Redefining rules for global gene control in bacteria

All lifeforms are a manifestation of information encoded by their DNA. Like any set of instructions, the DNA code is divided into specific sections. Each provides information about a given process and must be read before the information can be used. Inside cells, reading of DNA is a carefully controlled process. For instance, cells do not open their DNA "instruction manual" at random. Instead, cells identify which instructions need to be read at a given moment in time. This in turn depends on the challenges facing the cell. Often, to deal with complex situations, the cell must access multiple instructions simultaneously. This is referred to as a "global" response.

Changes in amounts of oxygen, food, and even numbers of neighbouring cells, provoke different global responses. In our project, we want to better understand how the different global response systems overlap and interact with each other. In our preliminary work, we have identified clues in the DNA sequence that suggest global responses are linked, in an unexpected way, that has been hidden until now. We will study this at three different scales:

1. EXAMINE THE COMPLETE SET OF INSTRUCTIONS encoded by DNA to identify links between the global response systems.

2. FOCUS ON INDIVIDUAL INSTRUCTIONS in fine detail to work out precisely how the different global responses interact.

3. Determine how interactions between global responses alter BEHAVIOUR OF THE CELL.


Our work has potential to benefit the UK economy. Throughout the project, we will engage with Occam Biosciences Ltd. Their goal, is to develop DNA based switches that can be used during industrial fermentation. In simple terms, conditions inside fermenters have to be carefully monitored. However, instrumentation for doing this is imperfect. Instead, Occam hope to modify cells to report their own population, oxygen and food levels during fermentation. This could be done using global response systems. For instance, the global response to oxygen starvation could be used to make cells fluoresce. This would inform the fermenter that oxygen levels should be increased. Occam Biosciences believe this could dramatically improve efficiency of commercial fermentation procedures. We will contribute ideas and expertise.

Given the high profile of DNA in science, society, and popular culture, we will also use our work to engage the next generation of scientists, and the public in general.

Understanding how cells control their genes is fundamental to all aspects of biology. Transcription factors play a major role so have been scrutinised intensely for many years. In bacteria, "global" transcription factors respond to major shifts in environmental conditions to control many genes. To exert their effect, these regulators bind to a preferred DNA consensus sequence located near regulated genes. Current opinion is that each global regulator has a distinct DNA consensus and so binds a largely unique set of coordinates across the genome. In preliminary work, we have mapped the binding of 5 global regulators across the genome of the bacterium Vibrio cholerae, which causes the human disease cholera. Contrary to the conventional view, the optimal DNA sequence for binding each regulator is not distinct. Instead, there are clear similarities between regulator binding sites that mean they can overlap in specific configurations. This indicates a potentially universal, but previously hidden, level of gene regulatory logic that our project seeks to understand.

Hypothesis: Widespread overlap in the DNA binding specificity of global regulators facilitates signal integration

Aim 1: Understand binding site and signal integration at the genome scale

Aim 2: Understand binding site and signal integration at the molecular scale

Aim 3: Understand binding site and signal integration at the phenotypic scale


Prokaryotic promoters are used widely in biotechnology and synthetic biology. Hence, better understanding their regulation has the potential to be exploited commercially. We will also use our project to enthuse the next generation of researchers and engage the general public. Our socio-economic impact aims are as follows:

1. Work with Occam Biosciences Ltd to identify opportunities for commercialisation.
2. Offer laboratory experience to young people interested in science.
3. Use the media to engage the wider public.