Bacterial growth: global effects on gene expression, growth feedback and proteome partition

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Highlights

  • Genes and genetic circuits exhibit growth-rate dependence.

  • Growth rate dependence reflects coupling of gene expression and physiological state of the cell.

  • Several types of growth rate dependencies are distinguished.

  • Growth rate dependence can mediate feedback if a gene product affects growth.

  • Simple growth relations arise from signals coordinating gene expression with metabolic fluxes.

The function of endogenous as well as synthetic genetic circuits is generically coupled to the physiological state of the cell. For exponentially growing bacteria, a key characteristic of the state of the cell is the growth rate and thus gene expression is often growth-rate dependent. Here we review recent results on growth-rate dependent gene expression. We distinguish different types of growth-rate dependencies by the mechanisms of regulation involved and the presence or absence of an effect of the gene product on growth. The latter can lead to growth feedback, feedback mediated by changes of the global state of the cell. Moreover, we discuss how growth rate dependence can be used as a guide to study the molecular implementation of physiological regulation.

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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