Uncovering the Mechanisms and Physiological Roles of Non-monotonic Response Dynamics in Bacterial Stress Response and Differentiation

Thursday, November 19, 2015 - 4:00pm - 5:00pm
Keller 3-180
Oleg Igoshin (Rice University)
Ability of bacterial cells to respond to environmental stress with large-scale changes in gene expression are central to pathogen infections, food spoilage and many other public health concerns. To control the responses, cells use their gene circuits – regulatory networks of sensors, signaling proteins, and transcription factors – to interpret extra- and intracellular
information and control outcomes. Recently, it became that response dynamics, i.e. the precise way concentrations change in time, play essential roles in cellular decision-making. In particular, non-monotonic (adaptive or pulsatile) responses to external stressors are found to occur in variety of bacterial species. In this talk, we discuss the dynamics of responses in
Mycobacterium tuberculosis cells exposed to hypoxia and of starvation-induced activation of sporulation in Bacillus subtilis.

In the first part, we investigate the network controlling the adaptive dynamical response of M. tuberculosis, the causative agent of tuberculosis to hypoxic stress. These responses are critical for bacterial success as pathogen as they are activated when bacteria infect host macrophages. First, we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. Then apply this theorem to analyze the non-monotonic dynamics of the σB-regulated glyoxylate shunt gene expression in M. tuberculosis. We demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of σB activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.

In the second part, we uncover the mechanisms and physiological consequences of a cell-cycle coordinated pulsatile response of the B. subtilis sporulation network. We show that the arrangement of sporulation network genes on the chromosome allows the network to coordinate its response with cell cycle by exploiting the transient gene dosage imbalance during chromosome replication and amplify this imbalance with underlying feedback loops. In addition, we demonstrate how this network evaluates the level of starvation without specific metabolite sensing by detecting changes in cellular growth rate. These design features allows cells to decide between sporulation and continued vegetative growth during each cell cycle spent in
starvation conditions. The simplicity of this cell-fate decision mechanism suggests that it may be widely applicable in a variety of gene regulatory and stress-response settings.
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