BACELL NETWORK
From gene regulation to gene function: Regulatory networks in the model Gram-positive bacterium Bacillus subtilis
Objectives
One of the major reasons for the success of bacteria as colonisers of diverse habitats is their extraordinary ability to adapt to and survive in continuously changing environments. In particular, their ability to respond rapidly to physical, chemical and nutrient stresses is often crucial to survival in a given environmental niche, be it in terrestrial or aquatic habitats, in food systems or in pathogenic interactions with humans, animals and plants. The responses modulate the metabolism and physiology of the cell to match the demands of the environment. The responses of bacteria to environmental stimuli have been studied for more than three decades, usually as specific responses to a single stimulus or groups of stimuli. However, as we enter the post-genomic era, new possibilities are opening up to study the global regulatory networks that living organisms use to integrate extracellular and intracellular signals to provide appropriate global responses. The overall object of this programme is to study the global regulatory networks of Bacillus subtilis, a well characterised Gram-positive bacterium. Whilst the project deliverables will be primarily of a fundamental/generic nature, they will also have significant implications for the biotechnology, pharmaceutical and agro-food industries.
Why study the regulatory networks in B. subtilis? B. subtilis is one of the most genetically amenable and intensively studied bacteria. The entire genome sequence was determined in 1997 and is available on WWW via the SubtiList database. Additionally, a consortium set up to initiate a systematic analysis of the function of unknown B. subtilis genes has generated a collection of about 1200 distinct integrational reporter gene mutants. This BSFA mutant collection is a virtually unique biological resource and, together with its database Micado, will be a major resource for the current proposals. Although some mechanistic differences between organisms are inevitable, B. subtilis clearly represents an ideal model organism in which to study global regulatory networks of bacteria in general and Gram-positive bacteria in particular.
Bacillus species are commercially important producers of high quality industrial enzymes, fine biochemicals, and polyketide and lipopeptide antimicrobial agents. The value and importance of studying a representative of the Gram-positive bacteria as a model is widely recognised by industry, who is keen to derive information that will, on the one hand, improve the Bacillus Cell Factory by extending the range and quality of products it is able to synthesise, while on the other, identify gene products that may be exploited as targets for novel antibiotics.
The Bacillus Functional Analysis (BFA) programme has revealed that a significant number of genes of unknown function are involved in regulatory responses to factors such as growth arrest, cell density, nutrient starvation and stress. These global responses may take the form of specific or general responses. In either case, they form part of a complex regulatory network designed to match cellular physiology with optimal growth and or survival. Put simply, global regulatory networks enable the bacterium to sense their intracellular and extracellular environments and to apply appropriate responses. The regulatory networks have profound effects on the life-style and fitness of the bacterium. For example, such networks are important in switching on virulence genes in human, animal and plant pathogens, to enable bacteria to survive in the matrix of food, and to determine physiological characteristics in industrial fermentations.
The primary objective of defining the global regulatory networks in B. subtilis will be achieved by: