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Identification of Gene Modules and Hub Genes Involved in Mastitis Development Using a Systems Biology Approach.

ABSTRACT: Objective:Mastitis is defined as the inflammation of the mammary gland, which impact directly on the production performance and welfare of dairy cattle. Since, mastitis is a multifactorial complex disease and the molecular pathways underlying this disorder have not been clearly understood yet, a system biology approach was used in this study to a better understanding of the molecular mechanisms behind mastitis. Methods:Publicly available RNA-Seq data containing samples from milk of five infected and five healthy Holstein cows at five time points were retrieved. Gene Co-expression network analysis (WGCNA) approach and functional enrichment analysis were then applied with the aim to find the non-preserved module of genes that their connectivity were altered under infected condition. Hub genes were identified in the non-preserved modules and were subjected to protein-protein interactions (PPI) network construction. Results:Among the 25 modules identified, eight modules were non-preserved and were also biologically associated with inflammation, immune response and mastitis development. Interestingly most of the hub genes in the eight modules were also densely connected in the PPI network. Of the hub genes, 250 genes were hubs in both co-expression and PPI networks and most of them were reported to play important roles in immune response or inflammatory pathways. The blue module was highly enriched in inflammatory responses and STAT1 was suggested to play an important role in mastitis development by regulating the immune related genes in this module. Moreover, a set of highly connected genes were identified such as BIRC3, PSMA6, FYN, F11R, NFKBIZ, NFKBIA, GRO1, PHB, CD3E, IL16, GSN, SOCS2, HCK, VAV1 and TLR6, which have been established to be critical for mastitis pathogenesis. Conclusion:This study improved the understanding of the mechanisms underlying bovine mastitis and suggested eight non-preserved modules along with several most important genes with promising potential in etiology of mastitis.

SUBMITTER: Bakhtiarizadeh MR

PROVIDER: S-EPMC7371005 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Identification of Gene Modules and Hub Genes Involved in Mastitis Development Using a Systems Biology Approach.

Bakhtiarizadeh Mohammad Reza MR Mirzaei Shabnam S Norouzi Milad M Sheybani Negin N Vafaei Sadi Mohammad Sadegh MS

Frontiers in genetics 20200713

<h4>Objective</h4>Mastitis is defined as the inflammation of the mammary gland, which impact directly on the production performance and welfare of dairy cattle. Since, mastitis is a multifactorial complex disease and the molecular pathways underlying this disorder have not been clearly understood yet, a system biology approach was used in this study to a better understanding of the molecular mechanisms behind mastitis.<h4>Methods</h4>Publicly available RNA-Seq data containing samples from milk o ...[more]

PMID: 32754201

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Project description:Background: Bovine respiratory disease (BRD) is the most common disease in the beef and dairy cattle industry. BRD is a multifactorial disease resulting from the interaction between environmental stressors and infectious agents. However, the molecular mechanisms underlying BRD are not fully understood yet. Therefore, this study aimed to use a systems biology approach to systematically evaluate this disorder to better understand the molecular mechanisms responsible for BRD. Methods: Previously published RNA-seq data from whole blood of 18 healthy and 25 BRD samples were downloaded from the Gene Expression Omnibus (GEO) and then analyzed. Next, two distinct methods of weighted gene coexpression network analysis (WGCNA), i.e., module-trait relationships (MTRs) and module preservation (MP) analysis were used to identify significant highly correlated modules with clinical traits of BRD and non-preserved modules between healthy and BRD samples, respectively. After identifying respective modules by the two mentioned methods of WGCNA, functional enrichment analysis was performed to extract the modules that are biologically related to BRD. Gene coexpression networks based on the hub genes from the candidate modules were then integrated with protein-protein interaction (PPI) networks to identify hub-hub genes and potential transcription factors (TFs). Results: Four significant highly correlated modules with clinical traits of BRD as well as 29 non-preserved modules were identified by MTRs and MP methods, respectively. Among them, two significant highly correlated modules (identified by MTRs) and six nonpreserved modules (identified by MP) were biologically associated with immune response, pulmonary inflammation, and pathogenesis of BRD. After aggregation of gene coexpression networks based on the hub genes with PPI networks, a total of 307 hub-hub genes were identified in the eight candidate modules. Interestingly, most of these hub-hub genes were reported to play an important role in the immune response and BRD pathogenesis. Among the eight candidate modules, the turquoise (identified by MTRs) and purple (identified by MP) modules were highly biologically enriched in BRD. Moreover, STAT1, STAT2, STAT3, IRF7, and IRF9 TFs were suggested to play an important role in the immune system during BRD by regulating the coexpressed genes of these modules. Additionally, a gene set containing several hub-hub genes was identified in the eight candidate modules, such as TLR2, TLR4, IL10, SOCS3, GZMB, ANXA1, ANXA5, PTEN, SGK1, IFI6, ISG15, MX1, MX2, OAS2, IFIH1, DDX58, DHX58, RSAD2, IFI44, IFI44L, EIF2AK2, ISG20, IFIT5, IFITM3, OAS1Y, HERC5, and PRF1, which are potentially critical during infection with agents of bovine respiratory disease complex (BRDC). Conclusion: This study not only helps us to better understand the molecular mechanisms responsible for BRD but also suggested eight candidate modules along with several promising hub-hub genes as diagnosis biomarkers and therapeutic targets for BRD.

Project description:Hepatocellular carcinoma (HCC) is a heterogeneous malignancy, which is a major cause of cancer morbidity and mortality worldwide. Thus, the aim of the present study was to identify the hub genes and underlying pathways of HCC via bioinformatics analyses. The present study screened three datasets, including GSE112790, GSE84402 and GSE74656 from the Gene Expression Omnibus (GEO) database, and downloaded the RNA-sequencing of HCC from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) in both the GEO and TCGA datasets were filtered, and the screened DEGs were subsequently analyzed for functional enrichment pathways. A protein-protein interaction (PPI) network was constructed, and hub genes were further screened to create the Kaplan-Meier curve using cBioPortal. The expression levels of hub genes were then validated in different datasets using the Oncomine database. In addition, associations between expression and tumor grade, hepatitis virus infection status, satellites and vascular invasion were assessed. A total of 126 DEGs were identified, containing 70 upregulated genes and 56 downregulated genes from the GEO and TCGA databases. By constructing the PPI network, the present study identified hub genes, including cyclin B1 (CCNB1), cell-division cycle protein 20 (CDC20), cyclin-dependent kinase 1, BUB1 mitotic checkpoint serine/threonine kinase ? (BUB1B), cyclin A2, nucleolar and spindle associated protein 1, ubiquitin-conjugating enzyme E2 C (UBE2C) and ZW10 interactor. Furthermore, upregulated CCNB1, CDC20, BUB1B and UBE2C expression levels indicated worse disease-free and overall survival. Moreover, a meta-analysis of tumor and healthy tissues in the Oncomine database demonstrated that BUB1B and UBE2C were highly expressed in HCC. The present study also analyzed the data of HCC in TCGA database using univariate and multivariate Cox analyses, and demonstrated that BUB1B and UBE2C may be used as independent prognostic factors. In conclusion, the present study identified several genes and the signaling pathways that were associated with tumorigenesis using bioinformatics analyses, which could be potential targets for the diagnosis and treatment of HCC.

Project description:Background: Intervertebral disc degeneration impairs the quality of patients lives. Even though there has been development of many therapeutic strategies, most of them remain unsatisfactory due to the limited understanding of the mechanisms that underlie the intervertebral disc degeneration. Questions/purposes: This study is meant to identify the key modules and hub genes related to the annulus fibrosus in intervertebral disc degeneration (IDD) through: (1) constructing a weighted gene co-expression network; (2) identifying key modules and hub genes; (3) verifying the relationships of key modules and hub genes with IDD; and (4) confirming the expression pattern of hub genes in clinical samples. Methods: The Gene Expression Omnibus provided 24 sets of annulus fibrosus microarray data. Differentially expressed genes between the annulus fibrosus of degenerative and non-degenerative intervertebral disc samples have gone through the Gene Ontology (GO) and pathway analysis. The construction of a gene network and classification of genes into different modules were conducted through performing Weighted Gene Co-expression Network Analysis. The identification of modules and hub genes that were most related to intervertebral disc degeneration was proceeded. In order to verify the relationships of the module and hub genes with intervertebral disc degeneration, Ingenuity Pathway Analysis was operated. Clinical samples were adopted to help verify the hub gene expression profile. Results: One thousand one hundred ninety differentially expressed genes were identified. Terms and pathways associated with intervertebral disc degeneration were presented by GO and pathway analysis. The construction of a Weighted Gene Coexpression Network was completed and clustering differentially expressed genes into four modules was also achieved. The module with the lowest P-value and the highest absolute correlation coefficient was selected and its relationship with intervertebral disc degeneration was confirmed by Ingenuity Pathway Analysis. The identification of hub genes and the confirmation of their expression profile were also realized. Conclusions: This study generated a comprehensive overview of the gene networks underlying annulus fibrosus in intervertebral disc degeneration. Clinical Relevance: Modules and hub genes identified in this study are highly associated with intervertebral disc degeneration, and may serve as potential therapeutic targets for intervertebral disc degeneration.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease, characterized by a decline in lung function. To date, the pathophysiologic mechanisms associated with lung dysfunction remain unclear, and no effective therapy has been identified to improve lung function.MethodsIn the present study, we used weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes associated with lung function in IPF. Three datasets, containing clinical information, were downloaded from Gene Expression Omnibus. WGCNA was performed on the GSE32537 dataset. Differentially expressed gene s (DEGs) between IPF patients and healthy controls were also identified to filter hub genes. The relationship between hub genes and lung function was then validated using the GSE47460 and GSE24206 datasets.ResultsThe red module, containing 267 genes, was positively correlated with the St. George's Respiratory Questionnaire score (r = 0.37, p < 0.001) and negatively correlated with the percent predicted forced vital capacity (FVC% predicted) (r = - 0.46, p < 0.001) and the percent predicted diffusion capacity of the lung for carbon monoxide (Dlco% predicted) (r = - 0.42, p < 0.001). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that the genes in the red module were primarily involved in inflammation and immune pathways. Based on Module Membership and Gene Significance, 32 candidate hub genes were selected in the red module to construct a protein-protein interaction network . Based on the identified DEGs and the degree of connectivity in the network, we identified three hub genes, including interleukin 6 (IL6), suppressor of cytokine signaling-3 (SOCS3), and serpin family E member 1 (SERPINE1). In the GSE47460 dataset, Spearman correlation coefficients between Dlco% predicted and expression levels of IL6, SERPINE1, SOCS3 were -0.32, -0.41, and -0.46, respectively. Spearman correlation coefficients between FVC% predicted and expression levels of IL6, SERPINE1, SOCS3 were -0.29, -0.33, and -0.27, respectively. In the GSE24206 dataset, all three hub genes were upregulated in patients with advanced IPF.ConclusionWe identified three hub genes that negatively correlated with the lung function of IPF patients. Our results provide insights into the pathogenesis underlying the progressive disruption of lung function, and the identified hub genes may serve as biomarkers and potential therapeutictargets for the treatment of IPF patients.

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Identification of Gene Modules and Hub Genes Involved in Mastitis Development Using a Systems Biology Approach.

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Identification of Gene Modules and Hub Genes Involved in Mastitis Development Using a Systems Biology Approach.

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