Although all cells must be able to switch genes on and off in response to changes in their environments, the cells of multicellular organisms have evolved this capacity to an extreme degree. In particular, once a cell in a multicellular organism becomes committed to differentiate into a specific cell type, the cell maintains this choice through many subsequent cell generations, which means that it remembers the changes in gene expression involved in the choice. This phenomenon of cell memory is a prerequisite for the creation of organized tissues and for the maintenance of stably differentiated cell types. In contrast, other changes in gene expression in eukaryotes, as well as most such changes in bacteria, are only transient. The tryptophan repressor, for example, switches off the tryptophan genes in bacteria only in the presence of tryptophan; as soon as tryptophan is removed from the medium, the genes are switched back on, and the descendants of the cell will have no memory that their ancestors had been exposed to tryptophan.
In this section, we shall examine not only cell memory mechanisms, but also how gene regulatory devices can be combined to create the “logic circuits” through which cells integrate signals and remember events in their past. We begin by considering one such complex gene control region in detail.
We have seen that transcription regulators can be positioned at multiple sites along long stretches of DNA and that these proteins can bring into play coactivators and co-repressors. Here, we discuss how the numerous transcription regulators that are bound to the control region of a gene can cause the gene to be transcribed at the proper place and time.
Consider the Drosophila Even-skipped (Eve) gene, whose expression plays an important part in the development of the Drosophila embryo. If this gene is inactivated by mutation, many parts of the embryo fail to form, and the embryo dies early in development. As discussed in Chapter 21, at the stage of development when Eve begins to be expressed, the embryo is a single giant cell containing multiple nuclei in a common cytoplasm. This cytoplasm contains a mixture of transcription regulators that are distributed unevenly along the length of the embryo, thus providing positional information that distinguishes one part of the embryo from another (Figure 7–26). Although the nuclei are initially identical, they rapidly begin to express different genes because they are exposed to different transcription regulators. For example, the nuclei near the anterior end of the developing embryo are exposed to a set of transcription regulators that is distinct from the set that influences nuclei at the middle or at the posterior end of the embryo.
The regulatory DNA sequences that control the Eve gene have evolved to “read” the concentrations of transcription regulators at each position along the length of the embryo, and they cause the Eve gene to be expressed in seven precisely positioned stripes, each initially five to six nuclei wide (Figure 7–27). How is this remarkable feat of information processing carried out? Although there is still much to learn, several general principles have emerged from studies of Eve and other genes that are similarly regulated.
The regulatory region of the Eve gene is very large (approximately 20,000 nucleotide pairs). It is formed from a series of relatively simple regulatory modules, each of which contains multiple cis-regulatory sequences and is responsible for specifying a particular stripe of Eve expression along the embryo. This modular organization of the Eve gene control region was revealed by experiments in which a particular regulatory module (say, that specifying stripe 2) is removed from its normal setting upstream of the Eve gene, placed in front of a reporter gene, and reintroduced into the Drosophila genome. When developing embryos derived from flies carrying this genetic construct are examined, the reporter gene is found to be expressed in precisely the position of stripe 2 (Figure 7–28). Similar experiments reveal the existence of other regulatory modules, each of which specifies other stripes.