9.5 Molecular Mechanisms of Transcription Repression and Activation

The repressors and activators that bind to specific sites in DNA and regulate expression of the associated protein-coding genes do so by three general mechanisms. First, these regulatory proteins act in concert with other proteins to modulate chromatin structure, inhibiting or stimulating the ability of general transcription factors to bind to promoters. Recall from Chapter 8 that the DNA in eukaryotic cells is not free, but is associated with a roughly equal mass of protein in the form of chromatin. The basic structural unit of chromatin is the nucleosome, which is composed of about 147 bp of DNA wrapped tightly around a disk-shaped core of histone proteins. Residues within the N-terminal region of each histone, and the C-terminal regions of histones H2A and H2B, called histone tails, extend from the surface of the nucleosome and can be reversibly modified (see Figure 8-26b). Such modifications influence the relative condensation of chromatin and thus its accessibility to proteins required for transcription initiation. Second, activators and repressors interact with a large multiprotein complex called the mediator of transcription complex, or simply Mediator. This complex, in turn, binds to Pol II and directly regulates assembly of the preinitiation complex. In addition, some activation domains interact with TFIID-TAF subunits or other components of the preinitiation complex, and these interactions contribute to preinitiation complex assembly. Finally, activation domains may also interact with the elongation factor P-TEFb (cyclin T–CDK9) and other as yet unknown factors to stimulate elongation by Pol II away from the promoter region.

In this section, we review the current understanding of how repressors and activators control chromatin structure and preinitiation complex assembly. In the next section of the chapter, we discuss how the concentrations and activities of activators and repressors themselves are controlled, so that gene expression is precisely attuned to the needs of the cell and organism.