Network analysis of temporal effects of intermittent and sustained hypoxia on rat lungs

The molecular networks underlying the lung response to hypoxia are not fully understood. We employed systems biology approaches to study temporal effects of intermittent or sustained hypoxia on gene expression in rat lungs. We obtained gene expression profiles from rats exposed to intermittent or sustained hypoxia lasting 0–30 days and identified differentially expressed genes, their patterns, biological processes, and regulatory networks critical for lung response to intermittent or sustained hypoxia. We validated selected genes with quantitative real-time PCR. Intermittent and sustained hypoxia induced two distinct sets of genes in rat lungs that displayed different temporal expression patterns. Intermittent hypoxia induced genes mostly involved in ion transport and homeostasis, neurological processes, and steroid hormone receptor activity, while sustained hypoxia induced genes principally participating in immune responses. The intermittent hypoxia-activated network suggested a role for cross talk between estrogen receptor 1 (ESR1) and other key proteins in hypoxic responses. The sustained hypoxia-activated network was indicative of vascular remodeling and pulmonary hypertension. We confirmed the temporal expression changes of 12 genes (including the Esr1 gene and 4 ESR1 target genes) in intermittent hypoxia and 8 genes in sustained hypoxia with quantitative real-time PCR. Conclusions: intermittent and sustained hypoxia induced distinct gene expression patterns in rat lungs. The functional characteristics of genes activated by these two distinct perturbations suggest their roles in the downstream physiological effects of intermittent and sustained hypoxia. Our results demonstrate the discovery potential of applying systems biology approaches to the understanding of mechanisms underlying hypoxic lung response.

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Systems Approaches to Treatment Response to Imatinib in Severe Asthma: A Pilot Study

Journal of Personalized Medicine ◽

10.3390/jpm11040240 ◽

2021 ◽

Vol 11 (4) ◽

pp. 240

Author(s):

Seung Han Baek ◽

Dinah Foer ◽

Katherine N. Cahill ◽

Elliot Israel ◽

Enrico Maiorino ◽

...

Keyword(s):

Gene Expression ◽

Clinical Trial ◽

Systems Biology ◽

Pilot Study ◽

Severe Asthma ◽

Treated Patient ◽

Expression Patterns ◽

Airflow Limitation ◽

Response To Treatment ◽

Imatinib Treatment

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV1) in a clinical trial of patients with severe asthma. In a pilot study, we applied systems biology approaches to epithelium gene expression from these clinical trial patients treated with imatinib to better understand lung function response with imatinib treatment. Bronchial brushings from ten imatinib-treated patient samples and 14 placebo-treated patient samples were analyzed. We used personalized perturbation profiles (PEEPs) to characterize gene expression patterns at the individual patient level. We found that strong responders—patients with greater than 20% increase in FEV1—uniquely shared multiple downregulated mitochondrial-related pathways. In comparison, weak responders (5–10% FEV1 increase), and non-responders to imatinib shared none of these pathways. The use of PEEP highlights its potential for application as a systems biology tool to develop individual-level approaches to predicting disease phenotypes and response to treatment in populations needing innovative therapies. These results support a role for mitochondrial pathways in airflow limitation in severe asthma and as potential therapeutic targets in larger clinical trials.

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Cloning, Characterization, and Expression Features of Chicken CDS2 Splicing Variants

10.21203/rs.3.rs-80587/v1 ◽

2020 ◽

Author(s):

Yuanyuan Xu ◽

Shuping Zhang ◽

Yujun Guo ◽

Wen Chen ◽

Yanqun Huang

Keyword(s):

Adipose Tissue ◽

Real Time ◽

Real Time Pcr ◽

Expression Patterns ◽

Mrna Levels ◽

Exogenous Insulin ◽

Quantitative Real Time Pcr ◽

Temporal Expression ◽

Spatio Temporal ◽

The Brain

Abstract Background: The CDS gene encodes the CDP-diacylglycerol synthase enzyme that catalyzes the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid. At present, there are no reports of CDS2 in birds. Here, we identified chicken CDS2 transcripts by combining conventional RT- PCR amplification, 5' RACE (Fig. 1A), and 3' RACE, explored the spatio-temporal expression profiles of total CDS2 and the longest transcript variant CDS2-4, and investigated the effect of exogenous insulin on total the mRNA level of CDS2 by quantitative real-time PCR. Results: Four transcripts of chicken CDS2 (CDS2-1, -2, -3, and -4) were identified, which were alternatively spliced at the 3′-untranslated region (UTR). CDS2 was widely expressed in all tissues examined and the longest variant CDS2-4 was the major transcript. Both total CDS2 and CDS2-4 were prominently expressed in adipose tissue and the heart, and exhibited low expression in the liver and pectoralis of 49 day-old chickens. Quantitative real-time PCR revealed that total CDS2 and CDS2-4 had different spatio-temporal expression patterns in chicken. Total CDS2 exhibited a similar temporal expression tendency with a high level in the later period of incubation (embryonic day 19 [E19] or 1-day-old) in the brain, liver, and pectoralis. While CDS2-4 presented a distinct temporal expression pattern in these tissues, CDS2-4 levels peaked at 21 days in the brain and pectoralis, while liver CDS2-4 mRNA levels were highest at the early stage of hatching (E10). Total CDS2 (P < 0.001) and CDS2-4 (P = 0.0090) mRNA levels in the liver were differentially regulated throughout development of the chicken. Exogenous insulin significantly downregulated the level of total CDS2 at 240 min in the pectoralis of Silky chickens (P < 0.01). Total CDS2 levels in the liver of Silky chickens were higher than that of the broiler in the basal state and after insulin stimulation. Conclusion: Chicken CDS2 has multiple transcripts with variation at the 3′-UTR, which was prominently expressed in adipose tissue. Total CDS2 and CDS2-4 presented distinct spatio-temporal expression patterns, and they were differentially regulated with age in liver. Insulin could regulate chicken CDS2 levels in a breed- and tissue-specific manner.

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Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Viruses ◽

10.3390/v12040426 ◽

2020 ◽

Vol 12 (4) ◽

pp. 426 ◽

Cited By ~ 1

Author(s):

Liana V. Basova ◽

James P. Kesby ◽

Marcus Kaul ◽

Svetlana Semenova ◽

Maria Cecilia Garibaldi Marcondes

Keyword(s):

Gene Expression ◽

Systems Biology ◽

Gene Transcription ◽

Gene Networks ◽

Expression Profiles ◽

Expression Patterns ◽

Global Gene Expression ◽

Sirtuin 1 ◽

The Brain ◽

Hiv 1

Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome.

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Autoregulation Is Essential for Precise Temporal and Steady-State Regulation by the Bordetella BvgAS Phosphorelay

Journal of Bacteriology ◽

10.1128/jb.01684-06 ◽

2006 ◽

Vol 189 (5) ◽

pp. 1974-1982 ◽

Cited By ~ 26

Author(s):

Corinne L. Williams ◽

Peggy A. Cotter

Keyword(s):

Gene Expression ◽

Steady State ◽

Response Regulator ◽

Expression Patterns ◽

State Regulation ◽

Temporal Expression ◽

Multiple Gene ◽

Insight Into

ABSTRACT The Bordetella BvgAS virulence control system is prototypical of phosphorelays that use a polydomain sensor and a response regulator to control gene expression in response to environmental cues. BvgAS controls the expression of at least three distinct phenotypic phases (Bvg−, Bvgi, and Bvg+) by differentially regulating the expression of at least four classes of genes. Among the loci regulated by BvgAS is bvgAS itself. We investigated the role of autoregulation in the ability of BvgAS to control multiple gene expression patterns in a temporal and steady-state manner by constructing Bordetella bronchiseptica strains in which the bvgAS promoter was replaced with constitutively active promoters. Our results show that positive autoregulation of bvgAS transcription is required for the temporal expression of multiple phenotypic phases that occurs in response to a shift from Bvg−-phase conditions to Bvg+-phase conditions. Autoregulation was also shown to contribute to steady-state regulation; it influences the sensitivity of the system in response to subtle differences in signal intensity. In addition, considered in relation to BvgA and BvgS activities demonstrated in vitro, our results provide insight into how BvgA and BvgS function mechanistically.

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BEST: a web server for brain expression Spatio-temporal pattern analysis

BMC Bioinformatics ◽

10.1186/s12859-019-3222-6 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 2

Author(s):

Liyuan Guo ◽

Wei Lin ◽

Yidan Zhang ◽

Wenhan Li ◽

Jing Wang

Keyword(s):

Gene Expression ◽

Expression Pattern ◽

Temporal Pattern ◽

Pattern Analysis ◽

Expression Patterns ◽

Temporal Expression ◽

Expression Pattern Analysis ◽

Brain Expression ◽

Spatio Temporal ◽

Temporal Expression Pattern

Abstract Background Dysregulated gene expression patterns have been reported in several mental disorders. Limited by the difficulty of obtaining samples, psychiatric molecular mechanism research still relies heavily on clues from genetics studies. By using reference data from brain expression studies, multiple types of comprehensive gene expression pattern analysis have been performed on psychiatric genetic results. These systems-level spatial-temporal expression pattern analyses provided evidence on specific brain regions, developmental stages and molecular pathways that are possibly involved in psychiatric pathophysiology. At present, there is no online tool for such systematic analysis, which hinders the applications of analysis by non-informatics researchers such as experimental biologists and clinical molecular biologists. Results We developed the BEST web server to support Brain Expression Spatio-Temporal pattern analysis. There are three highlighted features of BEST: 1) visualization: it generates user-friendly visual results that are easy to interpret, including heatmaps, Venn diagrams, gene co-expression networks and cluster-based Manhattan gene plots; these results illustrate the complex spatio-temporal expression patterns, including expression quantification and correlation between genes; 2) integration: it provides comprehensive human brain spatio-temporal expression patterns by integrating data from currently available databases; 3) multi-dimensionality: it analyses input genes as both a whole set and several subsets (clusters) which are enriched according to co-expression patterns, and it also presents the correlation between genetic and expression data. Conclusions To the best of our knowledge, BEST is the first data tool to support comprehensive human brain spatial-temporal expression pattern analysis. It helps to bridge disease-related genetic studies and mechanism studies, provides clues for key gene and molecular system identification, and supports the analysis of disease sensitive brain region and age stages. BEST is freely available at http://best.psych.ac.cn.

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Patterns of Expression of a Lolitrem Biosynthetic Gene in the Epichloë festucae–Perennial Ryegrass Symbiosis

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-21-2-0188 ◽

2008 ◽

Vol 21 (2) ◽

pp. 188-197 ◽

Cited By ~ 14

Author(s):

Kimberley J. May ◽

Michelle K. Bryant ◽

Xiuwen Zhang ◽

Barbara Ambrose ◽

Barry Scott

Keyword(s):

Gene Expression ◽

Developmental Stages ◽

Expression Patterns ◽

In Planta ◽

Temporal Expression ◽

Epichloë Festucae ◽

Gusa Reporter Gene ◽

Reporter Gene Analysis ◽

High Level ◽

Germinating Seeds

Lolitrem B is synthesized by Epichloë festucae in associations with Pooid grasses. A complex cluster of at least 10 genes (ltm genes) is required for its synthesis. An early step in this pathway is catalyzed by ltmM, a symbiosis-expressed gene. PltmM-gusA reporter gene analysis was used to monitor ltmM gene expression patterns in planta. The minimum promoter length required for high-level gusA expression in infected seedlings is in the range of 480 to 782 bp. gusA was expressed by the endophyte in all infected vegetative plant tissues and in epiphyllous hyphae. Spikelets from reproductive tillers were analyzed at different developmental stages. During pre-anthesis, gusA expression was observed in all infected floral organs except the immature gynoecium. In post-anthesis florets, gene expression occurred almost exclusively in the gynoecium. Expression of gusA by the endophyte was observed in germinating seeds 24 h postimbibition and seedlings older than 6 days postimbibition in hyphae from the mesocotyl to the tip of the emerging first leaf. This work provides a detailed analysis of the spatial and temporal expression patterns of a symbiosis-expressed gene in planta.

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Identification and evaluation of reference genes for quantitative real-time PCR analysis in Polygonum cuspidatum based on transcriptome data

BMC Plant Biology ◽

10.1186/s12870-019-2108-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 3

Author(s):

Xiaowei Wang ◽

Zhijun Wu ◽

Wenqi Bao ◽

Hongyan Hu ◽

Mo Chen ◽

...

Keyword(s):

Gene Expression ◽

Real Time ◽

Stress Responses ◽

Real Time Pcr ◽

Abiotic Stresses ◽

Reference Genes ◽

Expression Patterns ◽

Polygonum Cuspidatum ◽

Quantitative Real Time Pcr ◽

Different Tissues

Abstract Background Polygonum cuspidatum of the Polygonaceae family is a traditional medicinal plant with many bioactive compounds that play important roles in human health and stress responses. Research has attempted to identify biosynthesis genes and metabolic pathways in this species, and quantitative real-time PCR (RT-qPCR) has commonly been used to detect gene expression because of its speed, sensitivity, and specificity. However, no P. cuspidatum reference genes have been identified, which hinders gene expression studies. Here, we aimed to identify suitable reference genes for accurate and reliable normalization of P. cuspidatum RT-qPCR data. Results Twelve candidate reference genes, including nine common (ACT, TUA, TUB, GAPDH, EF-1γ, UBQ, UBC, 60SrRNA, and eIF6A) and three novel (SKD1, YLS8, and NDUFA13), were analyzed in different tissues (root, stem, and leaf) without treatment and in leaves under abiotic stresses (salt, ultraviolet [UV], cold, heat, and drought) and hormone stimuli (abscisic acid [ABA], ethylene [ETH], gibberellin [GA3], methyl jasmonate [MeJA], and salicylic acid [SA]). Expression stability in 65 samples was calculated using the △CT method, geNorm, NormFinder, BestKeeper, and RefFinder. Two reference genes (NDUFA13 and EF-1γ) were sufficient to normalize gene expression across all sample sets. They were also the two most stable genes for abiotic stresses and different tissues, whereas NDUFA13 and SKD1 were the top two choices for hormone stimuli. Considering individual experimental sets, GAPDH was the top-ranked gene under ABA, ETH, and GA3 treatments, while 60SrRNA showed good stability under MeJA and cold treatments. ACT, UBC, and TUB were suitable genes for drought, UV, and ABA treatments, respectively. TUA was not suitable because of its considerable variation in expression under different conditions. The expression patterns of PcPAL, PcSTS, and PcMYB4 under UV and SA treatments and in different tissues normalized by stable and unstable reference genes demonstrated the suitability of the optimal reference genes. Conclusions We propose NDUFA13 and EF-1γ as reference genes to normalize P. cuspidatum expression data. To our knowledge, this is the first systematic study of reference genes in P. cuspidatum which could help advance molecular biology research in P. cuspidatum and allied species.

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Invited Review: Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms

Journal of Applied Physiology ◽

10.1152/jappl.2001.90.5.1986 ◽

2001 ◽

Vol 90 (5) ◽

pp. 1986-1994 ◽

Cited By ~ 154

Author(s):

Nanduri R. Prabhakar

Keyword(s):

Gene Expression ◽

Cell Cultures ◽

Carotid Body ◽

Intermittent Hypoxia ◽

Oxygen Sensing ◽

Regulation Of Gene Expression ◽

Chronic Intermittent Hypoxia ◽

Carotid Body Chemoreceptors ◽

Sustained Hypoxia

To the majority of the population, recurrent episodes of hypoxia are more likely encountered in life than sustained hypoxia. Until recently, much of the information on the long-term effects of intermittent hypoxia has come from studies on human subjects experiencing chronic recurrent apneas. Recent development of animal models of intermittent hypoxia and techniques for exposing cell cultures to alternating cycles of hypoxia have led to new information on the effects of episodic hypoxia on oxygen-sensing mechanisms in the carotid body chemoreceptors and regulation of gene expression. The purpose of this review is to highlight some recent studies on the effects of intermittent hypoxia on oxygen sensing at the carotid bodies and regulation of gene expression. In a rodent model, chronic intermittent hypoxia selectively enhances hypoxic sensitivity of the carotid body chemoreceptors. More interestingly, chronic intermittent hypoxia also induces a novel form of plasticity in the carotid body, leading to long-term facilitation in the sensory discharge. Studies on cell cultures reveal that intermittent hypoxia is more potent in activating activator protein-1 and hypoxia-inducible factor-1 transcription factors than sustained hypoxia. Moreover, some evidence suggests that intermittent hypoxia utilizes intracellular signaling pathways distinct from sustained hypoxia. Reactive oxygen species generated during the reoxygenation phase of intermittent hypoxia might play a key role in the effects of intermittent hypoxia on carotid body function and gene expression. Global gene profile analysis in cell cultures suggests that certain genes are selectively affected by intermittent hypoxia, some upregulated and some downregulated. It is suggested that, in intact animals, coordinated gene regulation of gene expression might be critical for eliciting phenotypic changes in the cardiorespiratory systems in response to intermittent hypoxia. It is hoped that future studies will unravel new mechanisms that are unique to intermittent hypoxia that may lead to a better understanding of the changes in the cardiorespiratory systems and new therapies for diseases associated with chronic recurrent episodes of hypoxia.

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Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms20020421 ◽

2019 ◽

Vol 20 (2) ◽

pp. 421 ◽

Cited By ~ 6

Author(s):

Chen Zhao ◽

Yu Zhang ◽

Aleksander Popel

Keyword(s):

Gene Expression ◽

Systems Biology ◽

Complex Disease ◽

Expression Patterns ◽

Regulation Of Gene Expression ◽

Phenotypic Expression ◽

Human Diseases ◽

Regulatory Function ◽

Regulatory Pathways ◽

Disease Pathways

MicroRNAs (miRs) are endogenous non-coding RNA molecules that play important roles in human health and disease by regulating gene expression and cellular processes. In recent years, with the increasing scientific knowledge and new discovery of miRs and their gene targets, as well as the plentiful experimental evidence that shows dysregulation of miRs in a wide variety of human diseases, the computational modeling approach has emerged as an effective tool to help researchers identify novel functional associations between differential miR expression and diseases, dissect the phenotypic expression patterns of miRs in gene regulatory networks, and elucidate the critical roles of miRs in the modulation of disease pathways from mechanistic and quantitative perspectives. Here we will review the recent systems biology studies that employed different kinetic modeling techniques to provide mechanistic insights relating to the regulatory function and therapeutic potential of miRs in human diseases. Some of the key computational aspects to be discussed in detail in this review include (i) models of miR-mediated network motifs in the regulation of gene expression, (ii) models of miR biogenesis and miR–target interactions, and (iii) the incorporation of such models into complex disease pathways in order to generate mechanistic, molecular- and systems-level understanding of pathophysiology. Other related bioinformatics tools such as computational platforms that predict miR-disease associations will also be discussed, and we will provide perspectives on the challenges and opportunities in the future development and translational application of data-driven systems biology models that involve miRs and their regulatory pathways in human diseases.

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A nátrium-glutamát génexpresszióra gyakorolt hatásainak vizsgálata

Orvosi Hetilap ◽

10.1556/650.2017.30678 ◽

2017 ◽

Vol 158 (10) ◽

pp. 380-385 ◽

Cited By ~ 2

Author(s):

Júlia Vanda Jurasek ◽

László Bence Raposa ◽

Andrea Gubicskóné Kisbenedek ◽

Veronika Varga ◽

Zoltán Szabó ◽

...

Keyword(s):

Gene Expression ◽

Food Production ◽

Food Industry ◽

Expression Patterns ◽

Monosodium Glutamate ◽

Dna Methyltransferases ◽

Mrna Levels ◽

Quantitative Real Time Pcr ◽

Liver And Kidney ◽

Chemopreventive Effect

Abstract: Introduction: Nowadays, the food industry more often uses different type of additives during the food production. Aim: Our aim was to examine the monosodium-glutamate’s effect (in animal experiment) on DNA-methyltransferases in gene expression patterns of mRNA levels. Materials and method: In the investigation we used 24 (n=24) CD1 type female mice. The animals were fed with different equivalent human doses of the tested substance. After autopsy, mRNA was isolated from different tissues (lung, liver, kidney, spleen). DNMT1, DNMT3A and DNMT3B levels were determined by Quantitative Real-Time PCR. Results: DNMT1 significantly suppressed the gene expression in all the three treated groups (p<0.05). The DNMT3A expression patterns showed significant decreasing tendency in the 1. and 2. treated groups of the lung tissue (p<0,05) and 1, 2, 3. groups of liver and kidney tissues (p<0,05). Conclusions: Our results shows that the monosodium glutamate, suppressed the DNMT1 and DNMT3A gene expression – on mRNA levels of several organs – in mice. It can be a similar chemopreventive effect to epigallo-catechin-gallate’s, curcumin’s, genistein’s, likopine’s and rezveratrol’s effects. In this case it can be possible that the MSG has anticarcinogenic effects. Orv. Hetil., 2017, 158(10), 380–385.

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