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Expression of a gene is often regulated by controlling the amount of mRNA that is made from the gene. This is called transcriptional regulation. It makes sense to regulate gene expression at this level, as it is wasteful to make mRNAs if the expression of the gene is going to be inhibited at a later stage. Also, bacterial genes are often arranged in a polycistronic unit, or operon; if the genes in this unit are involved in a related function, they can all be regulated simultaneously by regulating the synthesis of the polycistronic mRNA of that operon.

Regulation of transcription of an operon usually occurs at the initial stages of transcription, at the promoter. Whether or not a gene is expressed depends on whether the promoter for the gene is used to make mRNA. Transcriptional regulation at the promoter for a gene can be determined by specific recognition of the promoter by RNA polymerase holoenzyme containing an alternative sigma factor. Regulation can also use regulatory proteins that can act either negatively or positively, depending on whether the regulatory gene product is a transcriptional repressor or a transcriptional activator, respectively. The difference between regulation of transcription by repressors and activators is illustrated in Figure 2.43. A repressor binds to the DNA at an operator sequence close to, or even overlapping, the promoter and prevents RNA polymerase from using the promoter, often by physically obstructing access to the promoter by the RNA polymerase. An activator, in contrast, usually binds upstream of the promoter at an activator site, where it can help the RNA polymerase bind to the promoter or help open the promoter after the RNA polymerase binds. Sometimes, a transcriptional regulator can be a repressor on some promoters and an activator on other promoters, depending on where it binds relative to the start site of transcription.

Figure 2.43 (A) The two general types of transcriptional regulation. In negative regulation, a repressor binds to a repressor-binding site (or operator) and turns expression of the operon off. In positive regulation, an activator protein binds upstream of the promoter and turns expression of the operon on. (B) Graph showing the most common locations of activator sites relative to repressor sites. Activator sites are usually farther upstream. Each data point indicates the middle of the known region on the DNA where a regulatory protein binds. Zero on the x axis marks the start point of transcription. Modified from Collado-Vides J, Magasanik B, Gralla JD, Microbiol Rev 55:371–394, 1991.

The activity of a regulatory protein can itself be modified by the binding of small molecules called effectors which affect its activity (note that the term effector is also used for proteins that are translocated by pathogens into eukaryotic cells). Effectors used in gene regulation are often molecules that can be used by the cell if the regulated operon is expressed or essential metabolites that do not have to be made by the cell if their concentration is already high. If the small-molecule effector causes transcription of the operon to be turned on (for example, by binding to a repressor and changing its structure so that the repressor can no longer bind to the DNA), the small molecule is called an inducer. If binding of the effector to a repressor causes the operon to be turned off, the small molecule is called a corepressor. The activity of regulatory proteins can also be modulated by posttranslational modification (e.g., phosphorylation [see Box 12.3]) or by interaction with other proteins or RNAs.

Not all transcriptional regulation occurs at the promoter, however. Sometimes transcription starts and then stops prematurely, resulting in synthesis of a truncated mRNA that does not include the protein-coding sequence. Such regulation is called attenuation of transcription. These and other mechanisms of transcriptional regulation are discussed in subsequent chapters.