Dose Response Relationship in Anti-Stress Gene Regulatory Networks

To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.: To maintain a stable intracellular environment, cells are equipped with multiple specialized defense programs that are launched in response to various external chemical and physical stressors. These anti-stress mechanisms comprise primarily gene regulatory networks, and like many manmade control devices, such as thermostats and automobile cruise controls, they are often organized into negative feedback circuits. A quantitative understanding of how these control circuits operate in the cell can help us to assess and predict more accurately the cellular impacts brought about by perturbing stressors, such as environmental toxicants. Using control theory and computer simulations, we explored nature's design principle for anti-stress gene regulatory networks, and the manner in which cells respond and adapt to perturbations. We showed that cells can exploit multiple mechanisms, such as protein homodimerization, cooperative binding, and auto-regulation, to enhance the feedback loop gain, which, according to control theory, is a basic principle for effective perturbation resistance. We also illustrated that the steady-state dose response curve is likely to transition through multiple phases as stressor level increases, and that the low-dose region is inherently nonlinear. Our results challenge the common practice of linear extrapolation for evaluating the low-dose effect, and would lead to improved human health risk assessment for exposures to environmental toxicants.