Network motifs in the transcriptional regulation network of Escherichia coli

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Abstract
Little is known about the design principles1,2,3,4,5,6,7,8,9,10 of transcriptional regulation networks that control gene expression in cells. Recent advances in data collection and analysis2,11,12, however, are generating unprecedented amounts of information about gene regulation networks. To understand these complex wiring diagrams1,2,3,4,5,6,7,8,9,10,13, we sought to break down such networks into basic building blocks2. We generalize the notion of motifs, widely used for sequence analysis, to the level of networks. We define 'network motifs' as patterns of interconnections that recur in many different parts of a network at frequencies much higher than those found in randomized networks. We applied new algorithms for systematically detecting network motifs to one of the best-characterized regulation networks, that of direct transcriptional interactions in Escherichia coli3,6. We find that much of the network is composed of repeated appearances of three highly significant motifs. Each network motif has a specific function in determining gene expression, such as generating temporal expression programs and governing the responses to fluctuating external signals. The motif structure also allows an easily interpretable view of the entire known transcriptional network of the organism. This approach may help define the basic computational elements of other biological networks.