scholarly journals Transcriptome analysis of wheat spikes in response to Tilletia controversa Kühn which cause wheat dwarf bunt

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhaoyu Ren ◽  
Jianjian Liu ◽  
Ghulam Muhae Ud Din ◽  
Han Zhang ◽  
Zhenzhen Du ◽  
...  
Keyword(s):  
Differential Expression Analysis ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Transcriptome Profile ◽  
Resistance Level ◽  
New Methods ◽  
Tilletia Controversa ◽  
Mitogen Activated Protein ◽  
Mock Infection ◽  
Dwarf Bunt

AbstractWheat dwarf bunt is caused by Tilletia controversa Kühn, which is one of the most destructive diseases of wheat worldwide. To explore the interaction of T. controversa and wheat, we analysed the transcriptome profile of spikes of the susceptible wheat cultivar Dongxuan 3, which was subjected to a T. controversa infection and a mock infection. The results obtained from a differential expression analysis of T. controversa-infected plants compared with mock-infected ones showed that 10,867 out of 21,354 genes were upregulated, while 10,487 genes were downregulated, and these genes were enriched in 205 different pathways. Our findings demonstrated that the genes associated with defence against diseases, such as PR-related genes, WRKY transcription factors and mitogen-activated protein kinase genes, were more highly expressed in response to T. controversa infection. Additionally, a number of genes related to physiological attributes were expressed during infection. Three pathways were differentiated based on the characteristics of gene ontology classification. KEGG enrichment analysis showed that twenty genes were expressed differentially during the infection of wheat with T. controversa. Notable changes were observed in the transcriptomes of wheat plants after infection. The results of this study may help to elucidate the mechanism governing the interactions between this pathogen and wheat plants and may facilitate the development of new methods to increase the resistance level of wheat against T. controversa, including the overexpression of defence-related genes.

scholarly journals Identification of pathways modulating vemurafenib resistance in melanoma cells via a genome-wide CRISPR/Cas9 screen

2021 ◽  
Vol 11 (2) ◽  
Author(s):  
Corinna Jie Hui Goh ◽  
Jin Huei Wong ◽  
Chadi El Farran ◽  
Ban Xiong Tan ◽  
Cynthia R Coffill ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Melanoma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Genome Wide ◽  
A Genome ◽  
Mitogen Activated Protein ◽  
Genome Scale

Abstract Vemurafenib is a BRAF kinase inhibitor (BRAFi) that is used to treat melanoma patients harboring the constitutively active BRAF-V600E mutation. However, after a few months of treatment patients often develop resistance to vemurafenib leading to disease progression. Sequence analysis of drug-resistant tumor cells and functional genomic screens has identified several genes that regulate vemurafenib resistance. Reactivation of mitogen-activated protein kinase (MAPK) pathway is a recurrent feature of cells that develop resistance to vemurafenib. We performed a genome-scale CRISPR-based knockout screen to identify modulators of vemurafenib resistance in melanoma cells with a highly improved CRISPR sgRNA library called Brunello. We identified 33 genes that regulate resistance to vemurafenib out of which 14 genes have not been reported before. Gene ontology enrichment analysis showed that the hit genes regulate histone modification, transcription and cell cycle. We discuss how inactivation of hit genes might confer resistance to vemurafenib and provide a framework for follow-up investigations.

scholarly journals Involvement of Essential Signaling Cascades and Analysis of Gene Networks in Diabesity

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1256
Author(s):  
Udhaya Kumar S. ◽  
Bithia Rajan ◽  
Thirumal Kumar D. ◽  
Anu Preethi V. ◽  
Taghreed Abunada ◽  
...  
Keyword(s):  
Gene Networks ◽  
Enrichment Analysis ◽  
Mapk Signaling ◽  
Clustering Coefficient ◽  
Mitogen Activated Protein Kinase ◽  
Increased Risk ◽  
Mitogen Activated Protein ◽  
Obesity Genes ◽  
Network Backbone ◽  
Igf1r Signaling

(1) Aims: Diabesity, defined as diabetes occurring in the context of obesity, is a serious health problem that is associated with an increased risk of premature heart attack, stroke, and death. To date, a key challenge has been to understand the molecular pathways that play significant roles in diabesity. In this study, we aimed to investigate the genetic links between diabetes and obesity in diabetic individuals and highlight the role(s) of shared genes in individuals with diabesity. (2) Methods: The interactions between the genes were analyzed using the Search Tool for the Retrieval of Interacting Genes (STRING) tool after the compilation of obesity genes associated with type 1 diabetes (T1D), type 2 diabetes (T2D), and maturity-onset diabetes of the young (MODY). Cytoscape plugins were utilized for enrichment analysis. (3) Results: We identified 546 obesity genes that are associated with T1D, T2D, and MODY. The network backbone of the identified genes comprised 514 nodes and 4126 edges with an estimated clustering coefficient of 0.242. The Molecular Complex Detection (MCODE) generated three clusters with a score of 33.61, 16.788, and 6.783, each. The highest-scoring nodes of the clusters were AGT, FGB, and LDLR genes. The genes from cluster 1 were enriched in FOXO-mediated transcription of oxidative stress, renin secretion, and regulation of lipolysis in adipocytes. The cluster 2 genes enriched in Src homology 2 domain-containing (SHC)-related events triggered by IGF1R, regulation of lipolysis in adipocytes, and GRB2: SOS produce a link to mitogen-activated protein kinase (MAPK) signaling for integrins. The cluster 3 genes ere enriched in IGF1R signaling cascade and insulin signaling pathway. (4) Conclusion: This study presents a platform to discover potential targets for diabesity treatment and helps in understanding the molecular mechanism.

Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation

2021 ◽  
Author(s):  
Katherine T Lind ◽  
Hannah V Chatwin ◽  
John DeSisto ◽  
Philip Coleman ◽  
Bridget Sanford ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Immunofluorescent Staining ◽  
Low Grade ◽  
Normal Brain ◽  
Mapk Activation ◽  
Low Grade Gliomas ◽  
Pathway Activation ◽  
Mitogen Activated Protein

Abstract Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.

scholarly journals Changes in Methylation across Structural and MicroRNA Genes Relevant for Progression and Metastasis in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5951
Author(s):  
Nitin Patil ◽  
Mohammed L. Abba ◽  
Chan Zhou ◽  
Shujian Chang ◽  
Timo Gaiser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cpg Islands ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Pathway Enrichment Analysis ◽  
Protein Coding ◽  
Normal Tissues ◽  
Mitogen Activated Protein ◽  
Microrna Genes

MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis.

scholarly journals Open Data for Differential Network Analysis in Glioma

2020 ◽  
Vol 21 (2) ◽  
pp. 547 ◽  
Author(s):  
Claire Jean-Quartier ◽  
Fleur Jeanquartier ◽  
Andreas Holzinger
Keyword(s):  
Network Analysis ◽  
Protein Complexes ◽  
Open Data ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Subtypes ◽  
Differential Network Analysis ◽  
Differential Network ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes. By using selected exemplary tools and open-access resources for cancer research and differential network analysis, we highlight disturbed signaling components in brain cancer subtypes of glioma.

scholarly journals Differential Gene Expression Profile of Human Neutrophils Cultured withPlasmodium falciparum-Parasitized Erythrocytes

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Mohamad Alaa Terkawi ◽  
Ryo Takano ◽  
Kentaro Kato
Keyword(s):  
Gene Expression ◽  
Inflammatory Diseases ◽  
Transcriptional Response ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Interventions ◽  
Human Neutrophils ◽  
Surface Receptors ◽  
Genes Encoding ◽  
Mitogen Activated Protein

Neutrophils (PMNs) are the most abundant cellular component of our innate immune system, where they play central roles in the pathogenesis of and resistance to a broad range of diseases. However, their roles in malarial infection remain poorly understood. Therefore, we examined the transcriptional gene profile of human PMNs in response toPlasmodium falciparum-parasitized erythrocytes (iRBCs) by using oligonucleotide microarrays. Results revealed that PMNs induced a broad and vigorous set of changes in gene expression in response to malarial parasites, represented by 118 upregulated and 216 downregulated genes. The transcriptional response was characterized by the upregulation of numerous genes encoding multiple surface receptors, proteins involved in signal transduction pathways, and defense response proteins. This response included a number of genes which are known to be involved in the pathogenesis of malaria and other inflammatory diseases. Gene enrichment analysis suggested that the biological pathways involved in the PMN responses to the iRBCs included insulin receptor, Jak-STAT signaling pathway, mitogen-activated protein kinase (MAPK), and interleukin and interferon-gamma (IFN-γ) signaling pathways. The current study provides fundamental knowledge on the molecular responses of neutrophils to malarial parasites, which may aid in the discovery of novel therapeutic interventions.

scholarly journals Substrate-based kinase activity inference identifies MK2 as driver of colitis

2019 ◽  
Vol 11 (7) ◽  
pp. 301-314 ◽  
Author(s):  
Samantha Dale Strasser ◽  
Phaedra C Ghazi ◽  
Alina Starchenko ◽  
Myriam Boukhali ◽  
Amanda Edwards ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Prior Knowledge ◽  
Mouse Models ◽  
Kinase Activity ◽  
Treatment Options ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Substrate ◽  
Mitogen Activated Protein

Abstract Inflammatory bowel disease (IBD) is a chronic and debilitating disorder that has few treatment options due to a lack of comprehensive understanding of its molecular pathogenesis. We used multiplexed mass spectrometry to collect high-content information on protein phosphorylation in two different mouse models of IBD. Because the biological function of the vast majority of phosphorylation sites remains unknown, we developed Substrate-based Kinase Activity Inference (SKAI), a methodology to infer kinase activity from phosphoproteomic data. This approach draws upon prior knowledge of kinase-substrate interactions to construct custom lists of kinases and their respective substrate sites, termed kinase-substrate sets that employ prior knowledge across organisms. This expansion as much as triples the amount of prior knowledge available. We then used these sets within the Gene Set Enrichment Analysis framework to infer kinase activity based on increased or decreased phosphorylation of its substrates in a dataset. When applied to the phosphoproteomic datasets from the two mouse models, SKAI predicted largely non-overlapping kinase activation profiles. These results suggest that chronic inflammation may arise through activation of largely divergent signaling networks. However, the one kinase inferred to be activated in both mouse models was mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2), a serine/threonine kinase that functions downstream of p38 stress-activated mitogen-activated protein kinase. Treatment of mice with active colitis with ATI450, an orally bioavailable small molecule inhibitor of the MK2 pathway, reduced inflammatory signaling in the colon and alleviated the clinical and histological features of inflammation. These studies establish MK2 as a therapeutic target in IBD and identify ATI450 as a potential therapy for the disease.

scholarly journals Identification of pathways modulating Vemurafenib resistance in melanoma cells via a genome-wide CRISPR/Cas9 screen

2020 ◽  
Author(s):  
Corinna Jie Hui Goh ◽  
Jin Huei Wong ◽  
Chadi El Farran ◽  
Ban Xiong Tan ◽  
Cynthia Coffill ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Melanoma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Genome Wide ◽  
A Genome ◽  
Mitogen Activated Protein ◽  
Genome Scale

ABSTRACTVemurafenib is a BRAF kinase inhibitor (BRAFi) that is used to treat melanoma patients harbouring the constitutively active BRAF-V600E mutation. However, after a few months of treatment patients often develop resistance to vemurafenib leading to disease progression. Sequence analysis of drug-resistant tumour cells and functional genomic screens have identified several genes that regulate vemurafenib resistance. Reactivation of mitogen-activated protein kinase (MAPK) pathway is a recurrent feature of cells that develop resistance to vemurafenib. We performed a genome-scale CRISPR-based knockout screen to identify modulators of vemurafenib resistance in melanoma cells with a highly improved CRISPR sgRNA library called Brunello. We identified 33 genes that regulate resistance to vemurafenib out of which 14 genes have not been reported before. Gene Ontology enrichment analysis showed that the hit genes regulate histone modification, transcription and cell cycle. We discuss how inactivation of hit genes might confer resistance to vemurafenib and provide a framework for follow-up investigations.

scholarly journals HDAC and MAPK/ERK Inhibitors Cooperate to Reduce Viability and Stemness in Medulloblastoma

2019 ◽  
Author(s):  
Mariane da Cunha Jaeger ◽  
Eduarda Chiesa Ghisleni ◽  
Paula Schoproni Cardoso ◽  
Marialva Siniglaglia ◽  
Tiago Falcon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Strategy ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Hdac Inhibition ◽  
Single Drug ◽  
Mitogen Activated Protein ◽  
Drug Treatments ◽  
Erk Inhibition ◽  
Developing Cerebellum

AbstractMedulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markersBMI1andCD133are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression ofBMI1andCD133and increased acetylation in human MB cells. Enrichment analysis of genes associated withCD133orBMI1expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumors. MAPK/ERK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and more effective approach in reducing MB proliferation when compared to single-drug treatments, through modulation of the stemness phenotype of MB cells.

scholarly journals GWAS Identifies Candidate Susceptibility Loci and Microrna Biomarkers for Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion

2021 ◽  
Author(s):  
Mariko Kasai ◽  
Yosuke Omae ◽  
Yosuke Kawai ◽  
Akiko Shibata ◽  
Ai Hoshino ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Acute Encephalopathy ◽  
Functional Variants ◽  
A Genome ◽  
Mitogen Activated Protein

Abstract Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe encephalopathy preceded by viral infections with high fever. AESD is a　multifactorial disease, however, few disease susceptibility genes have previously been identified. Here, we conducted a genome-wide association study (GWAS) and assessed functional variants in non-coding regions to study genetic susceptibility in AESD using 254 Japanese children with AESD and 799 adult healthy controls. We also performed a microRNA enrichment analysis using GWAS statistics to search for candidate biomarkers in AESD. The variant with the lowest p-value, rs1850440, was located in the intron of serine/threonine kinase 39 gene (STK39) on chromosome 2q24.3 (p = 2.44 × 10−7, odds ratio = 1.71). The minor allele T of rs1850440 correlated with the stronger expression of STK39 in peripheral blood. This variant possessed enhancer histone modification marks in STK39, the encoded protein of which activates the p38 mitogen-activated protein kinase (MAPK) pathway. One of the candidate microRNAs identified by the microRNA enrichment analysis was associated with inflammatory responses regulated by the MAPK pathway. This study identified STK39 as a novel susceptibility locus of AESD, found microRNAs as potential biomarkers, and implicated immune responses and the MAPK cascade in its pathogenesis.

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