Figure 8–83 Combinatorial control of gene expression. There are many ways in which gene expression can be controlled by two transcription regulators. To define precisely the relationship between the two inputs and the gene expression output, a regulatory circuit is often described as a specific type of logic gate, a term borrowed from electronic circuit design. A simple example is the OR logic gate (not shown here), in which a gene is controlled by two transcription activators, and one or the other can activate gene expression. (A) In a system with an activator A and repressor R, if transcription is turned on only when A is bound and R is not, then the result is an AND NOT logic gate. We saw an example of this logic in Chapter 7 (Figure 7–15).
(B) An AND gate results when two transcription activators, A1 and A2, are both required to turn on a gene.
Figure 8–84 How the quantitative output of a gene depends on both its combinatorial logic and the affinities of transcription regulators. (A) In a combinatorial gene regulatory system like that illustrated in Figure 8–83A, the fraction of promoters bound by activator A and not bound by repressor R are each determined as shown here. The product of these probabilities provides the probability, P(A, R), that a gene promoter is active. (B–E) In these four panels, red indicates high gene expression and blue indicates low gene expression. (B) and (C) depict gene expression from the system described in panel (A). The two panels demonstrate how the system behaves when the relative concentration of A1 concentration of A2 arabinose (mM) S. Kaplan et al., Mol. Cell 29:786–792, 2008.) 0.02 1.3 43 affinities of the two transcription regulators change as indicated above each panel.
(D) Gene expression in a case where the gene turns on only at high levels of both activating inputs (A1 and A2), as shown in Figure 8–83B. (E) Experimental data showing measured expression of a gene in E. coli that is combinatorially regulated by two inputs: arabinose and cAMP. Note the close resemblance to panel (D). (E, adapted from rate of protein synthesis rate of protein synthesis
Imagine that a sudden input signal immediately activates a transcription activator A and that the same input signal induces the much slower synthesis of a transcription repressor protein R that acts on the same gene X. If A and R control gene expression by an AND NOT logic function like that described above, our intuition tells us that this system should be able to generate a pulse of transcription: when A is activated (and R is absent), the transcription of gene X will begin and cause an increase in the concentration of protein X, but then transcription will shut off when the concentration of R increases to a sufficiently high value.
Arrangements of this type are common in the cell. In E. coli, for example, galactose metabolic genes are positively regulated by the catabolite activator protein (CAP), which is activated at high levels of cAMP. The same genes are repressed by the GalS repressor protein, which is encoded by a gene whose transcription is likewise activated by CAP. Thus, an increase in input (cAMP) activates A (CAP), and transcription of the galactose genes begins. But activation of A also causes a subsequent buildup of R (GalS), which causes the same genes to be repressed after a delay. This results in an incoherent feed-forward motif (Figure 8–85A).