scholarly journals A predictive model of gene expression reveals the role of network motifs in the mating response of yeast

2021 ◽  
Vol 14 (670) ◽  
pp. eabb5235 ◽  
Author(s):  
Amy E. Pomeroy ◽  
Matthew I. Peña ◽  
John R. Houser ◽  
Gauri Dixit ◽  
Henrik G. Dohlman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Network Motifs ◽  
Mating Response ◽  
Architectural Elements ◽  
Genetic Perturbations ◽  
Transcriptional Changes ◽  
Parameterized Model

Cells use signaling pathways to receive and process information about their environment. These nonlinear systems rely on feedback and feedforward regulation to respond appropriately to changing environmental conditions. Mathematical models describing signaling pathways often lack predictive power because they are not trained on data that encompass the diverse time scales on which these regulatory mechanisms operate. We addressed this limitation by measuring transcriptional changes induced by the mating response in Saccharomyces cerevisiae exposed to different dynamic patterns of pheromone. We found that pheromone-induced transcription persisted after pheromone removal and showed long-term adaptation upon sustained pheromone exposure. We developed a model of the regulatory network that captured both characteristics of the mating response. We fit this model to experimental data with an evolutionary algorithm and used the parameterized model to predict scenarios for which it was not trained, including different temporal stimulus profiles and genetic perturbations to pathway components. Our model allowed us to establish the role of four architectural elements of the network in regulating gene expression. These network motifs are incoherent feedforward, positive feedback, negative feedback, and repressor binding. Experimental and computational perturbations to these network motifs established a specific role for each in coordinating the mating response to persistent and dynamic stimulation.

scholarly journals A predictive model of gene expression reveals the role of regulatory motifs in the mating response of yeast

2020 ◽  
Author(s):  
Amy E. Pomeroy ◽  
Matthew I. Pena ◽  
John R. Houser ◽  
Gauri Dixit ◽  
Henrik G. Dohlman ◽  
...  
Keyword(s):  
Experimental Data ◽  
Signaling Pathways ◽  
Environmental Conditions ◽  
Transcriptional Response ◽  
Feedback Regulation ◽  
Regulatory Motifs ◽  
Mating Response ◽  
Parameterized Model

ABSTRACTCells use signaling pathways to receive and process information about their environment. These systems are nonlinear, relying on feedback and feedforward regulation to respond appropriately to changing environmental conditions. Mathematical models developed to describe signaling pathways often fail to show predictive power, because the models are not trained on data that probe the diverse time scales on which feedforward and feedback regulation operate. We addressed this limitation using microfluidics to expose cells to a broad range of dynamic environmental conditions. In particular, we focus on the well-characterized mating response pathway of S. cerevisiae (yeast). This pathway is activated by mating pheromone and initiates the transcriptional changes required for mating. Although much is known about the molecular components of the mating response pathway, less is known about how these components function as a dynamical system. Our experimental data revealed that pheromone-induced transcription persists following removal of pheromone and that long-term adaptation of the transcriptional response occurs when pheromone exposure is sustained. We developed a model of the regulatory network that captured both persistence and long-term adaptation of the mating response. We fit this model to experimental data using an evolutionary algorithm and used the parameterized model to predict scenarios for which it was not trained, including different temporal stimulus profiles and genetic perturbations to pathway components. Our model allowed us to establish the role of four regulatory motifs in coordinating pathway response to persistent and dynamic stimulation.

scholarly journals Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice

2006 ◽  
Vol 27 (3) ◽  
pp. 187-200 ◽  
Author(s):  
Colin Selman ◽  
Nicola D. Kerrison ◽  
Anisha Cooray ◽  
Matthew D. W. Piper ◽  
Steven J. Lingard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Caloric Restriction ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Proton Nuclear Magnetic Resonance ◽  
Cellular Transport ◽  
Expression Of Genes ◽  
Transcriptional Changes

Caloric restriction (CR) increases healthy life span in a range of organisms. The underlying mechanisms are not understood but appear to include changes in gene expression, protein function, and metabolism. Recent studies demonstrate that acute CR alters mortality rates within days in flies. Multitissue transcriptional changes and concomitant metabolic responses to acute CR have not been described. We generated whole genome RNA transcript profiles in liver, skeletal muscle, colon, and hypothalamus and simultaneously measured plasma metabolites using proton nuclear magnetic resonance in mice subjected to acute CR. Liver and muscle showed increased gene expressions associated with fatty acid metabolism and a reduction in those involved in hepatic lipid biosynthesis. Glucogenic amino acids increased in plasma, and gene expression for hepatic gluconeogenesis was enhanced. Increased expression of genes for hormone-mediated signaling and decreased expression of genes involved in protein binding and development occurred in hypothalamus. Cell proliferation genes were decreased and cellular transport genes increased in colon. Acute CR captured many, but not all, hepatic transcriptional changes of long-term CR. Our findings demonstrate a clear transcriptional response across multiple tissues during acute CR, with congruent plasma metabolite changes. Liver and muscle switched gene expression away from energetically expensive biosynthetic processes toward energy conservation and utilization processes, including fatty acid metabolism and gluconeogenesis. Both muscle and colon switched gene expression away from cellular proliferation. Mice undergoing acute CR rapidly adopt many transcriptional and metabolic changes of long-term CR, suggesting that the beneficial effects of CR may require only a short-term reduction in caloric intake.

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

2004 ◽  
Vol 287 (5) ◽  
pp. H1957-H1966 ◽  
Author(s):  
Faina Schwartz ◽  
Arvi Duka ◽  
Irena Duka ◽  
Jing Cui ◽  
Haralambos Gavras
Keyword(s):  
Gene Expression ◽  
Cardiac Remodeling ◽  
Unknown Function ◽  
Mouse Heart ◽  
Ang Ii ◽  
Coordinate Regulation ◽  
Transcriptional Changes ◽  
Novel Targets ◽  
Molecular Circuitry

Although the central role of ANG II in cardiovascular homeostasis is well appreciated, the molecular circuitry of its many actions is not completely understood. With the use of serial analysis of gene expression to assess global transcriptional changes in the heart of mice after continuous 7-day ANG II administration, we identified patterns of gene expression indicative of cardiac remodeling, including coordinate regulation of genes previously described in a context of processes associated with hypertrophy and fibrosis. In addition, we discovered several novel ANG II targets, including characterized genes of known function, recently annotated genes of unknown function, and the putative genes not yet present in current databases. The serial analysis of gene expression approach to assess the role of ANG II presented in this report provides new venues for inquiries into ANG II-mediated cardiac function.

scholarly journals Long Term Effects of Neonatal Hypoglycemia on Muscarinic Receptor Function in the Cerebellum

2017 ◽  
Vol 2 (1) ◽  
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Muscarinic Receptor ◽  
Receptor Subtype ◽  
Receptor Function ◽  
Long Term Effects ◽  
Neonatal Hypoglycemia ◽  
Neonatal Stress ◽  
Old Rats

Neonatal stress conditions like hypoglycemia cause brain damage by affecting various signaling pathways thereby causing long term effects on brain functions. A proper understanding of the signaling pathways affected by this stress will help to devise better neonatal care. The focus of the current study was to evaluate the effect of neonatal hypoglycemic insult on cerebellar metabotropic cholinergic receptor function in one month old rats. The receptor analysis of cholinergic muscarinic receptors were done by radioreceptor assays and gene expression was analysed using Real Time PCR. Neonatal hypoglycemia significantly reduced (p<0.001) the cerebellar muscarinic receptor density with a down regulation (p<0.001) of muscarinic M3 receptor subtype gene expression in one month old rats. Both muscarinic M1 and M2 receptor subtype expression were not significantly altered. The catabolic enzyme in acetyl choline metabolism- acetylcholine esterase – showed a significant (p<0.001) up regulation with no siginificant change in the anabolic enzyme – choline acetyl transferase, signifying a change in the turnover ratio. Targeting these pathways at different levels can be exploited to devise better treatment for neonatal stress management and also for diseases with impaired insulin secretion such as diabetes.

Role of macronutrient intake in the epigenetics of obesity

2022 ◽  
Author(s):  
Priyadarshni Patel ◽  
Jeganathan Ramesh Babu ◽  
Xu Wang ◽  
Thangiah Geetha
Keyword(s):  
Gene Expression ◽  
Animal Studies ◽  
Extensive Study ◽  
Epigenetic Alterations ◽  
Lifestyle Choices ◽  
Obesity Genes ◽  
The Relationship ◽  
Diet And Lifestyle

Obesity is caused by a combination of hereditary and environmental factors. Despite extensive study, contemporary through diet, exercise, education, surgery, and pharmacological treatments, no effective long-term solution has been found to this epidemic. Over the last decade, there has been a tremendous advancement in understanding the science of epigenetics, as well as a rise in public interest in learning more about the influence of diet and lifestyle choices on the health of an individual. Without affecting the underlying DNA sequence, epigenetic alterations impact gene expression. Previous animal studies have shown a link between the type of diet and expression or suppression of obesity genes, but there are very few human studies that demonstrate the relationship between dietary intake and obesity gene expression. This review highlights the effects of carbohydrates, lipids, and protein intake from the diet on obesity-related genes.

Construction and optimization of herpes simplex virus vectors for central nervous system gene delivery based on CRISPR/Cas9-mediated genome editing

2021 ◽  
Vol 21 ◽  
Author(s):  
Xinwei Huang ◽  
Xiuqing Li ◽  
Lijuan Yang ◽  
Pengfei Wang ◽  
Jingyuan Yan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Transgene Expression ◽  
Mouse Hippocampus ◽  
Simplex Virus ◽  
Hsv 1

Aims: We aim to define parameters affecting the safety and long-term transgene expression of attenuated HSV-1 vectors and optimize the expression cassettes to achieve robust and sustained expression in CNS. Background: Engineered, attenuated Herpes simplex virus (HSV) vectors are promising vehicles for gene delivery to the peripheral and central nervous systems. The virus latent promoter (LAP) is commonly used to drive exogenous gene expression; however, parameters affecting the safety and long-term transgene expression of attenuated HSV-1 vectors have not been fully understood. Objective: This study aimed to construct attenuated HSV-1 vectors using the CRISPR-Cas9 system and examine the influence of transgene cassette construction and insertion site on transgene expression and vector safety. Method: In this study, we used a CRISPR-Cas9 system to accurately and efficiently edit attenuated HSV-1 strain 1716, and constructed two series of recombinant virus LMR and LMRx with different sets of gene cassettes insertion in Exon1(LAP2) and 2.0 kb intron downstream of LAP, respectively. The transgene expression and viral gene transcriptional kinetics were compared in in-vitro cell lines. The reporter gene expression and safety profiles of each vector were further evaluated in the mouse hippocampus gene transduction model. Result: The in-vitro cell line analysis indicated that the insertion of a gene expression cassette would disrupt virus gene transcription. Mouse hippocampus transducing analysis suggested that complete expression cassette insertion at 2.0 kb intron could achieve robust and longtime gene expression than the other constructs. Recombinants with gene expression cassettes lacked Poly (A), which induced significant neuronal inflammation due to persistent viral antigen expression and microglia activation. Conclusion: Our results indicated that the integrity of LAT transcripts was not necessary for the establishment of long-term latent expression. Exogenous strong promoters (like cBh promoter) could remain active during latency when placed in Exon1 or 2.0 Kb Intron of LAT locus, although their transcriptional activity declined with time. Consistent with previous research, the foreign gene expression would last much longer when the gene cassette was located downstream of Exon1, which suggested a role of LAP2 in maintaining promoter activity during latency. Besides, over-transcription of the downstream part of LAT may induce continuous activation of the attenuated vectors, suggesting an important role of LAT in maintaining viral reactivation potential.

scholarly journals Nickel-induced transcriptional changes persist  post exposure through epigenetic reprogramming

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Cynthia C. Jose ◽  
Zhenjia Wang ◽  
Vinay Singh Tanwar ◽  
Xiaoru Zhang ◽  
Chongzhi Zang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Modification ◽  
Lung Epithelial Cells ◽  
Differentially Expressed ◽  
Nickel Ions ◽  
Post Exposure ◽  
Genome Wide ◽  
Transcriptional Changes ◽  
Nickel Exposure

Abstract Background Nickel is an occupational and environmental toxicant associated with a number of diseases in humans including pulmonary fibrosis, bronchitis and lung and nasal cancers. Our earlier studies showed that the nickel-exposure-induced genome-wide transcriptional changes, which persist even after the termination of exposure may underlie nickel pathogenesis. However, the mechanisms that drive nickel-induced persistent changes to the transcriptome remain elusive. Results To elucidate the mechanisms that underlie nickel-induced long-term transcriptional changes, in this study, we examined the transcriptome and the epigenome of human lung epithelial cells during nickel exposure and after the termination of exposure. We identified two categories of persistently differentially expressed genes: (i) the genes that were differentially expressed during nickel exposure; and (ii) the genes that were differentially expressed only after the termination of exposure. Interestingly, > 85% of the nickel-induced gene expression changes occurred only after the termination of exposure. We also found extensive genome-wide alterations to the activating histone modification, H3K4me3, after the termination of nickel exposure, which coincided with the post-exposure gene expression changes. In addition, we found significant post-exposure alterations to the repressive histone modification, H3K27me3. Conclusion Our results suggest that while modest first wave of transcriptional changes occurred during nickel exposure, extensive transcriptional changes occurred during a second wave of transcription for which removal of nickel ions was essential. By uncovering a new category of transcriptional and epigenetic changes, which occur only after the termination of exposure, this study provides a novel understanding of the long-term deleterious consequences of nickel exposure on human health.

scholarly journals Extracellular Matrix Protects Pancreatic  -Cells Against Apoptosis: Role of Short- and Long-Term Signaling Pathways

Diabetes ◽  
2004 ◽  
Vol 53 (8) ◽  
pp. 2034-2041 ◽  
Author(s):  
E. Hammar ◽  
G. Parnaud ◽  
D. Bosco ◽  
N. Perriraz ◽  
K. Maedler ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Signaling Pathways ◽  
Pancreatic Cells ◽  
Short And Long Term

Gene expression profiles predict the possible regulatory role of OPN-mediated signaling pathways in rat liver regeneration

Gene ◽  
2016 ◽  
Vol 576 (2) ◽  
pp. 782-790 ◽  
Author(s):  
Gaiping Wang ◽  
Shasha Chen ◽  
Congcong Zhao ◽  
Xiaofang Li ◽  
Ling Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Regeneration ◽  
Signaling Pathways ◽  
Rat Liver ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Regulatory Role ◽  
Rat Liver Regeneration

The role of vanin-1 and oxidative stress–related pathways in distinguishing acute and chronic pediatric ITP

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4569-4579 ◽  
Author(s):  
Bing Zhang ◽  
Clara Lo ◽  
Lei Shen ◽  
Ruchira Sood ◽  
Carol Jones ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Gene Expression Analysis ◽  
Mononuclear Cells ◽  
Stress Sensor ◽  
Chronic Itp ◽  
Acute Itp ◽  
And Oxidative Stress

Abstract Pediatric immune thrombocytopenia (ITP) is usually self-limited. However, approximately 20% of children develop chronic ITP, which can be associated with significant morbidity because of long-term immunosuppression and splenectomy in refractory cases. To explore the molecular mechanism of chronic ITP compared with acute ITP, we studied 63 pediatric patients with ITP. Gene expression analysis of whole blood revealed distinct signatures for acute and chronic ITP. Oxidative stress–related pathways were among the most significant chronic ITP-associated pathways. Overexpression of VNN1, an oxidative stress sensor in epithelial cells, was most strongly associated with progression to chronic ITP. Studies of normal persons demonstrated VNN1 expression in a variety of blood cells. Exposure of blood mononuclear cells to oxidative stress inducers elicited dramatic up-regulation of VNN1 and down-regulation of PPARγ, indicating a role for VNN1 as a peripheral blood oxidative stress sensor. Assessment of redox state by tandem mass spectrometry demonstrated statistically significant lower glutathione ratios in patients with ITP versus healthy controls; lower glutathione ratios were also seen in untreated patients with ITP compared with recently treated patients. Our work demonstrates distinct patterns of gene expression in acute and chronic ITP and implicates oxidative stress pathways in the pathogenesis of chronic pediatric ITP.

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