Cooperativity in transcriptional control

Transcription is controlled by promoter-selective factors, which bind to cis-regulatory elements in a specific subset of genes. Regulation by these factors involves direct interactions with the general transcriptional machinery as well as interactions with co-activators and co-repressors. These co-regulators often function by modifying the covalent or non-covalent structure of the chromatin template thereby altering promoter usage. Studies of the Escherichia coli bacteriophage λ cI protein, λ repressor, first established the importance of transcription factor cooperativity in gene regulation. λ repressor binds to multiple tandemly arranged sites in the λ genome to activate its own expression and to repress genes required for lytic growth of the bacteriophage. The binding is cooperative — adjacent repressor molecules interact to stabilize their association with the DNA template. Thus, small changes in the concentration of λ repressor result in large changes in binding site occupancy and therefore in a switch between lysogenic and lytic growth. In prokaryotes, transcription factor cooperativity is the exception rather than the rule. However, in eukaryotes, it seems to be critical to most aspects of transcription factor function. In eukaryotic cells, regulated transcription is almost always conferred by composite regulatory modules — enhancers — that contain binding sites for multiple factors. Enhancers contain the information that ensures each gene will be active at the correct times in the correct cells. Decoding this information depends on direct and indirect interactions between the DNA-bound factors, which often result in the cooperative assembly of an enhancer-bound complex. In addition, factors can cooperate by influencing one another’s regulatory activity or DNA-binding specificity. This review is a brief summary of three examples of cooperativity among transcription factors. These are: cooperative interactions that occur at the enhancer of the interferon-β (IFNβ) gene to assemble a multiprotein ‘enhanceosome’; cooperative interactions between Extradenticle (Exd) and factors encoded by the Drosophila and vertebrate homeotic (Hox) gene clusters, which partially account for the specificity of homeotic proteins; and a cooperative interaction involving the glucocorticoid receptor (GR), which is an example of transcription factor cooperativity that does not require cooperative binding to DNA.