In the natural environment, bacterial cells have to adjust their metabolism to alterations in the availability of food sources. The order and timing of gene expression are crucial in these situations to produce an appropriate response. We used the galactose regulation in Escherichia coli as a model system for understanding how cells integrate information about food availability and cAMP levels to adjust the timing and intensity of gene expression. We simulated the feast-famine cycle of bacterial growth by diluting stationary phase cells in fresh medium containing galactose as the sole carbon source. We followed the activities of six promoters of the galactose system as cells grew on and ran out of galactose. We found that the cell responds to a decreasing external galactose level by increasing the internal galactose level, which is achieved by limiting galactose metabolism and increasing the expression of transporters. We show that the cell alters gene expression based primarily on the current state of the cell and not on monitoring the level of extracellular galactose in real time. Some decisions have longer term effects; therefore, the current state does subtly encode the history of food availability. In summary, our measurements of timing of gene expression in the galactose system suggest that the system has evolved to respond to environments where future galactose levels are unpredictable rather than regular feast and famine cycles.
The p53 signalling pathway has hundreds of inputs and outputs. It can trigger cellular senescence, cell-cycle arrest and apoptosis in response to diverse stress conditions, including DNA damage, hypoxia and nutrient deprivation. Signals from all these inputs are channeled through a single node, the transcription factor p53. Yet, the pathway is flexible enough to produce different downstream gene expression patterns in response to different stresses.
Gene regulatory networks are based on simple building blocks such as promoters, transcription factors (TFs) and their binding sites on DNA. But how diverse are the functions that can be obtained by different arrangements of promoters and TF binding sites? In this work we constructed synthetic regulatory regions using promoter elements and binding sites of two noninteracting TFs, each sensing a single environmental input signal. We show that simply by combining these three kinds of elements, we can obtain 11 of the 16 Boolean logic gates that integrate two environmental signals in vivo. Further, we demonstrate how combination of logic gates can result in new logic functions. Our results suggest that simple elements of transcription regulation form a highly flexible toolbox that can generate diverse functions under natural selection.
Oscillations are commonly observed in cellular behavior and span a wide range of timescales, from seconds in calcium signaling to 24 hours in circadian rhythms. In between lie oscillations with time periods of 1-5 hours seen in NF-?B, p53 and Wnt signaling, which play key roles in the immune system, cell growth/death and embryo development, respectively. In the first part of this article, we provide a brief overview of simple deterministic models of oscillations. In particular, we explain the mechanism of saturated degradation that has been used to model oscillations in the NF-?B, p53 and Wnt systems. The second part deals with the potential physiological role of oscillations. We use the simple models described earlier to explore whether oscillatory signals can encode more information than steady-state signals. We then discuss a few simple genetic circuits that could decode information stored in the average, amplitude or frequency of oscillations. The presence of frequency-detector circuit downstream of NF-?B or p53 would be a strong clue that oscillations are important for the physiological response of these signaling systems.
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