Figure 7–31 The integration of multiple inputs at a promoter. Multiple sets of transcription regulators, coactivators, and co-repressors can work together to influence transcription initiation at a promoter, as they do in the Eve stripe 2 module illustrated in figure 7–29. it is not yet understood in detail how the cell achieves integration of multiple inputs, but it is likely that the final transcriptional activity of the gene results from a competition between activators and repressors that act by the mechanisms summarized in figures 7–17, 7–19, and 7–23.
We have seen that transcription regulators can act in combination to control the expression of an individual gene. It is also generally true that each transcription regulator in an organism contributes to the control of many genes. This point is illustrated schematically in Figure 7–33, which shows how combinatorial gene control makes it possible to generate a great deal of biological complexity even with relatively few transcription regulators.
Due to combinatorial control, a given transcription regulator does not necessarily have a single, simply definable function as commander of a particular battery of genes or specifier of a particular cell type. Rather, transcription regulators can be likened to the words of a language: they are used with different meanings in a variety of contexts and rarely alone; it is the well-chosen combination that conveys the information that specifies a gene regulatory event.
Combinatorial gene control causes the effect of adding a new transcription regulator to a cell to depend on that cell’s past history, since it is this history that determines which transcription regulators are already present. Thus, during development, a cell can accumulate a series of transcription regulators that need not initially alter gene expression. The addition of the final members of the requisite combination of transcription regulators will complete the regulatory message, and can lead to large changes in gene expression.
The importance of combinations of transcription regulators for the specification of cell types is most easily demonstrated by their ability—when expressed artificially—to convert one type of cell to another. Thus, the artificial expression of three neuron-specific transcription regulators in liver cells can convert the liver cells into functional nerve cells (Figure 7–34). In some cases, expression of even a single transcription regulator is sufficient to convert one cell type to another. For example, when the gene encoding the transcription regulator MyoD is artificially introduced into fibroblasts cultured from skin connective tissue, the fibroblasts form muscle-like cells. As discussed in Chapter 22, fibroblasts, which are derived from the same broad class of embryonic cells as muscle cells, have already accumulated many of the other necessary transcription regulators required for the
Figure 7–32 Some ways in which the activity of transcription regulators is controlled inside eukaryotic cells. (A) the protein is synthesized only when needed and is rapidly degraded by proteolysis so that it does not accumulate. (B) Activation by ligand binding. (C) Activation by covalent modification. phosphorylation is shown here, but many other modifications are possible (see table 3–3, p. 165).
formation of a complex between a DnA-binding protein and a separate protein with a transcription-activating domain.
Unmasking of an activation domain by the phosphorylation of an inhibitor protein.
Stimulation of nuclear entry by removal of an inhibitory protein that otherwise keeps the regulatory protein from entering the nucleus. (G) release of a transcription regulator from a membrane bilayer by regulated proteolysis.
combinatorial control of the muscle-specific genes, and the addition of MyoD completes the unique combination required to direct the cells to become muscle. An even more striking example is seen by artificially expressing, early in development, a single Drosophila transcription regulator (Eyeless) in groups of cells