
The Emerging Paradigm of Network Medicine in the Study of Human Disease.
S. Y. Chan and J. Loscalzo (2012)
Circ. Res. 111, 359-374
   Abstract »    Full Text »    PDF »
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. (2012)
Nucleic Acids Res. 40, 2377-2398
   Abstract »    Full Text »    PDF »
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 (2012)
Bioinformatics 28, 98-104
   Abstract »    Full Text »    PDF »
A system-level approach for deciphering the transcriptional response to prion infection.
M. Zampieri, G. Legname, D. Segre, and C. Altafini (2011)
Bioinformatics 27, 3407-3414
   Abstract »    Full Text »    PDF »
How to infer gene networks from expression profiles, revisited.
C. A. Penfold and D. L. Wild (2011)
Interface Focus 1, 857-870
   Abstract »    Full Text »    PDF »
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. (2011)
Nucleic Acids Res. 39, 8677-8688
   Abstract »    Full Text »    PDF »
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 (2011)
Bioinformatics 27, 2686-2691
   Abstract »    Full Text »    PDF »
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 (2011)
PNAS 108, 15522-15527
   Abstract »    Full Text »    PDF »
Discovering the Targets of Drugs Via Computational Systems Biology.
H. N. Chua and F. P. Roth (2011)
J. Biol. Chem. 286, 23653-23658
   Abstract »    Full Text »    PDF »
Inference of gene networks--application to Bifidobacterium.
D. Lai, X. Yang, G. Wu, Y. Liu, and C. Nardini (2011)
Bioinformatics 27, 232-237
   Abstract »    Full Text »    PDF »
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. (2010)
PNAS 107, 14621-14626
   Abstract »    Full Text »    PDF »
Causal relationship inference for a large-scale cellular network.
T. Zhou and Y.-L. Wang (2010)
Bioinformatics 26, 2020-2028
   Abstract »    Full Text »    PDF »
Cell cycle-dependent variations in protein concentration.
N. A. Cookson, S. W. Cookson, L. S. Tsimring, and J. Hasty (2010)
Nucleic Acids Res. 38, 2676-2681
   Abstract »    Full Text »    PDF »
Identification of genetic network dynamics with unate structure.
R. Porreca, E. Cinquemani, J. Lygeros, and G. Ferrari-Trecate (2010)
Bioinformatics 26, 1239-1245
   Abstract »    Full Text »    PDF »
Revealing strengths and weaknesses of methods for gene network inference.
D. Marbach, R. J. Prill, T. Schaffter, C. Mattiussi, D. Floreano, and G. Stolovitzky (2010)
PNAS 107, 6286-6291
   Abstract »    Full Text »    PDF »
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 (2010)
Bioinformatics 26, 896-904
   Abstract »    Full Text »    PDF »
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, and Z. N. Oltvai (2010)
PNAS 107, 1082-1087
   Abstract »    Full Text »    PDF »
Reconstructing transcriptional regulatory networks through genomics data.
Ning Sun and Hongyu Zhao (2009)
Statistical Methods in Medical Research 18, 595-617
   Abstract »    PDF »
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. (2009)
Mol. Cell. Proteomics 8, 2809-2826
   Abstract »    Full Text »    PDF »
Learning gene regulatory networks from gene expression measurements using non-parametric molecular kinetics.
T. Aijo and H. Lahdesmaki (2009)
Bioinformatics 25, 2937-2944
   Abstract »    Full Text »    PDF »
An overview of recent developments in genomics and associated statistical methods.
P. J. Bickel, J. B. Brown, H. Huang, and Q. Li (2009)
Phil Trans R Soc A 367, 4313-4337
   Abstract »    Full Text »    PDF »
An efficient method for identifying statistical interactors in gene association networks.
A. Andrei and C. Kendziorski (2009)
Biostat. 10, 706-718
   Abstract »    Full Text »    PDF »
New Connections, New Components, Real Dynamics.
J. S. Bader (2009)
Science Signaling 2, pe48
   Abstract »    Full Text »    PDF »
Transcriptional Regulatory Circuits: Predicting Numbers from Alphabets.
H. D. Kim, T. Shay, E. K. O'Shea, and A. Regev (2009)
Science 325, 429-432
   Abstract »    Full Text »    PDF »
List-decoding methods for inferring polynomials in finite dynamical gene network models.
J. Dingel and O. Milenkovic (2009)
Bioinformatics 25, 1686-1693
   Abstract »    Full Text »    PDF »
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. (2009)
PNAS 106, 6477-6482
   Abstract »    Full Text »    PDF »
Model-based redesign of global transcription regulation.
J. Carrera, G. Rodrigo, and A. Jaramillo (2009)
Nucleic Acids Res. 37, e38
   Abstract »    Full Text »    PDF »
Genetic network inference as a series of discrimination tasks.
S. Kimura, S. Nakayama, and M. Hatakeyama (2009)
Bioinformatics 25, 918-925
   Abstract »    Full Text »    PDF »
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 (2009)
Bioinformatics 25, 772-779
   Abstract »    Full Text »    PDF »
A network biology approach to aging in yeast.
D. R. Lorenz, C. R. Cantor, and J. J. Collins (2009)
PNAS 106, 1145-1150
   Abstract »    Full Text »    PDF »
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 (2008)
Phil Trans R Soc A 366, 3067-3089
   Abstract »    Full Text »    PDF »
SIRENE: supervised inference of regulatory networks.
F. Mordelet and J.-P. Vert (2008)
Bioinformatics 24, i76-i82
   Abstract »    Full Text »    PDF »
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 (2008)
Genome Res. 18, 939-948
   Abstract »    Full Text »    PDF »
Ensemble learning of genetic networks from time-series expression data.
D. Nam, S. H. Yoon, and J. F. Kim (2007)
Bioinformatics 23, 3225-3231
   Abstract »    Full Text »    PDF »
Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty.
C. L. Roth, C. Mastronardi, A. Lomniczi, H. Wright, R. Cabrera, A. E. Mungenast, S. Heger, H. Jung, C. Dubay, and S. R. Ojeda (2007)
Endocrinology 148, 5147-5161
   Abstract »    Full Text »    PDF »
Estrogen-Regulated Gene Networks in Human Breast Cancer Cells: Involvement of E2F1 in the Regulation of Cell Proliferation.
J. D. Stender, J. Frasor, B. Komm, K. C. N. Chang, W. L. Kraus, and B. S. Katzenellenbogen (2007)
Mol. Endocrinol. 21, 2112-2123
   Abstract »    Full Text »    PDF »
Refinement and expansion of signaling pathways: The osmotic response network in yeast.
I. Gat-Viks and R. Shamir (2007)
Genome Res. 17, 358-367
   Abstract »    Full Text »    PDF »
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 (2007)
J. Lipid Res. 48, 267-277
   Abstract »    Full Text »    PDF »
Building the power house: recent advances in mitochondrial studies through proteomics and systems biology.
T. D. Vo and B. O. Palsson (2007)
Am J Physiol Cell Physiol 292, C164-C177
   Abstract »    Full Text »    PDF »
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 (2006)
PNAS 103, 19033-19038
   Abstract »    Full Text »    PDF »
Reconstructing repressor protein levels from expression of gene targets in Escherichia coli.
R. Khanin, V. Vinciotti, and E. Wit (2006)
PNAS 103, 18592-18596
   Abstract »    Full Text »    PDF »
Strategies for dealing with incomplete information in the modeling of molecular interaction networks.
H. de Jong and D. Ropers (2006)
Brief Bioinform 7, 354-363
   Abstract »    Full Text »    PDF »
Systems interface biology.
F. J Doyle III and J. Stelling (2006)
J R Soc Interface 3, 603-616
   Abstract »    Full Text »    PDF »
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 (2006)
Nucleic Acids Res. 34, 4069-4080
   Abstract »    Full Text »    PDF »
Gradient directed regularization for sparse Gaussian concentration graphs, with applications to inference of genetic networks.
H. Li and J. Gui (2006)
Biostat. 7, 302-317
   Abstract »    Full Text »    PDF »
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 (2006)
Bioinformatics 22, 815-822
   Abstract »    Full Text »    PDF »
Bayesian sparse hidden components analysis for transcription regulation networks.
C. Sabatti and G. M. James (2006)
Bioinformatics 22, 739-746
   Abstract »    Full Text »    PDF »
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 (2006)
Bioinformatics 22, 477-484
   Abstract »    Full Text »    PDF »
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 (2006)
Appl. Envir. Microbiol. 72, 1515-1522
   Abstract »    Full Text »    PDF »
libSRES: a C library for stochastic ranking evolution strategy for parameter estimation.
X. Ji and Y. Xu (2006)
Bioinformatics 22, 124-126
   Abstract »    Full Text »    PDF »
Non-transcriptional pathway features reconstructed from secondary effects of RNA interference.
F. Markowetz, J. Bloch, and R. Spang (2005)
Bioinformatics 21, 4026-4032
   Abstract »    Full Text »    PDF »
Inferring the connectivity of a regulatory network from mRNA quantification in Synechocystis PCC6803.
S. Lemeille, A. Latifi, and J. Geiselmann (2005)
Nucleic Acids Res. 33, 3381-3389
   Abstract »    Full Text »    PDF »
Intracellular Signaling: Spatial and Temporal Control.
I. I. Moraru and L. M. Loew (2005)
Physiology 20, 169-179
   Abstract »    Full Text »    PDF »
The use of oscillatory signals in the study of genetic networks.
O. Lipan and W. H. Wong (2005)
PNAS 102, 7063-7068
   Abstract »    Full Text »    PDF »
CADLIVE dynamic simulator: Direct link of biochemical networks to dynamic models.
H. Kurata, K. Masaki, Y. Sumida, and R. Iwasaki (2005)
Genome Res. 15, 590-600
   Abstract »    Full Text »    PDF »
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 (2005)
Bioinformatics 21, 1194-1202
   Abstract »    Full Text »    PDF »
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 (2005)
Bioinformatics 21, 1112-1120
   Abstract »    Full Text »    PDF »
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 (2005)
Bioinformatics 21, 741-753
   Abstract »    Full Text »    PDF »
Reconstructing biological networks using conditional correlation analysis.
J. J. Rice, Y. Tu, and G. Stolovitzky (2005)
Bioinformatics 21, 765-773
   Abstract »    Full Text »    PDF »
Dynamics of cellular level function and regulation derived from murine expression array data.
B. de Bivort, S. Huang, and Y. Bar-Yam (2004)
PNAS 101, 17687-17692
   Abstract »    Full Text »    PDF »
Programmable cells: Interfacing natural and engineered gene networks.
H. Kobayashi, M. Kaern, M. Araki, K. Chung, T. S. Gardner, C. R. Cantor, and J. J. Collins (2004)
PNAS 101, 8414-8419
   Abstract »    Full Text »    PDF »
Identification of Genetic Networks.
M. Xiong, J. Li, and X. Fang (2004)
Genetics 166, 1037-1052
   Abstract »    Full Text »    PDF »
Transcriptome-based determination of multiple transcription regulator activities in Escherichia coli by using network component analysis.
K. C. Kao, Y.-L. Yang, R. Boscolo, C. Sabatti, V. Roychowdhury, and J. C. Liao (2004)
PNAS 101, 641-646
   Abstract »    Full Text »    PDF »
Network component analysis: Reconstruction of regulatory signals in biological systems.
J. C. Liao, R. Boscolo, Y.-L. Yang, L. M. Tran, C. Sabatti, and V. P. Roychowdhury (2003)
PNAS 100, 15522-15527
   Abstract »    Full Text »    PDF »
The Evolution of the Discipline of Vascular Biology: From Systems Physiology to Molecular Biology to Molecular Systems.
J. Loscalzo (2003)
Circ. Res. 93, 583-585
   Full Text »    PDF »
Biological Networks: The Tinkerer as an Engineer.
U. Alon (2003)
Science 301, 1866-1867
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

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