Thus far, we have seen how single switches can control the expression of single operons or two operons containing as many as a couple of dozen genes. Some physiological responses to changes in the environment require the coordinated expression of large sets of unlinked genes located throughout the genome to bring about dramatic physiological and even morphological changes. Analyses of these processes have revealed another twist in bacterial gene regulation: the control of large numbers of genes by alternative sigma (σ) factors of RNA polymerase. One such example, the process of sporulation in Bacillus subtilis, has been analyzed in great detail in the past few decades. Under stress, the bacterium forms spores that are remarkably resistant to heat and desiccation.

Early in the process of sporulation, the bacterium divides asymmetrically, generating two components of unequal size that have very different fates. The smaller compartment, the forespore, develops into the spore. The larger compartment, the mother cell, nurtures the developing spore and lyses when spore morphogenesis is complete to liberate the spore (Figure 11-31a). Genetic dissection of this process has entailed the isolation of many mutants that cannot sporulate. Detailed investigations have led to the characterization of several key regulatory proteins that directly regulate programs of gene expression that are specific to either the forespore or the mother cell. Four of these proteins are alternative σ factors.

Recall that transcription initiation in bacteria includes the binding of the σ subunit of RNA polymerase to the −35 and −11 regions of gene promoters. The σ factor disassociates from the complex when transcription begins and is recycled. In B. subtilis, two σ factors, σ^A and σ^H, are active in vegetative cells. During sporulation, a different σ factor, σ^F, becomes active in the forespore and activates a group of more than 40 genes. One gene activated by σ^F is a secreted protein that in turn triggers the proteolytic processing of the inactive precursor pro-σ^E, a distinct σ factor in the mother cell. The σ^E factor is required to activate sets of genes in the mother cell. Two additional σ factors, σ^K and σ^G, are subsequently activated in the mother cell and forespore, respectively (Figure 11-31a). The expression of distinct σ factors allows for the coordinated transcription of different sets of genes, or regulons, by a single RNA polymerase.

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How do these alternative σ factors control different aspects of the sporulation process? The answers have become crystal clear with the advent of new approaches for characterizing the expression of all genes in a genome (see Section 14.6). It is now possible to monitor the transcription of each B. subtilis gene during vegetative growth and spore formation and in different compartments of the spore. Several hundred genes have been identified in this fashion that are transcriptionally activated or repressed during spore formation.

How are the different sets of genes controlled by each σ factor? Each σ factor has different sequence-specific DNA-binding properties. The operons or individual genes regulated by particular σ factors have characteristic sequences in the −35 and −11 regions of their promoters that are bound by one σ factor and not others (Figure 11-31b). For example, σ^E binds to at least 121 promoters, within 34 operons and 87 individual genes, to regulate more than 250 genes, and σ^F binds to at least 36 promoters to regulate 48 genes.

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Alternative σ factors also play important roles in the virulence of human pathogens. For example, bacteria of the genus Clostridium produce potent toxins that are responsible for severe diseases such as botulism, tetanus, and gangrene. Key toxin genes of C. botulinum, C. tetani, and C. perfringens have recently been discovered to be controlled by related, alternative σ factors that recognize similar sequences in the −35 and −10 regions of the toxin genes. Understanding the mechanisms of toxin-gene regulation may lead to new means of disease prevention and therapy.