Dataset Information

Yeast model identifies ENTPD6 as a potential non-obstructive azoospermia pathogenic gene.

ABSTRACT: Approximately ten percent of male infertility is caused by non-obstructive azoospermia (NOA), but the etiologies of many NOA remain elusive. Recently, a genome-wide association study (GWAS) of NOA in Han Chinese men was conducted, and only a few genetic variants associated with NOA were found, which might have resulted from genetic heterogeneity. However, those variants that lack genome-wide significance might still be essential for fertility. Functional analysis of genes surrounding these variants in Drosophila identified some spermatogenesis-essential genes. As a complementary method of Drosophila screening, SK1 background Saccharomvces cerevisiae was used as a model to screen meiosis-related genes from the NOA GWAS data in this study. After functional screening, GDA1 (orthologous to humanENTPD6) was found to be a novel meiosis-related gene. The deletion of GDA1 resulted in the failure of yeast sporulation. Further investigations showed that Gda1p was important for pre-meiotic S phase entry. Interestingly, the meiotic role of Gda1p was dependent on its guanosine diphosphatase activity, but not it's cytoplasmic, transmembrane or stem domains. These yeast data suggest that ENTPD6 may be a novel meiosis-associated NOA-related gene, and the yeast model provides a good approach to analyze GWAS results of NOA.

SUBMITTER: Wang Q

PROVIDER: S-EPMC4495445 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Yeast model identifies ENTPD6 as a potential non-obstructive azoospermia pathogenic gene.

Wang Qian Q Liu Chao C Tang Chaoming C Guo Huiping H Liu Yujiao Y Wang Lina L Zhao Haichao H Shang Yongliang Y Wen Yang Y Lin Yuan Y Zhou Tao T Zhou Zuomin Z Dong Wen W Hu Zhibin Z Guo Xuejiang X Sha Jiahao J Li Wei W

Scientific reports 20150708

Approximately ten percent of male infertility is caused by non-obstructive azoospermia (NOA), but the etiologies of many NOA remain elusive. Recently, a genome-wide association study (GWAS) of NOA in Han Chinese men was conducted, and only a few genetic variants associated with NOA were found, which might have resulted from genetic heterogeneity. However, those variants that lack genome-wide significance might still be essential for fertility. Functional analysis of genes surrounding these varia ...[more]

PMID: 26152596

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Project description:Background: Non-obstructive azoospermia (NOA) is the most severe form of male infertility. Currently, the molecular mechanisms underlying NOA pathology have not yet been elucidated. Hence, elucidation of the mechanisms of NOA and exploration of potential biomarkers are essential for accurate diagnosis and treatment of this disease. In the present study, we aimed to screen for biomarkers and pathways involved in NOA and reveal their potential molecular mechanisms using integrated bioinformatics. Methods: We downloaded two gene expression datasets from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in NOA and matched the control group tissues were identified using the limma package in R software. Subsequently, Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), protein-protein interaction (PPI) network, gene-microRNAs network, and transcription factor (TF)-hub genes regulatory network analyses were performed to identify hub genes and associated pathways. Finally, we conducted immune infiltration analysis using CIBERSORT to evaluate the relationship between the hub genes and the NOA immune infiltration levels. Results: We identified 698 common DEGs, including 87 commonly upregulated and 611 commonly downregulated genes in the two datasets. GO analysis indicated that the most significantly enriched gene was protein polyglycylation, and KEGG pathway analysis revealed that the DEGs were most significantly enriched in taste transduction and pancreatic secretion signaling pathways. GSEA showed that DEGs affected the biological functions of the ribosome, focaladhesion, and protein_expor. We further identified the top 31 hub genes from the PPI network, and friends analysis of hub genes in the PPI network showed that NR4A2 had the highest score. In addition, immune infiltration analysis found that CD8+ T cells and plasma cells were significantly correlated with ODF3 expression, whereas naive B cells, plasma cells, monocytes, M2 macrophages, and resting mast cells showed significant variation in the NR4A2 gene expression group, and there were differences in T cell regulatory immune cell infiltration in the FOS gene expression groups. Conclusion: The present study successfully constructed a regulatory network of DEGs between NOA and normal controls and screened three hub genes using integrative bioinformatics analysis. In addition, our results suggest that functional changes in several immune cells in the immune microenvironment may play an important role in spermatogenesis. Our results provide a novel understanding of the molecular mechanisms of NOA and offer potential biomarkers for its diagnosis and treatment.

Project description:BackgroundNon-obstructive azoospermia (NOA) affects approximately 1% of the male population worldwide. The underlying mechanism and gene transcription remain unclear. This study aims to explore the potential pathogenesis for the detection and management of NOA.MethodsBased on four microarray datasets from the Gene Expression Omnibus database, integrated analysis and weighted correlation network analysis (WGCNA) were used to obtain the intersected common differentially expressed genes (DESs). Differential signaling pathways were identified via GO and GSVA-KEGG analyses. We constructed a seventeen-gene signature model using least absolute shrinkage and selection operation (LASSO) regression, and validated its efficacy in another two GEO datasets. Three patients with NOA and three patients with obstructive azoospermia were recruited. The mRNA levels of seven key genes were measured in testicular samples, and the gene expression profile was evaluated in the Human Protein Atlas (HPA) database.ResultsIn total, 388 upregulated and 795 downregulated common DEGs were identified between the NOA and control groups. ATPase activity, tubulin binding, microtubule binding, and metabolism- and immune-associated signaling pathways were significantly enriched. A seventeen-gene signature predictive model was constructed, and receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) values were 1.000 (training group), 0.901 (testing group), and 0.940 (validation set). The AUCs of seven key genes (REC8, CPS1, DHX57, RRS1, GSTA4, SI, and COX7B) were all > 0.8 in both the testing group and the validation set. The qRT-PCR results showed that consistent with the sequencing data, the mRNA levels of RRS1, GSTA4, and COX7B were upregulated, while CPS1, DHX57, and SI were downregulated in NOA. Four genes (CPS1, DHX57, RRS1, and SI) showed significant differences. Expression data from the HPA database showed the localization characteristics and trajectories of seven key genes in spermatogenic cells, Sertoli cells, and Leydig cells.ConclusionsOur findings suggest a novel seventeen-gene signature model with a favorable predictive power, and identify seven key genes with potential as NOA-associated marker genes. Our study provides a new perspective for exploring the underlying pathological mechanism in male infertility.

Project description:ObjectiveThe cause and mechanism of non-obstructive azoospermia (NOA) is complicated; therefore, an effective therapy strategy is yet to be developed. This study aimed to analyse the pathogenesis of NOA at the molecular biological level and to identify the core regulatory genes, which could be utilised as potential biomarkers.MethodsThree NOA microarray datasets (GSE45885, GSE108886, and GSE145467) were collected from the GEO database and merged into training sets; a further dataset (GSE45887) was then defined as the validation set. Differential gene analysis, consensus cluster analysis, and WGCNA were used to identify preliminary signature genes; then, enrichment analysis was applied to these previously screened signature genes. Next, 4 machine learning algorithms (RF, SVM, GLM, and XGB) were used to detect potential biomarkers that are most closely associated with NOA. Finally, a diagnostic model was constructed from these potential biomarkers and visualised as a nomogram. The differential expression and predictive reliability of the biomarkers were confirmed using the validation set. Furthermore, the competing endogenous RNA network was constructed to identify the regulatory mechanisms of potential biomarkers; further, the CIBERSORT algorithm was used to calculate immune infiltration status among the samples.ResultsA total of 215 differentially expressed genes (DEGs) were identified between NOA and control groups (27 upregulated and 188 downregulated genes). The WGCNA results identified 1123 genes in the MEblue module as target genes that are highly correlated with NOA positivity. The NOA samples were divided into 2 clusters using consensus clustering; further, 1027 genes in the MEblue module, which were screened by WGCNA, were considered to be target genes that are highly correlated with NOA classification. The 129 overlapping genes were then established as signature genes. The XGB algorithm that had the maximum AUC value (AUC=0.946) and the minimum residual value was used to further screen the signature genes. IL20RB, C9orf117, HILS1, PAOX, and DZIP1 were identified as potential NOA biomarkers. This 5 biomarker model had the highest AUC value, of up to 0.982, compared to other single biomarker models; additionally, the results of this biomarker model were verified in the validation set.ConclusionsAs IL20RB, C9orf117, HILS1, PAOX, and DZIP1 have been determined to possess the strongest association with NOA, these five genes could be used as potential therapeutic targets for NOA patients. Furthermore, the model constructed using these five genes, which possessed the highest diagnostic accuracy, may be an effective biomarker model that warrants further experimental validation.

Dataset Information

Yeast model identifies ENTPD6 as a potential non-obstructive azoospermia pathogenic gene.

Publications

Yeast model identifies ENTPD6 as a potential non-obstructive azoospermia pathogenic gene.

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