The cis-regulatory sequences to which eukaryotic transcription activator proteins bind were originally called enhancers because their presence “enhanced” the rate of transcription initiation. It came as a surprise when it was discovered that these sequences could be found tens of thousands of nucleotide pairs away from the promoter; as we have seen, DNA looping, which was not widely appreciated at the time, can now explain this initially puzzling observation.
Once bound to DNA, how do assemblies of activator proteins increase the rate of transcription initiation? At most genes, mechanisms work in concert. Their function is both to attract and position RNA polymerase II at the promoter and to release it so that transcription can begin.
Some activator proteins bind directly to one or more of the general transcription factors, accelerating their assembly on a promoter that has been brought in proximity—through DNA looping—to that activator. Most transcription activators, however, attract coactivators that then perform the biochemical tasks needed to initiate transcription. One of the most prevalent coactivators is the large Mediator protein complex, composed of more than 30 subunits. About the same size as RNA polymerase itself, Mediator serves as a bridge between DNA-bound transcription activators, RNA polymerase, and the general transcription factors, facilitating their assembly at the promoter (see Figure 7–17).
eukaryotic transcription Activators Direct the Modification of local Chromatin Structure
The eukaryotic general transcription factors and RNA polymerase are unable, on their own, to assemble on a promoter that is packaged in nucleosomes. Thus, in addition to directing the assembly of the transcription machinery at the promoter, eukaryotic transcription activators promote transcription by triggering changes to the chromatin structure of the promoters, making the underlying DNA more accessible.
The most important ways of locally altering chromatin are through covalent histone modifications, nucleosome remodeling, nucleosome removal, and his-tone replacement (discussed in Chapter 4). Eukaryotic transcription activators use all four of these mechanisms: thus they attract coactivators that include his-tone modification enzymes, ATP-dependent chromatin remodeling complexes, and histone chaperones, each of which can alter the chromatin structure of
Figure 7–18 Eukaryotic transcription regulators assemble into complexes on DNA. (A) Seven transcription regulators are shown. the nature and function of the complex they form depend on the specific cis-regulatory sequences that seed their assembly. (B) Some assembled complexes activate gene transcription, while another represses transcription. note that the light green and dark green proteins are shared by both activating and repressing complexes. proteins that do not themselves bind DnA but assemble on other DnA-bound transcription regulators are termed coactivators or co-repressors. in some cases (lower right), rnA molecules are found in these assemblies. As described later in this chapter, these rnAs often act as scaffolds to hold a group of proteins together.
promoters (Figure 7–19). These local alterations in chromatin structure provide greater access to DNA, thereby facilitating the assembly of the general transcription factors at the promoter. In addition, some histone modifications specifically attract these proteins to the promoter. These mechanisms often work together during transcription initiation (Figure 7–20). Finally, as discussed earlier in this chapter, the local chromatin changes directed by one transcriptional regulator can allow the binding of additional regulators. By repeated use of this principle, large assemblies of proteins can form on control regions of genes to regulate their transcription.