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Dose response relationship in anti-stress gene regulatory networks.

Zhang Q, Andersen ME - PLoS Comput. Biol. (2006)

Bottom Line: Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis.Each phase relies on specific gain-changing events that come into play as stressor level increases.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Computational Biology, CIIT Centers for Health Research, Research Triangle Park, North Carolina, United States of America. qzhang@ciit.org

ABSTRACT
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.

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Analogy between the Anti-Stress Gene Regulatory Network and Proportional Negative Feedback Control System(A) The generalized anti-stress gene regulatory system. Stressor S increases production of controlled variable Y, which is cleared by gene product G; Y activates transcription factor T, which upregulates gene expression of G; r0 − r3 are local gains.(B) Proportional negative feedback system and its closed-loop gain. A is the open-loop gain, F is the feedback gain, and AF is the loop gain.(C) The feedback system in (A) is rearranged so that S is the input, and the species of interest (Y, T, and G) is positioned as the output. The systems-level gain for each of the species can be generalized in terms of the open-loop gain (r0, r0r1, r0r1r2 for Y, T, G, respectively) and loop gain /r1r2r3/, conforming to the closed-loop gain in (B).
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pcbi-0030024-g002: Analogy between the Anti-Stress Gene Regulatory Network and Proportional Negative Feedback Control System(A) The generalized anti-stress gene regulatory system. Stressor S increases production of controlled variable Y, which is cleared by gene product G; Y activates transcription factor T, which upregulates gene expression of G; r0 − r3 are local gains.(B) Proportional negative feedback system and its closed-loop gain. A is the open-loop gain, F is the feedback gain, and AF is the loop gain.(C) The feedback system in (A) is rearranged so that S is the input, and the species of interest (Y, T, and G) is positioned as the output. The systems-level gain for each of the species can be generalized in terms of the open-loop gain (r0, r0r1, r0r1r2 for Y, T, G, respectively) and loop gain /r1r2r3/, conforming to the closed-loop gain in (B).

Mentions: In this section, we set out to investigate the steady-state dose response relationships for the generalized negative feedback control scheme (Figure 2A; for model details see Figure S2 and Tables S1–S3). We defined that stress signal S increases the production rate of controlled variable Y with a local gain r0. Y then activates transcription factor T with a gain r1. T induces gene expression of enzyme G with a gain r2. Finally, G catalyzes the clearance of Y with a gain r3. Since G negatively regulates Y, the local gain r3 has a negative value. The total stress S is composed of S0 and Se (S = S0 + Se) where S0 is the background stress level at the basal condition, and Se is the stress level introduced by external stressors. The total stress level S is expressed as multiples of S0. Levels of Y, T, and G are also normalized to their respective levels at the basal condition where S = S0. For simplicity, we first considered the circumstance where all local gains are independent of each other and remain constant as the value of S is varied.


Dose response relationship in anti-stress gene regulatory networks.

Zhang Q, Andersen ME - PLoS Comput. Biol. (2006)

Analogy between the Anti-Stress Gene Regulatory Network and Proportional Negative Feedback Control System(A) The generalized anti-stress gene regulatory system. Stressor S increases production of controlled variable Y, which is cleared by gene product G; Y activates transcription factor T, which upregulates gene expression of G; r0 − r3 are local gains.(B) Proportional negative feedback system and its closed-loop gain. A is the open-loop gain, F is the feedback gain, and AF is the loop gain.(C) The feedback system in (A) is rearranged so that S is the input, and the species of interest (Y, T, and G) is positioned as the output. The systems-level gain for each of the species can be generalized in terms of the open-loop gain (r0, r0r1, r0r1r2 for Y, T, G, respectively) and loop gain /r1r2r3/, conforming to the closed-loop gain in (B).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808489&req=5

pcbi-0030024-g002: Analogy between the Anti-Stress Gene Regulatory Network and Proportional Negative Feedback Control System(A) The generalized anti-stress gene regulatory system. Stressor S increases production of controlled variable Y, which is cleared by gene product G; Y activates transcription factor T, which upregulates gene expression of G; r0 − r3 are local gains.(B) Proportional negative feedback system and its closed-loop gain. A is the open-loop gain, F is the feedback gain, and AF is the loop gain.(C) The feedback system in (A) is rearranged so that S is the input, and the species of interest (Y, T, and G) is positioned as the output. The systems-level gain for each of the species can be generalized in terms of the open-loop gain (r0, r0r1, r0r1r2 for Y, T, G, respectively) and loop gain /r1r2r3/, conforming to the closed-loop gain in (B).
Mentions: In this section, we set out to investigate the steady-state dose response relationships for the generalized negative feedback control scheme (Figure 2A; for model details see Figure S2 and Tables S1–S3). We defined that stress signal S increases the production rate of controlled variable Y with a local gain r0. Y then activates transcription factor T with a gain r1. T induces gene expression of enzyme G with a gain r2. Finally, G catalyzes the clearance of Y with a gain r3. Since G negatively regulates Y, the local gain r3 has a negative value. The total stress S is composed of S0 and Se (S = S0 + Se) where S0 is the background stress level at the basal condition, and Se is the stress level introduced by external stressors. The total stress level S is expressed as multiples of S0. Levels of Y, T, and G are also normalized to their respective levels at the basal condition where S = S0. For simplicity, we first considered the circumstance where all local gains are independent of each other and remain constant as the value of S is varied.

Bottom Line: Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis.Each phase relies on specific gain-changing events that come into play as stressor level increases.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Computational Biology, CIIT Centers for Health Research, Research Triangle Park, North Carolina, United States of America. qzhang@ciit.org

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus