Just as repressors function through co-repressors that bind to their repression domains, the activation domains of DNA-binding activators function by binding multisubunit co-activator complexes, protein complexes that interact with or modify chromatin, Pol II, or general transcription factors to activate transcription. One of the first co-activator complexes to be characterized was the yeast SAGA complex, which functions with the Gcn4 activator protein described in Section 9.4. Early genetic studies indicated that full activity of the Gcn4 activator required a protein called Gcn5. The clue to Gcn5’s function came from biochemical studies of a histone acetylase purified from the protozoan Tetrahymena, the first histone acetylase to be purified. Sequence analysis revealed homology between the Tetrahymena protein and yeast Gcn5, which was soon shown to have histone acetylase activity as well. Further genetic and biochemical studies revealed that Gcn5 is one subunit of a multiprotein co-activator complex, named the SAGA complex after genes encoding some of the subunits. Another subunit of this histone acetylase complex binds to activation domains in multiple yeast activator proteins, including Gcn4. The model shown in Figure 9-37b is consistent with the observation that nucleosomes near the promoter region of a gene regulated by the Gcn4 activator are specifically hyperacetylated compared with most histones in the cell. This activator-directed hyperacetylation of nucleosomes near a promoter region opens the chromatin structure so as to facilitate the binding of other proteins required for transcription initiation. The chromatin structure is less condensed than most chromatin, as indicated by its sensitivity to digestion with nucleases in isolated nuclei.

In addition to leading to the decondensation of chromatin, the acetylation of specific histone lysines generates binding sites for proteins containing bromodomains. A bromodomain is a sequence of about 110 amino acids that folds into a domain that binds acetylated lysine. One or more bromodomains are found in several chromosome-associated proteins that contribute to transcriptional activation. For example, a subunit of the general transcription factor TFIID contains two bromodomains, which bind to acetylated nucleosomes with high affinity. Recall that TFIID binding to a promoter initiates assembly of an RNA polymerase II preinitiation complex (see Figure 9-19). Nucleosomes at promoter regions of virtually all active genes have acetylated lysines in their H3 and H4 histone tails.

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A similar activation mechanism operates in higher eukaryotes. Mammalian cells contain multisubunit histone acetylase co-activator complexes that are homologous to the yeast SAGA complex. They also express two related 300-kDa, multidomain proteins called CBP and p300, which function similarly. As noted earlier, one domain of CBP binds the phosphorylated acidic activation domain in the CREB transcription factor. Other domains of CBP interact with different activation domains in other activators. Yet another domain of CBP has histone acetylase activity, and another CBP domain associates with additional multisubunit histone acetylase complexes. CREB and many other mammalian activators function in part by directing CBP and the associated histone acetylase complex to specific nucleosomes, where they acetylate histone tails, facilitating the interaction of general transcription factors with promoter DNA.