Circadian regulation of cell division in cyanobacteria: mechanism and function

Many organisms, from simple bacteria to complex mammals, have an internal 'circadian' clock that helps regulate essential life processes on a 24-hour cycle. The circadian clock is a network of interacting genes and proteins, which in turn interact with other processes in cells to switch genes on or off. One such process is the cell division cycle - the process by which a parent cell replicates its DNA and divides into two new cells.

The clock controls the speed and timing of this cycle and clock defects cause serious problems. In humans, these include cancer (an unregulated cell cycle is a hallmark of cancer progression) and metabolic syndrome.

Our goal is to understand both how and why the clock and the cell cycle work together. To do so, we will study the simplest known clock, which is found in a type of bacteria, the photosynthetic cyanobacterium Synechococcus elongatus. By studying this simple system, we can establish the principles of how clocks and the cell cycle interact, which we can then apply to more complicated organisms.

For many years, it was believed that the circadian clock of cyanobacteria 'blocks' cell division at certain times of day, and has no influence at other times. In previous work, we showed that the clock continuously orchestrates cell division throughout the day. The identities of the molecules and how they work together (i.e. the mechanism of this control) remain, however, unknown.

We hypothesise that the circadian clock controls when cells divide by regulating the levels of a protein called FtsZ, which accumulates in cyanobacterial cells at the place where the cell will divide. To test our hypothesis, we will combine mathematical modelling - to quantitatively validate our understanding - with cutting-edge experimental techniques.

Our approach will provide high-resolution data on the behaviour of individual cells (rather than whole populations averaged together). Differences between individual cells are often crucial to distinguish between hypotheses. It is also important that this data is dynamic, as otherwise causality cannot be determined.

We will track thousands of cells over time under a microscope, continuously measuring the location and rate of FtsZ production in each cell. We will match the amount of FtsZ produced in cells to the patterns of cell division over 24-hour cycles. Combining these observations with our mathematical models, we will determine the precise relation between the clock, FtsZ and the cell cycle, and identify any other molecules involved.

Turning to the question of why the clock regulates the cell cycle, we need to explore how the clock engages with and responds to environmental changes. To do this, we will regulate the ambient light levels and use microfluidics, where the local environment of individual cells can be precisely controlled and rapidly modified. Stimulating cells to produce FtsZ in a pattern that is 'out of sync' with both the clock and the environmental day/night cycle, we will observe how the cells are affected and, from this, infer the purpose of the clock's control of the cell cycle.

By providing a comprehensive, quantitative understanding of the mechanism and consequences of the regulation of the cell cycle by the circadian clock in cyanobacteria, this project will establish a firm foundation for further studies of the interplay between these two critical cell systems. Our conceptual framework will be applicable to more complex organisms, such as humans, where the clock and the cell cycle also interact tightly to maintain health and mechanistic understanding remains extremely limited.

Having a thorough understanding of cell division control is the first step towards developing the capabilities to control it, which could be relevant for future research in the diverse areas involving cell division as well as for applications in biomedicine and synthetic biology.