Transcription regulation networks seem to be built of a few regulatory patterns called network motifs.
Each network motif can carry out defined information-processing functions. These functions have been experimentally studied in selected systems, mostly Escherichia coli.
Negative autoregulation can speed up responses and reduce fluctuations, whereas positive autoregulation slows responses and increases variations.
Coherent feedforward loops can show persistence detection, whereas incoherent feedforward loops show pulse generation and response acceleration.
Single-input modules can generate temporal programmes of expression.
Dense overlapping regulons can act as arrays of gates for combinatorial decision making.
Developmental networks display these network motifs, and additional motifs, such as two-point positive-feedforward loops for decision making and memory, and cascades for regulating slow multi-step processes.
Network motifs in systems that have been studied experimentally so far seem to be wired together in a 'modular' way that allows us to understand the dynamics of each individual motif, even when it is connected to the rest of the network.
Evolution seems to have converged on the same motifs in different systems and different organisms, suggesting that they are selected for again and again on the basis of their biological functions.
Other biological networks, such as signalling and neuronal networks, also show network motifs, some of which are similar to the motifs that are found in transcription networks.
Transcription regulation networks control the expression of genes. The transcription networks of well-studied microorganisms appear to be made up of a small set of recurring regulation patterns, called network motifs. The same network motifs have recently been found in diverse organisms from bacteria to humans, suggesting that they serve as basic building blocks of transcription networks. Here I review network motifs and their functions, with an emphasis on experimental studies. Network motifs in other biological networks are also mentioned, including signalling and neuronal networks.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Nature Communications Open Access 02 November 2022
Journal of Cheminformatics Open Access 19 September 2022
Nature Communications Open Access 08 September 2022
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Alon, U. Introduction to Systems Biology: Design Principles Of Biological Circuits (CRC, Boca Raton, 2006).
Davidson, E. H. The Regulatory Genome: Gene Regulatory Networks In Development And Evolution, (Academic, Burlington, 2006).
Ptashne, M. & Gann, A. Genes & Signals (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2002).
Levine, M. & Davidson, E. H. Gene regulatory networks for development. Proc. Natl Acad. Sci. USA 102, 4936–4942 (2005).
Thieffry, D., Huerta, A. M., Perez-Rueda, E. & Collado-Vides, J. From specific gene regulation to genomic networks: a global analysis of transcriptional regulation in Escherichia coli. Bioessays 20, 433–440 (1998).
Shen-Orr, S. S., Milo, R., Mangan, S. & Alon, U. Network motifs in the transcriptional regulation network of Escherichia coli. Nature Genet. 31, 64–68 (2002).
Milo, R. et al. Network motifs: simple building blocks of complex networks. Science 298, 824–827 (2002).
Eichenberger, P. et al. The program of gene transcription for a single differentiating cell type during sporulation in Bacillus subtilis. PLoS Biol. 2, e328 (2004).
Mangan, S., Zaslaver, A. & Alon, U. The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks. J. Mol. Biol. 334, 197–204 (2003).
Lee, T. I. et al. Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298, 799–804 (2002).
Odom, D. T. et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 303, 1378–1381 (2004).
Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).
Saddic, L. A. et al. The LEAFY target LMI1 is a meristem identity regulator and acts together with LEAFY to regulate expression of CAULIFLOWER. Development 133, 1673–1682 (2006).
Swiers, G., Patient, R. & Loose, M. Genetic regulatory networks programming hematopoietic stem cells and erythroid lineage specification. Dev. Biol. 294, 525–540 (2006).
Iranfar, N., Fuller, D. & Loomis, W. F. Transcriptional regulation of post-aggregation genes in Dictyostelium by a feed-forward loop involving GBF and LagC. Dev. Biol. 290, 460–469 (2006).
Milo, R. et al. Superfamilies of designed and evolved networks. Science 303, 1538–1542 (2004).
Rosenfeld, N., Elowitz, M. B. & Alon, U. Negative autoregulation speeds the response times of transcription networks. J. Mol. Biol. 323, 785–793 (2002).
Savageau, M. A. Comparison of classical and autogenous systems of regulation in inducible operons. Nature 252, 546–549 (1974).
Becskei, A. & Serrano, L. Engineering stability in gene networks by autoregulation. Nature 405, 590–593 (2000).
Camas, F. M., Blazquez, J. & Poyatos, J. F. Autogenous and nonautogenous control of response in a genetic network. Proc. Natl Acad. Sci. USA 103, 12718–12723 (2006).
Zaslaver, A. et al. A comprehensive library of fluorescent transcriptional reporters for Escherichia coli. Nature Methods 3, 623–628 (2006).
Kaern, M., Elston, T. C., Blake, W. J. & Collins, J. J. Stochasticity in gene expression: from theories to phenotypes. Nature Rev. Genet. 6, 451–464 (2005).
Dublanche, Y., Michalodimitrakis, K., Kummerer, N., Foglierini, M. & Serrano, L. Noise in transcription negative feedback loops: simulation and experimental analysis. Mol. Syst. Biol. 2, 41 (2006).
Kalir, S., Mangan, S. & Alon, U. The coherent feed-forward loop with a SUM input function prolongs flagella production in Escherichia coli. Mol. Syst. Biol. 1, 2005.0006 (2005).
Maeda, Y. T. & Sano, M. Regulatory dynamics of synthetic gene networks with positive feedback. J. Mol. Biol. 359, 1107–1124 (2006).
Becskei, A., Seraphin, B. & Serrano, L. Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion. EMBO J. 20, 2528–2535 (2001).
Kramer, B. P. & Fussenegger, M. Hysteresis in a synthetic mammalian gene network. Proc. Natl Acad. Sci. USA 102, 9517–9522 (2005).
Wolf, D. M. & Arkin, A. P. Motifs, modules and games in bacteria. Curr. Opin. Microbiol. 6, 125–134 (2003).
Yuh, C. H., Bolouri, H. & Davidson, E. H. Genomic cis-regulatory logic: experimental and computational analysis of a sea urchin gene. Science 279, 1896–1902 (1998).
Buchler, N. E., Gerland, U. & Hwa, T. On schemes of combinatorial transcription logic. Proc. Natl Acad. Sci. USA 100, 5136–5141 (2003).
Kalir, S. & Alon, U. Using a quantitative blueprint to reprogram the dynamics of the flagella gene network. Cell 117, 713–720 (2004).
Setty, Y., Mayo, A. E., Surette, M. G. & Alon, U. Detailed map of a cis-regulatory input function. Proc. Natl Acad. Sci. USA 100, 7702–7707 (2003).
Ma, H. W. et al. An extended regulatory network of Escherichia coli and analysis of its hierarchical structure and network motifs. Nucleic A cids Res. 32, 6643–6649 (2004).
Mangan, S. & Alon, U. Structure and function of the feed-forward loop network motif. Proc. Natl Acad. Sci. USA 100, 11980–11985 (2003).
Basu, S., Mehreja, R., Thiberge, S., Chen, M. T. & Weiss, R. Spatiotemporal control of gene expression with pulse-generating networks. Proc. Natl Acad. Sci. USA 101, 6355–6360 (2004).
Mangan, S., Zaslaver, A. & Alon, U. The incoherent feed-forward loop accelerates the response-time of the gal system of Escherichia coli. J. Mol. Biol. 356, 1073–1081 (2006).
Hornstein, E. & Shomron, N. Canalization of development by microRNAs. Nature Genet. 38, S20–S24 (2006).
O'Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V. & Mendell, J. T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).
Johnston, R. J. Jr. et al. An unusual Zn-finger/FH2 domain protein controls a left/right asymmetric neuronal fate decision in C. elegans. Development 133, 3317–3328 (2006).
Ghosh, B., Karmakar, R. & Bose, I. Noise characteristics of feed forward loops. Phys. Biol. 2, 36–45 (2005).
Wall, M. E., Dunlop, M. J. & Hlavacek, W. S. Multiple functions of a feed-forward-loop gene circuit. J. Mol. Biol. 349, 501–514 (2005).
Hayot, F. & Jayaprakash, C. A feedforward loop motif in transcriptional regulation: induction and repression. J. Theor. Biol. 234, 133–143 (2005).
Ishihara, S., Fujimoto, K. & Shibata, T. Cross talking of network motifs in gene regulation that generates temporal pulses and spatial stripes. Genes Cells 10, 1025–1038 (2005).
Kashtan, N., Itzkovitz, S., Milo, R. & Alon, U. Topological generalizations of network motifs. Phys. Rev. E 70, 031909 (2004).
Dobrin, R., Beg, Q. K., Barabasi, A. L. & Oltvai, Z. N. Aggregation of topological motifs in the Escherichia coli transcriptional regulatory network. BMC Bioinformatics 5, 10 (2004).
Ronen, M., Rosenberg, R., Shraiman, B. I. & Alon, U. Assigning numbers to the arrows: parameterizing a gene regulation network by using accurate expression kinetics. Proc. Natl Acad. Sci. USA 99, 10555–10560 (2002).
Zaslaver, A. et al. Just-in-time transcription program in metabolic pathways. Nature Genet. 36, 486–491 (2004).
Kalir, S. et al. Ordering genes in a flagella pathway by analysis of expression kinetics from living bacteria. Science 292, 2080–2083 (2001).
Laub, M. T., McAdams, H. H., Feldblyum, T., Fraser, C. M. & Shapiro, L. Global analysis of the genetic network controlling a bacterial cell cycle. Science 290, 2144–2148 (2000).
McAdams, H. H. & Shapiro, L. A bacterial cell-cycle regulatory network operating in time and space. Science 301, 1874–1877 (2003).
Spellman, P. T. et al. Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol. Biol. Cell 9, 3273–3297 (1998).
Ingram, P. J., Stumpf, M. P., Stark, J. Network motifs: structure does not determine function. BMC Genomics 5, 108 (2006).
Pilpel, Y., Sudarsanam, P. & Church, G. M. Identifying regulatory networks by combinatorial analysis of promoter elements. Nature Genet. 29, 153–159 (2001).
Beer, M. & Tavazoie, S. Predicting gene expression from sequence. Cell 117, 185–198 (2004).
Rosenfeld, N. & Alon, U. Response delays and the structure of transcription networks. J. Mol. Biol. 329, 645–654 (2003).
Babu, M. M., Luscombe, N. M., Aravind, L., Gerstein, M. & Teichmann, S. A. Structure and evolution of transcriptional regulatory networks. Curr. Opin. Struct. Biol. 14, 283–291 (2004).
Yu, H., Luscombe, N. M., Qian, J. & Gerstein, M. Genomic analysis of gene expression relationships in transcriptional regulatory networks. Trends Genet. 19, 422–427 (2003).
Luscombe, N. M. et al. Genomic analysis of regulatory network dynamics reveals large topological changes. Nature 431, 308–312 (2004).
Amit, I. et al. A module of negative feedback regulators defines growth factor signaling. Nature Genet. 39, 503–512 (2007).
Davidson, E. H. et al. A genomic regulatory network for development. Science 295, 1669–1678 (2002).
Longabaugh, W. J., Davidson, E. H. & Bolouri, H. Computational representation of developmental genetic regulatory networks. Dev. Biol. 283, 1–16 (2005).
Johnston, R. J. Jr, Chang, S., Etchberger, J. F., Ortiz, C. O. & Hobert, O. MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. Proc. Natl Acad. Sci. USA 102, 12449–12454 (2005).
Xiong, W. & Ferrell, J. E. Jr. A positive-feedback-based bistable 'memory module' that governs a cell fate decision. Nature 426, 460–465 (2003).
Brandman, O., Ferrell, J. E. Jr, Li, R. & Meyer, T. Interlinked fast and slow positive feedback loops drive reliable cell decisions. Science 310, 496–498 (2005).
Gardner, T. S., Cantor, C. R. & Collins, J. J. Construction of a genetic toggle switch in Escherichia coli. Nature 403, 339–342 (2000).
Bolouri, H. & Davidson, E. H. Transcriptional regulatory cascades in development: initial rates, not steady state, determine network kinetics. Proc. Natl Acad. Sci. USA 100, 9371–9376 (2003).
Hooshangi, S., Thiberge, S. & Weiss, R. Ultrasensitivity and noise propagation in a synthetic transcriptional cascade. Proc. Natl Acad. Sci. USA 102, 3581–3586 (2005).
Rappaport, N., Winter, S. & Barkai, N. The ups and downs of biological timers. Theor. Biol. Med. Model. 2, 22 (2005).
Conant, G. C. & Wagner, A. Convergent evolution of gene circuits. Nature Genet. 34, 264–266 (2003).
Dekel, E. & Alon, U. Optimality and evolutionary tuning of the expression level of a protein. Nature 436, 588–592 (2005).
Ihmels, J. et al. Rewiring of the yeast transcriptional network through the evolution of motif usage. Science 309, 938–940 (2005).
Madan Babu, M., Teichmann, S. A. & Aravind, L. Evolutionary dynamics of prokaryotic transcriptional regulatory networks. J. Mol. Biol. 358, 614–633 (2006).
Dekel, E., Mangan, S. & Alon, U. Environmental selection of the feed-forward loop circuit in gene-regulation networks. Phys. Biol. 2, 81–88 (2005).
Prill, R. J., Iglesias, P. A. & Levchenko, A. Dynamic properties of network motifs contribute to biological network organization. PLoS Biol. 3, e343 (2005).
Kashtan, N., Itzkovitz, S., Milo, R. & Alon, U. Efficient sampling algorithm for estimating subgraph concentrations and detecting network motifs. Bioinformatics 20, 1746–1758 (2004).
Yeger-Lotem, E. et al. Network motifs in integrated cellular networks of transcription-regulation and protein–protein interaction. Proc. Natl Acad. Sci. USA 101, 5934–5939 (2004).
Zhang, L. V. et al. Motifs, themes and thematic maps of an integrated Saccharomyces cerevisiae interaction network. J. Biol. 4, 6 (2005).
Elowitz, M. B. & Leibler, S. A synthetic oscillatory network of transcriptional regulators. Nature 403, 335–338 (2000).
Lahav, G. et al. Dynamics of the p53–Mdm2 feedback loop in individual cells. Nature Genet. 36, 147–150 (2004).
Friedman, N., Vardi, S., Ronen, M., Alon, U. & Stavans, J. Precise temporal modulation in the response of the SOS DNA repair network in individual bacteria. PLoS Biol. 3, e238 (2005).
Hoffmann, A., Levchenko, A., Scott, M. L. & Baltimore, D. The IκB–NF-κB signaling module: temporal control and selective gene activation. Science 298, 1241–1245 (2002).
Nelson, D. E. et al. Oscillations in NF-κB signaling control the dynamics of gene expression. Science 306, 704–708 (2004).
Barkai, N. & Leibler, S. Circadian clocks limited by noise. Nature 403, 267–268 (2000).
Tyson, J. J., Chen, K. C. & Novak, B. Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr. Opin. Cell Biol. 15, 221–231 (2003).
Tyson, J. J., Csikasz-Nagy, A. & Novak, B. The dynamics of cell cycle regulation. Bioessays 24, 1095–1109 (2002).
Pomerening, J. R., Sontag, E. D. & Ferrell, J. E. Jr. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nature Cell Biol. 5, 346–351 (2003).
Suel, G. M., Garcia-Ojalvo, J., Liberman, L. M. & Elowitz, M. B. An excitable gene regulatory circuit induces transient cellular differentiation. Nature 440, 545–550 (2006).
Ptacek, J. et al. Global analysis of protein phosphorylation in yeast. Nature 438, 679–684 (2005).
Itzkovitz, S. et al. Coarse-graining and self-dissimilarity of complex networks. Phys. Rev. E 71, 016127 (2005).
Ma'ayan, A. et al. Formation of regulatory patterns during signal propagation in a mammalian cellular network. Science 309, 1078–1083 (2005).
Hertz, J., Krogh, A. & Palmer, R. G. Introduction to the Theory of Neural Computation (Perseus Books, Boulder, 1991).
Bray, D. Protein molecules as computational elements in living cells. Nature 376, 307–312 (1995).
Lund, R. D. Synaptic patterns of the superficial layers of the superior colliculus of the rat. J. Comp. Neurol. 135, 179–208 (1969).
White, E. L. Cortical Circuits (Birkhauser, Boston, 1989).
White, J., Southgate, E., Thomson, J. & Brenner, S. The nervous system of Caenorhabditis elegans. Philos.Trans. R. Soc. London B Biol. Sci. 314, 1 (1986).
Itzkovitz, S. & Alon, U. Subgraphs and network motifs in geometric networks. Phys. Rev. E 71, 026117 (2005).
Sporns, O. & Kotter, R. Motifs in brain networks. PLoS Biol. 2, e369 (2004).
Sakata, S., Komatsu, Y. & Yamamori, T. Local design principles of mammalian cortical networks. Neurosci. Res. 51, 309–315 (2005).
Song, S., Sjostrom, P. J., Reigl, M., Nelson, S. & Chklovskii, D. B. Highly nonrandom features of synaptic connectivity in local cortical circuits. PLoS Biol. 3, e68 (2005).
Alon, U. Biological networks: the tinkerer as an engineer. Science 301, 1866–1867 (2003).
I thank my laboratory members for stimulating discussions, especially R. Milo, S. Itzkovitz, S. Mangan, S. Shen-Orr and N. Kashtan. I thank M. Elowitz, M. Surette, S. Leibler and H. Westerhoff for discussions, and the Israel Science Foundation, the Human Frontiers Science Foundation, Minerva, National Institutes of Health (USA) and the Kahn Family Foundation for support
The author declares no competing financial interests.
About this article
Cite this article
Alon, U. Network motifs: theory and experimental approaches. Nat Rev Genet 8, 450–461 (2007). https://doi.org/10.1038/nrg2102
This article is cited by
Journal of Cheminformatics (2022)
Periodic synchronization of isolated network elements facilitates simulating and inferring gene regulatory networks including stochastic molecular kinetics
BMC Bioinformatics (2022)
Genome Biology (2022)
Additional insights into the organization of transcriptional regulatory modules based on a 3D model of the Saccharomyces cerevisiae genome
BMC Research Notes (2022)
Nature Communications (2022)