Gene regulation and systems biology最新文献_第2页

A Transcriptional Regulatory Role for the Membrane Type-1 Matrix Metalloproteinase in Carcinogen-Induced Inflammasome Gene Expression. 膜1型基质金属蛋白酶在致癌炎性小体基因表达中的转录调控作用。

Gene regulation and systems biology Pub Date : 2017-06-08 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017713996

Samuel Sheehy, Borhane Annabi

{"title":"A Transcriptional Regulatory Role for the Membrane Type-1 Matrix Metalloproteinase in Carcinogen-Induced Inflammasome Gene Expression.","authors":"Samuel Sheehy, Borhane Annabi","doi":"10.1177/1177625017713996","DOIUrl":"https://doi.org/10.1177/1177625017713996","url":null,"abstract":"Signal-transducing functions driven by the cytoplasmic domain of membrane type-1 matrix metalloproteinase (MT1-MMP) are believed to regulate many inflammation-associated cancer cell functions including migration, proliferation, and survival. Aside from upregulation of the inflammation biomarker cyclooxygenase-2 (COX-2) expression, MT1-MMP's role in relaying intracellular signals triggered by extracellular pro-inflammatory cues remains poorly understood. Here, we triggered inflammation in HT1080 fibrosarcoma cells with phorbol-12-myristate-13-acetate (PMA), an inducer of COX-2 and of MT1-MMP. To assess the global transcriptional regulatory role that MT1-MMP may exert on inflammation biomarkers, we combined gene array screens with a transient MT1-MMP gene silencing strategy. Expression of MT1-MMP was found to exert both stimulatory and repressive transcriptional control of several inflammasome-related biomarkers such as interleukin (IL)-1B, IL-6, IL-12A, and IL-33, as well as of transcription factors such as EGR1, ELK1, and ETS1/2 in PMA-treated cells. Among the signal-transducing pathways explored, the silencing of MT1-MMP prevented PMA from phosphorylating extracellular signal-regulated kinase, inhibitor of κB, and p105 nuclear factor κB (NF-κB) intermediates. We also found a signaling axis linking MT1-MMP to MMP-9 transcriptional regulation. Altogether, our data indicate a significant involvement of MT1-MMP in the transcriptional regulation of inflammatory biomarkers consolidating its contribution to signal transduction functions in addition to its classical hydrolytic activity.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017713996","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35106830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Overexpression and Knockdown of Hypoxia-Inducible Factor 1 Disrupt the Expression of Steroidogenic Enzyme Genes and Early Embryonic Development in Zebrafish. 低氧诱导因子1的过表达和敲低干扰斑马鱼体内类固醇生成酶基因的表达和早期胚胎发育。

Gene regulation and systems biology Pub Date : 2017-06-08 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017713193

Tianfeng Tan, Richard Man Kit Yu, Rudolf Shiu Sun Wu, Richard Yuen Chong Kong

{"title":"Overexpression and Knockdown of Hypoxia-Inducible Factor 1 Disrupt the Expression of Steroidogenic Enzyme Genes and Early Embryonic Development in Zebrafish.","authors":"Tianfeng Tan, Richard Man Kit Yu, Rudolf Shiu Sun Wu, Richard Yuen Chong Kong","doi":"10.1177/1177625017713193","DOIUrl":"https://doi.org/10.1177/1177625017713193","url":null,"abstract":"Hypoxia is an important environmental stressor leading to endocrine disruption and reproductive impairment in fish. Although the hypoxia-inducible factor 1 (HIF-1) is known to regulate the transcription of various genes mediating oxygen homeostasis, its role in modulating steroidogenesis-related gene expression remains poorly understood. In this study, the regulatory effect of HIF-1 on the expression of 9 steroidogenic enzyme genes was investigated in zebrafish embryos using a \"gain-of-function and loss-of-function\" approach. Eight of the genes, CYP11a, CYP11b2, 3β-HSD, HMGCR, CYP17a1, 17β-HSD2, CYP19a, and CYP19b, were found to be differentially upregulated at 24 and 48 hpf following zHIF-1α-ΔODD overexpression (a mutant zebrafish HIF-1α protein with proline-414 and proline-557 deleted). Knockdown of zHIF-1α also affected the expression pattern of the steroidogenic enzyme genes. Overexpression of zHIF-1α and hypoxia exposure resulted in downregulated StAR expression but upregulated CYP11a and 3β-HSD expression in zebrafish embryos. Conversely, the expression patterns of these 3 genes were reversed in embryos in which zHIF-1α was knocked down under normoxia, suggesting that these 3 genes are regulated by HIF-1. Overall, the findings from this study indicate that HIF-1-mediated mechanisms are likely involved in the regulation of specific steroidogenic genes.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017713193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35106828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 25

Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses. 药物性肝损伤的机制建模:研究先天免疫反应的作用。

Gene regulation and systems biology Pub Date : 2017-05-30 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017696074

Lisl Km Shoda, Christina Battista, Scott Q Siler, David S Pisetsky, Paul B Watkins, Brett A Howell

{"title":"Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses.","authors":"Lisl Km Shoda, Christina Battista, Scott Q Siler, David S Pisetsky, Paul B Watkins, Brett A Howell","doi":"10.1177/1177625017696074","DOIUrl":"https://doi.org/10.1177/1177625017696074","url":null,"abstract":"Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration. The representation of innate immune responses, detailed here, consolidates much of the available data on the innate immune response in DILI within a single framework and affords the opportunity to systematically investigate the contribution of the innate response to DILI.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017696074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35091098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22

Effects of High-Fat Feeding on Skeletal Muscle Gene Expression in Diabetic Goto-Kakizaki Rats. 高脂肪喂养对糖尿病后藤- kakizaki大鼠骨骼肌基因表达的影响

Gene regulation and systems biology Pub Date : 2017-05-29 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017710009

Jing Nie, Debra C DuBois, Bai Xue, William J Jusko, Richard R Almon

引用次数: 6

The Synergistic Role of Light-Feeding Phase Relations on Entraining Robust Circadian Rhythms in the Periphery. 取光期关系对外周强生理节律的协同作用。

Gene regulation and systems biology Pub Date : 2017-04-20 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017702393

Seul-A Bae, Ioannis P Androulakis

{"title":"The Synergistic Role of Light-Feeding Phase Relations on Entraining Robust Circadian Rhythms in the Periphery.","authors":"Seul-A Bae, Ioannis P Androulakis","doi":"10.1177/1177625017702393","DOIUrl":"https://doi.org/10.1177/1177625017702393","url":null,"abstract":"The feeding and fasting cycles are strong behavioral signals that entrain biological rhythms of the periphery. The feeding rhythms synchronize the activities of the metabolic organs, such as liver, synergistically with the light/dark cycle primarily entraining the suprachiasmatic nucleus. The likely phase misalignment between the feeding rhythms and the light/dark cycles appears to induce circadian disruptions leading to multiple physiological abnormalities motivating the need to investigate the mechanisms behind joint light-feeding circadian entrainment of peripheral tissues. To address this question, we propose a semimechanistic mathematical model describing the circadian dynamics of peripheral clock genes in human hepatocyte under the control of metabolic and light rhythmic signals. The model takes the synergistically acting light/dark cycles and feeding rhythms as inputs and incorporates the activity of sirtuin 1, a cellular energy sensor and a metabolic enzyme activated by nicotinamide adenine dinucleotide. The clock gene dynamics was simulated under various light-feeding phase relations and intensities, to explore the feeding entrainment mechanism as well as the convolution of light and feeding signals in the periphery. Our model predicts that the peripheral clock genes in hepatocyte can be completely entrained to the feeding rhythms, independent of the light/dark cycle. Furthermore, it predicts that light-feeding phase relationship is a critical factor in robust circadian oscillations.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017702393","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34964661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 29

Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification. 通过模型简化模拟果糖负荷诱导的肝脏去新生脂肪生成。

Gene regulation and systems biology Pub Date : 2017-04-12 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017690133

Richard J Allen, Cynthia J Musante

{"title":"Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification.","authors":"Richard J Allen, Cynthia J Musante","doi":"10.1177/1177625017690133","DOIUrl":"https://doi.org/10.1177/1177625017690133","url":null,"abstract":"Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes. To accomplish this we developed a novel simplification technique which uses the available information about the properties of the individual enzymes to bound the parameters of a single governing 'transfer function'. This method should be applicable to any model with linear chains of enzymes that are well stimulated. We validated this approach with computational simulations and analytical justification in a limiting case. Using this technique we generated a simple model of hepatic de-novo lipogenesis in these experimental conditions that matched prior data. This model can be used to assess pharmacological intervention at specific points on this pathway. We have demonstrated this with prospective simulation of acetyl-CoA carboxylase inhibition. This simplification technique suggests how the constituent properties of an enzymatic chain of reactions gives rise to the sensitivity (to substrate) of the pathway as a whole.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017690133","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34964655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Time Course Expression Analysis of 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole Induction of Cytoprotection in Human Endothelial Cells. 1[2-氰-3,12-二氧齐烷-1,9(11)-二烯-28-油基]咪唑诱导人内皮细胞保护的时间过程表达分析。

Gene regulation and systems biology Pub Date : 2017-04-07 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017701106

James A Bynum, Xinyu Wang, Salomon A Stavchansky, Phillip D Bowman

{"title":"Time Course Expression Analysis of 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole Induction of Cytoprotection in Human Endothelial Cells.","authors":"James A Bynum, Xinyu Wang, Salomon A Stavchansky, Phillip D Bowman","doi":"10.1177/1177625017701106","DOIUrl":"https://doi.org/10.1177/1177625017701106","url":null,"abstract":"1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a synthetic derivative of oleanolic acid that exhibits antioxidant and anti-inflammatory activity in several animal and in vitro models, has been shown to be beneficial if given after injury. Although induction of heme oxygenase 1 appears to be a major effector of cytoprotection, the mechanism by which the overall effect is mediated is largely unknown. This study evaluated temporal gene expression profiles to better characterize the early transcriptional events and their relationship to the dynamics of the cytoprotective response in human umbilical vein endothelial cells (HUVEC) to CDDO-Im. Time-course gene expression profiling was performed on HUVEC treated with CDDO-Im for 0.5, 1, 3, 6, and 24 hours. More than 10 000 genes were statistically altered in their expression in at least 1 time point across the time course. Large alterations in immediate-early gene expression were readily detectable within 0.5 hour after administration of CDDO-Im.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017701106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34964659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Use of Biomedical Ontologies for Integration of Biological Knowledge for Learning and Prediction of Adverse Drug Reactions. 利用生物医学本体整合生物知识，以学习和预测药物不良反应。

Gene regulation and systems biology Pub Date : 2017-03-15 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017696075

Shadia Zaman, Sirarat Sarntivijai, Darrell R Abernethy

{"title":"Use of Biomedical Ontologies for Integration of Biological Knowledge for Learning and Prediction of Adverse Drug Reactions.","authors":"Shadia Zaman, Sirarat Sarntivijai, Darrell R Abernethy","doi":"10.1177/1177625017696075","DOIUrl":"https://doi.org/10.1177/1177625017696075","url":null,"abstract":"Drug-induced toxicity is a major public health concern that leads to patient morbidity and mortality. To address this problem, the Food and Drug Administration is working on the PredicTox initiative, a pilot research program on tyrosine kinase inhibitors, to build mechanistic and predictive models for drug-induced toxicity. This program involves integrating data acquired during preclinical studies and clinical trials within pharmaceutical company development programs that they have agreed to put in the public domain and in publicly available biological, pharmacological, and chemical databases. The integration process is accommodated by biomedical ontologies, a set of standardized vocabularies that define terms and logical relationships between them in each vocabulary. We describe a few programs that have used ontologies to address biomedical questions. The PredicTox effort is leveraging the experience gathered from these early initiatives to develop an infrastructure that allows evaluation of the hypothesis that having a mechanistic understanding underlying adverse drug reactions will improve the capacity to understand drug-induced clinical adverse drug reactions.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017696075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34964658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

Graphical Modeling Meets Systems Pharmacology. 图形建模满足系统药理学。

Gene regulation and systems biology Pub Date : 2017-03-10 eCollection Date: 2017-01-01 DOI: 10.1177/1177625017691937

Rosario Lombardo, Corrado Priami

引用次数: 4

Identifying Cell Type-Specific Transcription Factors by Integrating ChIP-seq and eQTL Data–Application to Monocyte Gene Regulation 整合ChIP-seq和eQTL数据鉴定细胞类型特异性转录因子-在单核细胞基因调控中的应用

Gene regulation and systems biology Pub Date : 2016-12-13 DOI: 10.4137/GRSB.S40768

Mudra Choudhury, S. Ramsey

{"title":"Identifying Cell Type-Specific Transcription Factors by Integrating ChIP-seq and eQTL Data–Application to Monocyte Gene Regulation","authors":"Mudra Choudhury, S. Ramsey","doi":"10.4137/GRSB.S40768","DOIUrl":"https://doi.org/10.4137/GRSB.S40768","url":null,"abstract":"We describe a novel computational approach to identify transcription factors (TFs) that are candidate regulators in a human cell type of interest. Our approach involves integrating cell type-specific expression quantitative trait locus (eQTL) data and TF data from chromatin immunoprecipitation-to-tag-sequencing (ChIP-seq) experiments in cell lines. To test the method, we used eQTL data from human monocytes in order to screen for TFs. Using a list of known monocyte-regulating TFs, we tested the hypothesis that the binding sites of cell type-specific TF regulators would be concentrated in the vicinity of monocyte eQTLs. For each of 397 ChIP-seq data sets, we obtained an enrichment ratio for the number of ChIP-seq peaks that are located within monocyte eQTLs. We ranked ChIP-seq data sets according to their statistical significances for eQTL overlap, and from this ranking, we observed that monocyte-regulating TFs are more highly ranked than would be expected by chance. We identified 27 TFs that had significant monocyte enrichment scores and mapped them into a protein interaction network. Our analysis uncovered two novel candidate monocyte-regulating TFs, BCLAF1 and SIN3A. Our approach is an efficient method to identify candidate TFs that can be used for any cell/tissue type for which eQTL data are available.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4137/GRSB.S40768","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70703028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3