Bacterial growth: global effects on gene expression, growth feedback and proteome partition
Graphical abstract
Introduction
Many bacteria can grow exponentially with a wide range of growth rates, depending on the nutrient-content of the growth medium. Escherichia coli for example can grow with doubling times ranging from 20 min to many hours. The study of bacterial growth has played a central role in the development of modern microbial physiology as well as in the discovery of the regulation of gene expression [1, 2, 3]. It constitutes a rather natural subject of interest for systems biology [4, 5], as cell growth obviously is a systems-level phenomenon that depends on the coordinated functions of many cellular components [6], and new experimental tools allow to study growth with unprecedented control over the growth conditions [7••].
Moreover, bacterial growth provides a model system for studying the coupling between individual genetic circuits and the global state of the cell. With recent progress in designing synthetic genetic circuits [8, 9, 10] and in quantitative studies of physiological gene regulation systems [11, 12•], it has become clear that genetic circuits are not strictly insulated from their ‘host’ cell, but rather are coupled to the physiological state of the cells as a whole. For example, gene expression requires RNA polymerases and ribosomes, and the concentration of these macromolecular machineries is dependent on the growth conditions [13, 14]. These observations point towards the limitations of analogies between genetic and electronic circuits and of metaphors that describe the host cell of a circuit as a ‘chassis’ [15, 16], a rigid framework onto which the circuit is mounted: Changes in gene expression are often desired in response to changes in the environment, which typically also affect the cell's physiological state, for example, a slow-down of growth. Thus, changes in gene expression occur in conjunction with adaptation of the physiology of the cell as a whole. For synthetic gene circuits, such coupling may mostly be an undesired complication [17, 18], but for endogenous systems, the regulatory mechanisms have likely evolved to work in such conjunction with the global physiological adaptation of the cell.
While the coupling between physiology and gene expression can be expected to be a general phenomenon, exponentially growing bacteria provide a reasonably simple model system for its quantitative study, because the global state of a cell can to a large extent be characterized by the growth rate as a key parameter [19]. In this article, we review different types of growth-rate dependent gene expression (summarized in Table 1) and discuss the use of growth-rate dependencies as a physiological guide for studying regulatory mechanisms.
Section snippets
Passive dependence of gene expression on growth-rate
The simplest cases of growth-rate dependence are given by genes, whose products are neutral with respect to growth and present in low abundance, so that negative effects of overexpression on growth are negligible. Specifically, constitutively expressed genes can be used to separate growth-rate dependence from the effects of gene regulation [20, 21•] (Figure 1 and cases 1a, 1b in Table 1). Already in the 1970s, several studies [22, 23] showed that the concentrations of the protein product of
Growth-mediated feedback
If the product of a gene has a (positive or negative) effect on growth, growth provides a feedback mechanism for the expression of that gene [20]. Whether the feedback is positive or negative depends on the functional form of the growth rate dependence of gene expression (determined by the regulation of that gene) and on the mode of growth-limitation. The effect on growth may be gene-specific (e.g. because the gene product is toxic or because it is required to process a limiting nutrient) or
Growth-rate dependence based on growth-related physiological signals
Finally, growth-rate dependence of gene expression can arise from regulation by growth-related physiological signals that coordinate expression of certain genes with metabolic fluxes. Even though such regulation may be complex, it can lead to surprisingly simple growth-rate dependencies that can be understood based on the economic rationale underlying that regulation. Perhaps the best known such case is the linear growth-rate dependence of ribosomal protein obtained for cells growing in media
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
This work was supported by the Max Planck Society (SK), by the NSF through Grant PHY1058793 (to TH) and through the Center for Theoretical Biological Physics (Grant PHY-0822283), and by the NIH through Grant RO1GM077298 (to TH).
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