scholarly journals Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate target genes to improve treatment outcomes

2019 ◽  
Author(s):  
Saket Choudhary ◽  
Suzanne C. Burns ◽  
Hoda Mirsafian ◽  
Wenzheng Li ◽  
Dat T. Vo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Early Response ◽  
Radiation Sensitivity ◽  
Integrated Analysis ◽  
High Dose ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Improve Treatment ◽  
Main Component

AbstractBackgroundHigh-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response.MethodsWe conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation.ResultsChanges at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio-resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy.ConclusionsOur integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

scholarly journals Integrated analyses of early responses to radiation in glioblastoma identify new alterations in RNA processing and candidate targets to improve treatment outcomes

2020 ◽  
Author(s):  
Saket Choudhary ◽  
Suzanne Burns ◽  
Hoda Mirsafian ◽  
Whenzheng LI ◽  
Dat Vo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Early Response ◽  
Radiation Sensitivity ◽  
Integrated Analysis ◽  
High Dose ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Improve Treatment ◽  
Expression Of Genes ◽  
Main Component

Abstract BackgroundHigh-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response. Methods: We conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation. ResultsChanges at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio- resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy. ConclusionsOur integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

scholarly journals Genomic analyses of early responses to radiation in glioblastoma reveal new alterations at transcription, splicing, and translation levels

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Saket Choudhary ◽  
Suzanne C. Burns ◽  
Hoda Mirsafian ◽  
Wenzheng Li ◽  
Dat T. Vo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Early Response ◽  
Radiation Sensitivity ◽  
Integrated Analysis ◽  
High Dose ◽  
Transcriptional Level ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Post Radiation ◽  
Main Component

Abstract High-dose radiation is the main component of glioblastoma therapy. Unfortunately, radio-resistance is a common problem and a major contributor to tumor relapse. Understanding the molecular mechanisms driving response to radiation is critical for identifying regulatory routes that could be targeted to improve treatment response. We conducted an integrated analysis in the U251 and U343 glioblastoma cell lines to map early alterations in the expression of genes at three levels: transcription, splicing, and translation in response to ionizing radiation. Changes at the transcriptional level were the most prevalent response. Downregulated genes are strongly associated with cell cycle and DNA replication and linked to a coordinated module of expression. Alterations in this group are likely driven by decreased expression of the transcription factor FOXM1 and members of the E2F family. Genes involved in RNA regulatory mechanisms were affected at the mRNA, splicing, and translation levels, highlighting their importance in radiation-response. We identified a number of oncogenic factors, with an increased expression upon radiation exposure, including BCL6, RRM2B, IDO1, FTH1, APIP, and LRIG2 and lncRNAs NEAT1 and FTX. Several of these targets have been previously implicated in radio-resistance. Therefore, antagonizing their effects post-radiation could increase therapeutic efficacy. Our integrated analysis provides a comprehensive view of early response to radiation in glioblastoma. We identify new biological processes involved in altered expression of various oncogenic factors and suggest new target options to increase radiation sensitivity and prevent relapse.

scholarly journals Integrated Analysis of miRNA and mRNA Expression Profiles in Spleen of Specific Pathogen-Free Chicken Infected with Avian Reticuloendotheliosis Virus Strain SNV

2019 ◽  
Vol 20 (5) ◽  
pp. 1041 ◽  
Author(s):  
Shuo Gao ◽  
Hao Jiang ◽  
Jie Sun ◽  
Youxiang Diao ◽  
Yi Tang ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
High Dose ◽  
Specific Pathogen Free ◽  
Reticuloendotheliosis Virus ◽  
Specific Pathogen

The Reticuloendotheliosis virus (REV) primarily causes avian severe immunosuppression, in addition to other symptoms, which include avian dwarfing syndrome and chronic tumors in lymphoid and other tissue. To date, REV’s molecular mechanisms leading to immunosuppression have not been fully elucidated. In the current study, we aimed to elucidate the role of microRNAs (miRNA) in regulating gene expression during REV infections. Therefore, we used a high-dose spleen necrosis virus (SNV) model of REV to inoculate one-day-old specific pathogen-free (SPF) chickens, thereby inducing congenital infections. We analyzed miRNA and mRNA expression profiles using Next Generation Sequencing (NGS) in a total of 19 spleen samples that were collected at 7, 14, and 21 days post infection (dpi). The results showed that 63 differentially expressed miRNAs (DEmiRNAs) (30 known miRNAs and 33 novel miRNAs) and 482 differentially expressed target genes (DETGs) were identified. Integration analysis identified 886 known miRNA–mRNA and 580 novel miRNA–mRNA interaction pairs, which involved miRNAs that were inversely correlated with the above DETGs. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the DETGs were considerably enriched in the immune-relevant pathways category, such as immune system, cell growth and death, signaling molecules and interaction, signal transduction, etc. We further verified selected immune-relevant miRNA and their DETGs while using quantitative RT-PCR (qRT-PCR). Overall, our data revealed valuable immune-related miRNA–mRNA interaction information that occurred during REV infections, thereby broadening our understanding of the REV-induced immunosuppression.

Drugs used to treat bipolar disorder act via microRNAs to regulate expression of genes involved in neurite outgrowth

2020 ◽  
Vol 34 (3) ◽  
pp. 370-379 ◽  
Author(s):  
Srisaiyini Kidnapillai ◽  
Ben Wade ◽  
Chiara C Bortolasci ◽  
Bruna Panizzutti ◽  
Briana Spolding ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Neurite Outgrowth ◽  
Neural Plasticity ◽  
Drug Combination ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Drug Effects ◽  
Differentially Expressed ◽  
Transcriptional Level ◽  
Expression Of Genes

Background: The drugs commonly used to treat bipolar disorder have limited efficacy and drug discovery is hampered by the paucity of knowledge of the pathophysiology of this disease. This study aims to explore the role of microRNAs in bipolar disorder and understand the molecular mechanisms of action of commonly used bipolar disorder drugs. Methods: The transcriptional effects of bipolar disorder drug combination (lithium, valproate, lamotrigine and quetiapine) in cultured human neuronal cells were studied using next generation sequencing. Differential expression of genes ( n=20) and microRNAs ( n=6) was assessed and the differentially expressed microRNAs were confirmed with TaqMan MicroRNA Assays. The expression of the differentially expressed microRNAs were inhibited to determine bipolar disorder drug effects on their target genes ( n=8). Independent samples t-test was used for normally distributed data and Kruskal-Wallis/Mann-Whitney U test was used for data not distributed normally. Significance levels were set at p<0.05. Results: We found that bipolar disorder drugs tended to increase the expression of miR-128 and miR-378 ( p<0.05). Putative target genes of these microRNAs targeted pathways including those identified as “neuron projection development” and “axonogenesis”. Many of the target genes are inhibitors of neurite outgrowth and neurogenesis and were downregulated following bipolar disorder drug combination treatment (all p<0.05). The bipolar disorder drug combination tended to decrease the expression of the target genes ( NOVA1, GRIN3A, and VIM), however this effect could be reversed by the application of microRNA inhibitors. Conclusions: We conclude that at a transcriptional level, bipolar disorder drugs affect several genes in concert that would increase neurite outgrowth and neurogenesis and hence neural plasticity, and that this effect is mediated (at least in part) by modulation of the expression of these two key microRNAs.

scholarly journals 3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

2016 ◽  
Vol 56 (4) ◽  
pp. 311-323 ◽  
Author(s):  
Julika Lietzow ◽  
Janine Golchert ◽  
Georg Homuth ◽  
Uwe Völker ◽  
Wenke Jonas ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Phase Iii ◽  
Whole Body ◽  
High Dose ◽  
Thyroid Hormone Metabolism ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Novel Target

The endogenous thyroid hormone (TH) metabolite 3,5-diiodo-l-thyronine (3,5-T2) acts as a metabolically active substance affecting whole-body energy metabolism and hepatic lipid handling in a desirable manner. Considering possible adverse effects regarding thyromimetic action of 3,5-T2 treatment in rodents, the current literature remains largely controversial. To obtain further insights into molecular mechanisms and to identify novel target genes of 3,5-T2 in liver, we performed a microarray-based liver tissue transcriptome analysis of male lean and diet-induced obese euthyroid mice treated for 4 weeks with a dose of 2.5 µg/g bw 3,5-T2. Our results revealed that 3,5-T2 modulates the expression of genes encoding Phase I and Phase II enzymes as well as Phase III transporters, which play central roles in metabolism and detoxification of xenobiotics. Additionally, 3,5-T2 changes the expression of TH responsive genes, suggesting a thyromimetic action of 3,5-T2 in mouse liver. Interestingly, 3,5-T2 in obese but not in lean mice influences the expression of genes relevant for cholesterol and steroid biosynthesis, suggesting a novel role of 3,5-T2 in steroid metabolism of obese mice. We concluded that treatment with 3,5-T2 in lean and diet-induced obese male mice alters the expression of genes encoding hepatic xenobiotic-metabolizing enzymes that play a substantial role in catabolism and inactivation of xenobiotics and TH and are also involved in hepatic steroid and lipid metabolism. The administration of this high dose of 3,5-T2 might exert adverse hepatic effects. Accordingly, the conceivable use of 3,5-T2 as pharmacological hypolipidemic agent should be considered with caution.

scholarly journals Integrated analysis of sex-biased mRNA and miRNA expression profiles in the gonad of the discus fish (Symphysodon aequifasciatus)

2018 ◽  
Author(s):  
yuanshuai Fu ◽  
Zhe Xu ◽  
Zaizhong Chen ◽  
Bin Wen ◽  
Jianzhong Gao
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
High Efficiency ◽  
Expression Profiles ◽  
Gonad Development ◽  
Differentially Expressed ◽  
Cdna Libraries ◽  
Integrated Analysis ◽  
Illumina Hiseq ◽  
Differentially Expressed Mirnas

The discus fish (Symphysodon aequifasciatus) is an ornamental fish that is well-known around the world. Phenotype investigation indicated that there are no significant differences in appearance between males and females of the discus fish. To better understand the sexual development mechanisms and obtain a high efficiency sex identification method in the artificial reproduction process of the discus fish, we constructed six cDNA libraries from three adult testes and three adult ovaries, and perform RNA-sequencing for identifying sex-biased candidate genes, microRNA (miRNA), and metabolic pathway using the Illumina Hiseq 4000. A total of 50,082 non-redundant genes (unigenes) were identified, of which 18,570 unigenes were significantly overexpressed in testes, and 11,182 unigenes were significantly overexpressed in ovaries, and 8 differentially expressed unigenes were validated by quantitative Real-Time PCR (qPCR). A total of 551 miRNAs were identified, of which 47 miRNAs were differentially expressed between testes and ovaries, and 7 differentially expressed miRNAs and one non-differential miRNA were validated by qPCR. Twenty-four of these differentially expressed miRNAs and their 15 predicted target genes constituted 41 important miRNA-mRNA interaction pairs, which may be important candidates for sex-related miRNAs and sex-related genes in the discus fish. Some of vital sex-related metabolic pathways were also identified that may play key roles in regulating gonad development of the discus fish. These results can provide important insights to better understand molecular mechanisms for sexual dimorphism in gonads development.

scholarly journals Molecular Manipulation of the miR396 and miR399 Expression Modules Alters the Response of Arabidopsis thaliana to Phosphate Stress

Plants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 2570
Author(s):  
Joseph L. Pegler ◽  
Duc Quan Nguyen ◽  
Jackson M. J. Oultram ◽  
Christopher P. L. Grof ◽  
Andrew L. Eamens
Keyword(s):  
Arabidopsis Thaliana ◽  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Plant Cells ◽  
Acid Synthesis ◽  
Early Step ◽  
Molecular Alteration ◽  
Altered Expression ◽  
Molecular Manipulation

In plant cells, the molecular and metabolic processes of nucleic acid synthesis, phospholipid production, coenzyme activation and the generation of the vast amount of chemical energy required to drive these processes relies on an adequate supply of the essential macronutrient, phosphorous (P). The requirement of an appropriate level of P in plant cells is evidenced by the intricately linked molecular mechanisms of P sensing, signaling and transport. One such mechanism is the posttranscriptional regulation of the P response pathway by the highly conserved plant microRNA (miRNA), miR399. In addition to miR399, numerous other plant miRNAs are also required to respond to environmental stress, including miR396. Here, we exposed Arabidopsis thaliana (Arabidopsis) transformant lines which harbor molecular modifications to the miR396 and miR399 expression modules to phosphate (PO4) starvation. We show that molecular alteration of either miR396 or miR399 abundance afforded the Arabidopsis transformant lines different degrees of tolerance to PO4 starvation. Furthermore, RT-qPCR assessment of PO4-starved miR396 and miR399 transformants revealed that the tolerance displayed by these plant lines to this form of abiotic stress most likely stemmed from the altered expression of the target genes of these two miRNAs. Therefore, this study forms an early step towards the future development of molecularly modified plant lines which possess a degree of tolerance to growth in a PO4 deficient environment.

Novel nuclear target for thrombin: activation of the Elk1 transcription factor leads to chemokine gene expression

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3696-3706 ◽  
Author(s):  
Qi-Jing Li ◽  
Sucheta Vaingankar ◽  
Frances M. Sladek ◽  
Manuela Martins-Green
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Gene Activation ◽  
Tumor Development ◽  
Growth Factor Receptor ◽  
Early Response ◽  
Transcriptional Level ◽  
Binding Domains ◽  
Thrombin Activation

Thrombin is primarily known for its role in homeostasis and thrombosis. However, this enzyme also plays important roles in wound healing and pathologic situations such as inflammation and tumorigenesis. Among the molecules stimulated by thrombin in these latter processes are the stress response proteins, chemokines. Chemokines are also known for their roles in inflammatory responses and tumor development. These correlative observations strongly suggest that chemokines may be mediators of some of thrombin's functions in these processes. Elucidation of the molecular mechanisms of stimulation of chemokines by thrombin may help to unravel the ways in which their expression can be modulated. Up-regulation of the chemokine 9E3/cCAF by thrombin occurs via its proteolytically activated receptor with subsequent transactivation of the epidermal growth factor receptor tyrosine kinase. This study shows that stimulation by thrombin very rapidly activates this chemokine at the transcriptional level, that 2 Elk1 binding elements located between −534 and −483 bp of the promoter are major thrombin response elements, that activation occurs via the Elk1 transcription factor, and that the latter is directly activated by MEK1/ERK2. The common occurrence of Elk1 binding domains in the promoters of immediate early response genes suggests that it may be characteristically involved in gene activation by stress-inducing agents.

scholarly journals Serum microRNAs as Tool to Predict Early Response to Benralizumab in Severe Eosinophilic Asthma

2021 ◽  
Vol 11 (2) ◽  
pp. 76
Author(s):  
José A. Cañas ◽  
Marcela Valverde-Monge ◽  
José M. Rodrigo-Muñoz ◽  
Beatriz Sastre ◽  
Marta Gil-Martínez ◽  
...  
Keyword(s):  
Target Genes ◽  
Early Response ◽  
Mapk Signaling ◽  
Economic Problem ◽  
Biological Drugs ◽  
Eosinophilic Asthma ◽  
Altered Expression ◽  
Asthmatic Patients ◽  
Severe Eosinophilic Asthma ◽  
Before And After

Severe eosinophilic asthma poses a serious health and economic problem, so new therapy approaches have been developed to control it, including biological drugs such as benralizumab, which is a monoclonal antibody that binds to IL-5 receptor alpha subunit and depletes peripheral blood eosinophils rapidly. Biomarkers that predict the response to this drug are needed so that microRNAs (miRNAs) can be useful tools. This study was performed with fifteen severe eosinophilic asthmatic patients treated with benralizumab, and serum miRNAs were evaluated before and after treatment by semi-quantitative PCR (qPCR). Patients showed a clinical improvement after benralizumab administration. Additionally, deregulation of miR-1246, miR-5100 and miR-338-3p was observed in severe asthmatic patients after eight weeks of therapy, and a correlation was found between miR-1246 and eosinophil counts, including a number of exacerbations per year in these severe asthmatics. In silico pathway analysis revealed that these three miRNAs are regulators of the MAPK signaling pathway, regulating target genes implicated in asthma such as NFKB2, NFATC3, DUSP1, DUSP2, DUSP5 and DUSP16. In this study, we observed an altered expression of miR-1246, miR-5100 and miR-338-3p after eight weeks of benralizumab administration, which could be used as early response markers.

scholarly journals Integrated Analysis of Transcriptome and Prognosis Data Identifies FGF22 as a Prognostic Marker of Lung Adenocarcinoma

2019 ◽  
Vol 18 ◽  
pp. 153303381982731 ◽  
Author(s):  
Hong-Yan Liu ◽  
Hui Zhao ◽  
Wen-Xing Li
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Lung Adenocarcinoma ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Profiles ◽  
Mapk Signaling ◽  
Integrated Analysis ◽  
Fibroblast Growth

Lung adenocarcinoma is one of the most common cancers worldwide. However, the molecular mechanisms of lung adenocarcinoma development are still unclear. This study aimed to investigate the expression profiles of anti-lung cancer target genes in different cancer stages and to explore their functions in tumor development. Lung adenocarcinoma transcriptome and clinical data were downloaded from Genomic Data Commons Data Portal, and the anti-lung cancer target genes were retrieved from the Thomson Reuters Integrity database. The results showed that 16 anti-lung target genes were deregulated in all stages. Among these target genes, fibroblast growth factor 22 showed the most important role in transcription regulatory networks. Further analysis revealed that APC, BRIP1, and PTTG1 may regulate fibroblast growth factor 22 and subsequently influence MAPK signaling pathway, Rap1 signaling pathways, and other tumorigenic processes in all stages. Moreover, high fibroblast growth factor 22 expression leads to poor overall survival (hazard ratio = 1.55, P = .019). These findings provide valuable information for the pathological research and treatment of lung adenocarcinoma. Future studies are needed to verify these results.

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