Phase resetting reveals network dynamics underlying a bacterial cell cycle

TL;DR

This study introduces a novel method called chemical perturbation spectroscopy to analyze bacterial cell cycle networks by observing phase resetting, revealing modular and asymmetric oscillatory dynamics in Caulobacter crescentus.

Contribution

The paper presents a new approach to directly probe network dynamics and modular organization in biological systems through phase resetting analysis.

Findings

Delay is strongly favored over advance in cell division timing.

Network comprises two autonomous, asymmetrically coupled oscillatory modules.

Proposes a phenomenological model explaining tight cell cycle control.

Abstract

Genomic and proteomic methods yield networks of biological regulatory interactions but do not provide direct insight into how those interactions are organized into functional modules, or how information flows from one module to another. In this work we introduce an approach that provides this complementary information and apply it to the bacterium Caulobacter crescentus, a paradigm for cell-cycle control. Operationally, we use an inducible promoter to express the essential transcriptional regulatory gene ctrA in a periodic, pulsed fashion. This chemical perturbation causes the population of cells to divide synchronously, and we use the resulting advance or delay of the division times of single cells to construct a phase resetting curve. We find that delay is strongly favored over advance. This finding is surprising since it does not follow from the temporal expression profile of CtrA and, in turn, simulations of existing network models. We propose a phenomenological model that suggests that the cell-cycle network comprises two distinct functional modules that oscillate autonomously and couple in a highly asymmetric fashion. These features collectively provide a new mechanism for tight temporal control of the cell cycle in C. crescentus. We discuss how the procedure can serve as the basis for a general approach for probing network dynamics, which we term chemical perturbation spectroscopy (CPS).