Professor and Vice Chair
There are fundamental gaps in understanding how bacteria differentially regulate their gene expression. This information is important because bacteria, including pathogens, regulate gene expression in order to survive environmental insults, to disseminate in the environment, and to resist antibiotics, host defenses, and disinfectants. A striking example of the results of differential gene regulation by many important bacterial pathogens is the formation of a new differentiated cell type called an endospore (e.g., Bacillus anthracis, Bacillus cereus, Clostridium difficile). The endospore is a dormant, environmentally resistant cell that is easily disseminated and is resistant to antibiotics and disinfectants. Our long-term goal is to understand how gene expression is controlled during spore formation in order to identify novel targets for disrupting spore development or to prevent spore germination. Moreover, our studies may result in the discovery of mechanisms that control gene expression in a wide range of pathogenic bacteria.
The fundamental mechanism in regulation of gene expression during endospore development in the model bacterium, Bacillus subtilis, is the sequential appearance of four new RNA polymerase sigma factors that replace one another and confer on the RNA polymerase different specificities for the recognition of different classes of promoters. Early after the onset of endospore formation the cell divides asymmetrically giving rise to two dissimilar sibling cells. One of these cells (the forespore) develops into the endospore, while the other (the mother cell) becomes a terminally differentiated cell that nurtures the developing endospore. Sigma factors σF and σG are active sequentially in the forespore, while σE and σK are active sequentially in the mother cell. Moreover, sigma factor activity is coordinated between the forespore and mother cell, but the mechanisms responsible for the coordination are mostly unclear. Currently we are seeking to answer two general questions. 1. How is sigma factor activity in one cell (forespore or mother cell) controlled by sigma activity in the other cell? This question is significant because little is known about intercellular communication between bacterial cells. 2. How are sigma factors silenced so that their activity can be replaced by the next sigma active in the cascade? This question is significant because in no case is it known how a newly active secondary sigma factor replaces the primary or previously active sigma factor. The answers to these questions will provide significant new information on intercellular communication and regulation of gene expression in bacteria, including pathogens. Therefore, these studies may illuminate new potential targets for therapeutic or diagnostic reagents.