Signal Integration And Combinatorial Control

Activators Work Together Synergistically to Integrate Signals

In bacteria we saw examples of signal integration in gene regulation, Recall, for example, that the lac genes of E. coli are efficiently expressed only when both lactose is present and glucose absent. The two signals are communicated to the gene through separate regulators—one an activator and the other a repressor. In multicellular organisms signal integration is used extensively. In some cases numerous signals are required to switch a gene on. But just as in bacteria, each signal is transmitted to the gene by a separate regulator, so at many genes multiple activators must work together to switch the gene on.

When multiple activators work together, they do so synergistically. That is, the effect of, say, two activators working together is greater (usually much greater) than the sum of each of them working alone. Synergy can result from multiple activators recruiting a single component of the transcriptional machinery; multiple activators each recruiting a different component; or multiple activators helping each other bind to their sites upstream of the gene they control. We briefly consider all three strategies before giving examples.

Two activators can recruit a single complex—for example, the Mediator—by touching different parts of it. The combined binding energy will have an exponential effect on recruitment (see Chapter Table 3-1). In cases where the activators recruit different complexes (neither of which would bind efficiently without help), synergy is even easier to picture.

Synergy can also result from activators helping each other bind under conditions where the binding of one depends on binding of the other. This cooperativity can be of the type we encountered in bacteria, whereby the two activators touch each other when they bind their sites on DNA. But it can work in other ways as well: one activator can recruit something that helps the second activator bind. Figure 17-14 illustrates the different ways activators help each other bind DNA. These include "classical" cooperative binding; recruitment of a modifier by one activator to help a second bind; and binding of one activator to nucleosornal DNA uncovering the binding site for another.

Synergy is critical for signal integration by activators. Consider a gene whose product is only needed when two signals are received. Each signal is communicated to the gene by a separate activator. The gene must be efficiently expressed when both activators are present but be relatively impervious to the action of either activator alone.

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