Transcription factor effector domains

Abstract

The last decade has seen an incredible breakthrough in technologies that allow histones, transcription factors (TFs), and RNA polymerases to be precisely mapped throughout the genome. From this research, it is clear that there is a complex interaction between the chromatin landscape and the general transcriptional machinery and that the dynamic control of this interface is central to gene regulation. However, the chromatin remodeling enzymes and general TFs cannot, on their own, recognize and stably bind to promoter or enhancer regions. Rather, they are recruited to cis regulatory regions through interaction with site-specific DNA binding TFs and/or proteins that recognize epigenetic marks such as methylated cytosines or specifically modified amino acids in histones. These "recruitment" factors are modular in structure, reflecting their ability to interact with the genome via one region of the protein and to simultaneously bind to other regulatory proteins via "effector" domains. In this chapter, we provide examples of common effector domains that can function in transcriptional regulation via their ability to (a) interact with the basal transcriptional machinery and general co-activators, (b) interact with other TFs to allow cooperative binding, and (c) directly or indirectly recruit histone and chromatin modifying enzymes.

Fig. 12.1

Regulation of transcription. Shown is a schematic representing the three steps needed for productive transcription, including Step 1: the creation of open chromatin, which involves interactions between DNA-bound proteins and histone modifying enzymes (e.g. a HAT which can create an acetylated (Ac) histone); Step 2: assembly of the preinitiation complex, which can involve interactions between different DNA binding proteins and between DNA-bound proteins and general factors (such as TBP which binds to the TATA box); and Step 3: transition to productive elongation, which involves interaction between DNA-bound proteins and enzymes such as the pTEFb kinase. Although in this schematic the TFs are shown binding to transcription factor binding sites (TFBS) proximal to the transcription start site (indicated by the bent arrow), many transcriptional regulators can also bind to sites quite far from the core promoter regions

Fig. 12.2

Modular structure of effector domain-containing proteins. Effector domains can be recruited to specific genomic regions via a DNA binding domains that recognize short DNA sequence motifs (TFBS), b recognition of a methylated cytosine (shown as a black ball), and c recognition of a modified amino acid of a histone (e.g. an acetylated histone, shown as Ac)

Fig. 12

Effector domains interact with different types of proteins to confer transcriptional regulation. The effector domains of both ubiquitously expressed factors such as E2F1 (panel a) and cell type-specific factors such as the glucocorticoid receptor (panel b) can interact with many different proteins, resulting in either transcriptional activation or transcriptional repression (see text for references and descriptions of the various proteins; see also [118] for a review on context-dependent transcriptional regulation)