Bacterial Plasmid Segregation: Two Heads, One Hat
An interdisciplinary study reveals a unified model for plasmid distribution in bacterial cell division
Using a combination of biology and mathematics, researchers at the Max Planck Institute for Terrestrial Microbiology have uncovered a common principle of bacterial plasmid segregation. The team led by Seán Murray was able to show that the forces at work in different models are fundamentally of the same nature. The new directed motion model unifies previously contradictory models for plasmid segregation and probably also applies to chromosomal systems.
The faithful inheritance of genetic material during cell division is a crucial process of life. However, especially for bacteria, which represent the vast majority of organisms, the underlying mechanisms of the spatial relocation of newly copied DNA material toward the daughter cells (DNA segregation) are poorly understood. Besides chromosomes, bacteria have additional genetic elements: small, ring-shaped self-replicating plasmids that confer additional capabilities. Because of their small size and ease of engineering, plasmids are an important tool in fundamental research as well as biotechnological applications. At the same time, from a human perspective, they represent a concern for public health, because they can encode virulence factors or antibiotic resistance.
For low-copy number plasmids and chromosomes, segregation by random diffusion is not reliable enough: an active mechanism is required to ensure stable inheritance. This is most commonly mediated by a three-component system, called Par. The most common of these, ParABS, consists of two proteins and a specific DNA site. However, it remains unclear how this system leads to accurate plasmid segregation. In particular, it remained unsolved whether plasmids are directed towards certain target positions or exhibit oscillatory movements.
Measuring dynamics of cell cycles
Now the Max Planck research team led by Seán Murray was able to uncover the true nature of these forces. In a cross-disciplinary approach, the researchers measured the dynamics of many thousand cell cycles in live cell situations and combined their data with stochastic modeling. They analyzed the dynamical nature of two different distantly-related systems from the human gut bacterium Escherichia coli: F plasmid, the major carrier of antibiotic resistance genes, and pB171, the virulence plasmid of a pathogenic strain.
Intriguingly, their results reveal a common nature of movement in both systems. “Our model shows that there is one dominant type of plasmid movement: directed positioning in which the plasmids are actively brought to specific subcellular positions, “says first author of the study, Robin Köhler. According to the model, ParABS regularly positions plasmids across the nucleoid but operates just below the threshold of an oscillatory instability. He adds: “Our simulations indicate that this minimises energy consumption by the system.”
This study was made possible due to the interdisciplinary combination of high-throughput experiments and mathematical modelling. According to Seán Murray, mathematical modeling building on substantial experimental foundations can be very successful in finding the underlying principle of a biological mechanism: “Our work unifies previously contradictory models for plasmid segregation and provides a robust mechanistic basis for self-organized plasmid spacing that may be applicable to other Par systems. In particular, our model may shed light on how chromosomal ParABS systems function, about which much is still unknown.”