scholarly journals Phase space characterization for gene circuit design

2019 ◽  
Author(s):  
Macarena A. Muñoz Silva ◽  
Tamara Matute ◽  
Isaac Nuñez ◽  
Ambrosio Valdes ◽  
Carlos A. Ruiz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phase Space ◽  
Circuit Design ◽  
Piecewise Linear ◽  
Genetic Circuit ◽  
Cell Physiology ◽  
Gene Circuits ◽  
Linear Dynamics ◽  
Relative Expression ◽  
Cellular Context

ABSTRACTGenetic circuit design requires characterization of the dynamics of synthetic gene expression. This is a difficult problem since gene expression varies in complex ways over time and across different contexts. Here we present a novel method for characterizing the dynamics of gene expression with a few parameters that account for changes in cellular context (host cell physiology) and compositional context (adjacent genes). The dynamics of gene circuits were characterized by a trajectory through a multi-dimensional phase space parameterized by the expression levels of each of their constituent transcriptional units (TU). These trajectories followed piecewise linear dynamics, with each dynamical regime corresponding to different growth regimes, or cellular contexts. Thus relative expression rates were changed by transitions between growth regimes, but were constant in each regime. We present a plausible two-factor mathematical model for this behavior based on resource consumption. By analyzing different combinations of TUs, we then showed that relative expression rates were significantly affected by the neighboring TU (compositional context), but maintained piecewise linear dynamics across cellular and compositional contexts. Taken together these results show that TU expression dynamics could be predicted by a reference TU up to a context dependent scaling factor. This model provides a framework for design of genetic circuits composed of TUs. A common sharable reference TU may be chosen and measured in the cellular contexts of interest. The output of each TU in the circuit may then be predicted from a simple function of the output of the reference TU in the given cellular context. This will aid in genetic circuit design by providing simple models for the dynamics of gene circuits and their constituent TUs.

scholarly journals Generating effective models and parameters for RNA genetic circuits

2015 ◽  
Author(s):  
Chelsea Y Hu ◽  
Jeffrey D Varner ◽  
Julius B Lucks
Keyword(s):  
Gene Expression ◽  
Circuit Design ◽  
Core Gene ◽  
Equation Model ◽  
Genetic Circuit ◽  
Test Case ◽  
Genetic Circuits ◽  
Modeling Framework ◽  
Broad Array ◽  
Effective Models

RNA genetic circuitry is emerging as a powerful tool to control gene expression. However, little work has been done to create a theoretical foundation for RNA circuit design. A prerequisite to this is a quantitative modeling framework that accurately describes the dynamics of RNA circuits. In this work, we develop an ordinary differential equation model of transcriptional RNA genetic circuitry, using an RNA cascade as a test case. We show that parameter sensitivity analysis can be used to design a set of four simple experiments that can be performed in parallel using rapid cell-free transcription-translation (TX-TL) reactions to determine the thirteen parameters of the model. The resulting model accurately recapitulates the dynamic behavior of the cascade, and can be easily extended to predict the function of new cascade variants that utilize new elements with limited additional characterization experiments. Interestingly, we show that inconsistencies between model predictions and experiments led to the model-guided discovery of a previously unknown maturation step required for RNA regulator function. We also determine circuit parameters in two different batches of TX-TL, and show that batch-to-batch variation can be attributed to differences in parameters that are directly related to the concentrations of core gene expression machinery. We anticipate the RNA circuit models developed here will inform the creation of computer aided genetic circuit design tools that can incorporate the growing number of RNA regulators, and that the parameterization method will find use in determining functional parameters of a broad array of natural and synthetic regulatory systems.

Advances in genetic circuit design: novel biochemistries, deep part mining, and precision gene expression

2013 ◽  
Vol 17 (6) ◽  
pp. 878-892 ◽  
Author(s):  
Alec AK Nielsen ◽  
Thomas H Segall-Shapiro ◽  
Christopher A Voigt
Keyword(s):  
Gene Expression ◽  
Circuit Design ◽  
Genetic Circuit ◽  
Deep Part

Relative Expression of Mouse Udp-glucuronosyl Transferase 2b1 Gene in the Livers, Kidneys, and Hearts: The Influence of Nonsteroidal Anti-inflammatory Drug Treatment

2019 ◽  
Vol 20 (11) ◽  
pp. 918-923 ◽  
Author(s):  
Yazun Jarrar ◽  
Qais Jarrar ◽  
Mohammad Abu-Shalhoob ◽  
Abdulqader abed ◽  
Esra'a Sha'ban
Keyword(s):  
Gene Expression ◽  
Strongly Correlated ◽  
Chain Reaction ◽  
Inflammatory Drug ◽  
Relative Expression ◽  
Elimination Half ◽  
Endogenous Compounds ◽  
Polymerase Chain ◽  
Anti Inflammatory ◽  
Glucuronosyl Transferase

Background: Mouse Udp-glucuronosyl Transferase (UGT) 2b1 is equivalent to the human UGT2B7 enzyme, which is a phase II drug-metabolising enzyme and plays a major role in the metabolism of xenobiotic and endogenous compounds. This study aimed to find the relative expression of the mouse ugt2b1 gene in the liver, kidney, and heart organs and the influence of Nonsteroidal Anti-inflammatory Drug (NSAID) administration. Methods: Thirty-five Blab/c mice were divided into 5 groups and treated with different commonly-used NSAIDs; diclofenac, ibuprofen, meloxicam, and mefenamic acid for 14 days. The livers, kidneys, and hearts were isolated, while the expression of ugt2b1 gene was analysed with a quantitative real-time polymerase chain reaction technique. Results: It was found that the ugt2b1 gene is highly expressed in the liver, and then in the heart and the kidneys. NSAIDs significantly upregulated (ANOVA, p < 0.05) the expression of ugt2b1 in the heart, while they downregulated its expression (ANOVA, p < 0.05) in the liver and kidneys. The level of NSAIDs’ effect on ugt2b1 gene expression was strongly correlated (Spearman’s Rho correlation, p < 0.05) with NSAID’s lipophilicity in the liver and its elimination half-life in the heart. Conclusion: This study concluded that the mouse ugt2b1 gene was mainly expressed in the liver, as 14-day administration of different NSAIDs caused alterations in the expression of this gene, which may influence the metabolism of xenobiotic and endogenous compounds.

scholarly journals Pericytes contribute to the islet basement membranes to promote beta-cell gene expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lina Sakhneny ◽  
Alona Epshtein ◽  
Limor Landsman
Keyword(s):  
Gene Expression ◽  
Cell Function ◽  
Basement Membranes ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Cell Clustering ◽  
Β Cell Function ◽  
Cell Gene Expression ◽  
Glucose Stimulated Insulin Secretion

Abstractβ-Cells depend on the islet basement membrane (BM). While some islet BM components are produced by endothelial cells (ECs), the source of others remains unknown. Pancreatic pericytes directly support β-cells through mostly unidentified secreted factors. Thus, we hypothesized that pericytes regulate β-cells through the production of BM components. Here, we show that pericytes produce multiple components of the mouse pancreatic and islet interstitial and BM matrices. Several of the pericyte-produced ECM components were previously implicated in β-cell physiology, including collagen IV, laminins, proteoglycans, fibronectin, nidogen, and hyaluronan. Compared to ECs, pancreatic pericytes produce significantly higher levels of α2 and α4 laminin chains, which constitute the peri-islet and vascular BM. We further found that the pericytic laminin isoforms differentially regulate mouse β-cells. Whereas α2 laminins promoted islet cell clustering, they did not affect gene expression. In contrast, culturing on Laminin-421 induced the expression of β-cell genes, including Ins1, MafA, and Glut2, and significantly improved glucose-stimulated insulin secretion. Thus, alongside ECs, pericytes are a significant source of the islet BM, which is essential for proper β-cell function.

scholarly journals H2O2 Induces Major Phosphorylation Changes in Critical Regulators of Signal Transduction, Gene Expression, Metabolism and Developmental Networks in Aspergillus nidulans

2021 ◽  
Vol 7 (8) ◽  
pp. 624
Author(s):  
Ulises Carrasco-Navarro ◽  
Jesús Aguirre
Keyword(s):  
Gene Expression ◽  
Protein Phosphorylation ◽  
Aspergillus Nidulans ◽  
Regulation Of Gene Expression ◽  
Antioxidant Response ◽  
Eukaryotic Cell ◽  
Cell Physiology ◽  
Tor Signaling ◽  
Developmental Networks ◽  
General Metabolism

Reactive oxygen species (ROS) regulate several aspects of cell physiology in filamentous fungi including the antioxidant response and development. However, little is known about the signaling pathways involved in these processes. Here, we report Aspergillus nidulans global phosphoproteome during mycelial growth and show that under these conditions, H2O2 induces major changes in protein phosphorylation. Among the 1964 phosphoproteins we identified, H2O2 induced the phosphorylation of 131 proteins at one or more sites as well as the dephosphorylation of a larger set of proteins. A detailed analysis of these phosphoproteins shows that H2O2 affected the phosphorylation of critical regulatory nodes of phosphoinositide, MAPK, and TOR signaling as well as the phosphorylation of multiple proteins involved in the regulation of gene expression, primary and secondary metabolism, and development. Our results provide a novel and extensive protein phosphorylation landscape in A. nidulans, indicating that H2O2 induces a shift in general metabolism from anabolic to catabolic, and the activation of multiple stress survival pathways. Our results expand the significance of H2O2 in eukaryotic cell signaling.

scholarly journals Canards in piecewise-linear systems: explosions and super-explosions

2013 ◽  
Vol 469 (2154) ◽  
pp. 20120603 ◽  
Author(s):  
Mathieu Desroches ◽  
Emilio Freire ◽  
S. John Hogan ◽  
Enrique Ponce ◽  
Phanikrishna Thota
Keyword(s):  
Phase Space ◽  
Linear Systems ◽  
Limit Cycles ◽  
Piecewise Linear ◽  
Single Parameter ◽  
Van Der Pol ◽  
Piecewise Linear Systems ◽  
Homoclinic Connections ◽  
Limiting Case

We show that a planar slow–fast piecewise-linear (PWL) system with three zones admits limit cycles that share a lot of similarity with van der Pol canards, in particular an explosive growth. Using phase-space compactification, we show that these quasi-canard cycles are strongly related to a bifurcation at infinity. Furthermore, we investigate a limiting case in which we show the existence of a continuum of canard homoclinic connections that coexist for a single-parameter value and with amplitude ranging from an order of ε to an order of 1, a phenomenon truly associated with the non-smooth character of this system and which we call super-explosion .

Epigenetic control of cellular senescence in disease: opportunities for therapeutic intervention

2007 ◽  
Vol 9 (7) ◽  
pp. 1-26 ◽  
Author(s):  
Stuart P. Atkinson ◽  
W. Nicol Keith
Keyword(s):  
Gene Expression ◽  
Cellular Senescence ◽  
Chromatin Remodelling ◽  
Telomere Maintenance ◽  
Cell Physiology ◽  
Gene Promoters ◽  
Epigenetic Mechanisms ◽  
Histone Proteins ◽  
Regulate Gene Expression ◽  
Regulate Gene

AbstractUnderstanding how senescence is established and maintained is an important area of study both for normal cell physiology and in tumourigenesis. Modifications to N-terminal tails of histone proteins, which can lead to chromatin remodelling, appear to be key to the regulation of the senescence phenotype. Epigenetic mechanisms such as modification of histone proteins have been shown to be sufficient to regulate gene expression levels and specific gene promoters can become epigenetically altered at senescence. This suggests that epigenetic mechanisms are important in senescence and further suggests epigenetic deregulation could play an important role in the bypass of senescence and the acquisition of a tumourigenic phenotype. Tumour suppressor proteins and cellular senescence are intimately linked and such proteins are now known to regulate gene expression through chromatin remodelling, again suggesting a link between chromatin modification and cellular senescence. Telomere dynamics and the expression of the telomerase genes are also both implicitly linked to senescence and tumourigenesis, and epigenetic deregulation of the telomerase gene promoters has been identified as a possible mechanism for the activation of telomere maintenance mechanisms in cancer. Recent studies have also suggested that epigenetic deregulation in stem cells could play an important role in carcinogenesis, and new models have been suggested for the attainment of tumourigenesis and bypass of senescence. Overall, proper regulation of the chromatin environment is suggested to have an important role in the senescence pathway, such that its deregulation could lead to tumourigenesis.

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