Simple gene regulatory switches can be combined to create all sorts of control devices, just as simple electronic switching elements in a computer can be linked to perform different types of operations. An analysis of gene regulatory circuits reveals that certain simple types of arrangements (called network motifs) are found over and over again in cells from widely different species. For example, positive and negative feedback loops are common in all cells (Figure 7–40). Whereas the former provides a simple memory device, the latter is often used to keep the expression of a gene close to a standard level despite the variations in biochemical conditions inside a cell. Suppose, for example, that a transcription repressor protein binds to the regulatory region of its own gene and exerts a strong negative feedback, such that transcription falls to a very low rate when the concentration of the repressor protein is above some critical value (determined by its affinity for its DNA binding site). The concentration of the protein can then be held close to the critical value, since any circumstance that causes a fall below that value can lead to a steep increase in synthesis, and any that causes a rise above that value will lead to synthesis being switched off. Such adjustments will, however, take time, so that an abrupt change of conditions will cause a disturbance of gene expression that is strong but transient. If there is a delay in the feedback loop, the result may be spontaneous oscillations in the expression of the gene (see Figure 15–18). The different types of behavior produced by a feedback loop will depend on the details of the system; for example, how tightly the transcription regulator binds to its cis-regulatory sequence, its rate of synthesis, and its rate of decay. We discuss these issues in quantitative terms and in more detail in Chapter 8.
With two or more transcription regulators, the possible range of circuit behaviors becomes more complex. Some bacterial viruses contain a common type of two-gene circuit that can flip-flop between expression of one gene and expression of the other. Another common circuit arrangement is called a feed-forward loop; such a loop can serve as a filter, responding to input signals that are prolonged but disregarding those that are brief (Figure 7–41). These various network motifs resemble miniature logic devices, and they can process information in surprisingly sophisticated ways.
The simple types of devices just illustrated are found to be interwoven in eukaryotic cells, creating exceedingly complex circuits (Figure 7–42). Each cell in a developing multicellular organism is equipped with similarly complex control
Figure 7–40 Common types of network motifs in transcription circuits. A and B represent transcription regulators, arrows indicate positive transcription control, while lines with bars depict negative transcription control. in the feed-forward loop, A and B represent transcription regulators that both activate the transcription of target gene Z (see also figure 8–86).
machinery, and it must, in effect, use its intricate system of interlocking transcription switches to compute how it should behave at each time point in response to the many different past and present inputs received. We are only beginning to understand how to study such complex intracellular control networks. Indeed, without new approaches, coupled with quantitative information that is far more precise and complete than we now possess, it will be impossible to predict the behavior of a system such as that shown in Figure 7–42. As explained in Chapter 8, a circuit diagram by itself is not enough.
Figure 7–41 How a feed-forward loop can measure the duration of a signal.
in this theoretical example, transcription regulators A and B are both required for transcription of Z, and A becomes active only when an input signal is present.
if the input signal to A is brief, A does not stay active long enough for B to accumulate, and the Z gene is not transcribed. (C) if the signal to A persists, B accumulates, A remains active, and Z is transcribed. this arrangement allows the cell to ignore rapid fluctuations of the input signal and respond only to persistent levels. this strategy could be used, for example, to distinguish between random noise and a true signal.