Article

Negative auto-regulation increases the input dynamic-range of the arabinose system of Escherichia coli

Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
BMC Systems Biology (Impact Factor: 2.44). 07/2011; 5(1):111. DOI: 10.1186/1752-0509-5-111
Source: PubMed

ABSTRACT

Gene regulation networks are made of recurring regulatory patterns, called network motifs. One of the most common network motifs is negative auto-regulation, in which a transcription factor represses its own production. Negative auto-regulation has several potential functions: it can shorten the response time (time to reach halfway to steady-state), stabilize expression against noise, and linearize the gene's input-output response curve. This latter function of negative auto-regulation, which increases the range of input signals over which downstream genes respond, has been studied by theory and synthetic gene circuits. Here we ask whether negative auto-regulation preserves this function also in the context of a natural system, where it is embedded within many additional interactions. To address this, we studied the negative auto-regulation motif in the arabinose utilization system of Escherichia coli, in which negative auto-regulation is part of a complex regulatory network.
We find that when negative auto-regulation is disrupted by placing the regulator araC under constitutive expression, the input dynamic range of the arabinose system is reduced by 10-fold. The apparent Hill coefficient of the induction curve changes from about n = 1 with negative auto-regulation, to about n = 2 when it is disrupted. We present a mathematical model that describes how negative auto-regulation can increase input dynamic-range, by coupling the transcription factor protein level to the input signal.
Here we demonstrate that the negative auto-regulation motif in the native arabinose system of Escherichia coli increases the range of arabinose signals over which the system can respond. In this way, negative auto-regulation may help to increase the input dynamic-range while maintaining the specificity of cooperative regulatory systems. This function may contribute to explaining the common occurrence of negative auto-regulation in biological systems.

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    • "Besides, the conservation of transcriptional repression might give some slight biological advantage over activation because homeostatic control is usually implemented through negative regulation, a recurrent motif in metabolic and gene regulatory processes[48]. Moreover, it is known that negative auto-regulation (whenappropriately tuned) can speed up responses in cellular systems[49,50]and this dynamical response may contribute to the maintenance of cellular homeostasis regardless the physiological state of the organism[51]. Finally, the preponderance of dual TFs in small genomes might be explained from the fact that these regulators permit more flexible control (positive and negative) over their target genes. "
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    • "Concerning araBAD, operons araC and araBAD are divergent and share the same regulatory region (Madar et al., 2011; Schleif, 2000). Moreover, AraA both activates and represses the arabinose utilization operon araBAD using a DNA looping mechanism (Lobell and Schleif, 1990; Madar et al., 2011; Seabold and Schleif, 1998); the araBAD operon starts transcription when AraC, Crp and RNA polymerase bind to DNA (Ogden et al., 1980), and its full induction depends on Crp (Kolodrubetz and Schleif, 1981b). From the above-mentioned regulatory mechanisms, it can be inferred that glucose is the preferred carbon source over arabinose. "
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    • "± 2.46 and R out = 8.85 ± 0.04 for the wild-type system (inset in Figure 3A). This regime of values, which are captured by our model (Figure S3A), demonstrates that dual regulation increases the sensitivity of the response with respect to a circuit without feedback, in a qualitatively similar manner to negative autoregulation (Figure S3B) (Nevozhay et al., 2009; Madar et al., 2011). "

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