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Computational identification of key genes that may regulate gene expression reprogramming in Alzheimer's patients.

ABSTRACT: The dementia epidemic is likely to expand worldwide as the aging population continues to grow. A better understanding of the molecular mechanisms that lead to dementia is expected to reveal potentially modifiable risk factors that could contribute to the development of prevention strategies. Alzheimer's disease is the most prevalent form of dementia. Currently we only partially understand some of the pathophysiological mechanisms that lead to development of the disease in aging individuals. In this study, Switch Miner software was used to identify key switch genes in the brain whose expression may lead to the development of Alzheimer's disease. The results indicate that switch genes are enriched in pathways involved in the proteasome, oxidative phosphorylation, Parkinson's disease, Huntington's disease, Alzheimer's disease and metabolism in the hippocampus and posterior cingulate cortex. Network analysis identified the krupel like factor 9 (KLF9), potassium channel tetramerization domain 2 (KCTD2), Sp1 transcription factor (SP1) and chromodomain helicase DNA binding protein 1 (CHD1) as key transcriptional regulators of switch genes in the brain of AD patients. These transcriptions factors have been implicated in conditions associated with Alzheimer's disease, including diabetes, glucocorticoid signaling, stroke, and sleep disorders. The specific pathways affected reveal potential modifiable risk factors by lifestyle changes.

SUBMITTER: Potashkin JA

PROVIDER: S-EPMC6756555 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Computational identification of key genes that may regulate gene expression reprogramming in Alzheimer's patients.

Potashkin Judith A JA Bottero Virginie V Santiago Jose A JA Quinn James P JP

PloS one 20190923 9

The dementia epidemic is likely to expand worldwide as the aging population continues to grow. A better understanding of the molecular mechanisms that lead to dementia is expected to reveal potentially modifiable risk factors that could contribute to the development of prevention strategies. Alzheimer's disease is the most prevalent form of dementia. Currently we only partially understand some of the pathophysiological mechanisms that lead to development of the disease in aging individuals. In t ...[more]

PMID: 31545826

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Project description:BackgroundAlzheimer's disease (AD) represents profound degenerative conditions of the brain that cause significant deterioration in memory and cognitive function. Despite extensive research on the significant contribution of lipid metabolism to AD progression, the precise mechanisms remain incompletely understood. Hence, this study aimed to identify key differentially expressed lipid metabolism-related genes (DELMRGs) in AD progression.MethodsComprehensive analyses were performed to determine key DELMRGs in AD compared to controls in GSE122063 dataset from Gene Expression Omnibus. Additionally, the ssGSEA algorithm was utilized for estimating immune cell levels. Subsequently, correlations between key DELMRGs and each immune cell were calculated specifically in AD samples. The key DELMRGs expression levels were validated via two external datasets. Furthermore, gene set enrichment analysis (GSEA) was utilized for deriving associated pathways of key DELMRGs. Additionally, miRNA-TF regulatory networks of the key DELMRGs were constructed using the miRDB, NetworkAnalyst 3.0, and Cytoscape software. Finally, based on key DELMRGs, AD samples were further segmented into two subclusters via consensus clustering, and immune cell patterns and pathway differences between the two subclusters were examined.ResultsSeventy up-regulated and 100 down-regulated DELMRGs were identified. Subsequently, three key DELMRGs (DLD, PLPP2, and PLAAT4) were determined utilizing three algorithms [(i) LASSO, (ii) SVM-RFE, and (iii) random forest]. Specifically, PLPP2 and PLAAT4 were up-regulated, while DLD exhibited downregulation in AD cerebral cortex tissue. This was validated in two separate external datasets (GSE132903 and GSE33000). The AD group exhibited significantly altered immune cell composition compared to controls. In addition, GSEA identified various pathways commonly associated with three key DELMRGs. Moreover, the regulatory network of miRNA-TF for key DELMRGs was established. Finally, significant differences in immune cell levels and several pathways were identified between the two subclusters.ConclusionThis study identified DLD, PLPP2, and PLAAT4 as key DELMRGs in AD progression, providing novel insights for AD prevention/treatment.

Project description:Atherosclerotic cardiovascular disease (ASCVD) caused by atherosclerosis (AS) is one of the highest causes of mortality worldwide. Although there have been many studies on AS, its etiology remains unclear. In order to carry out molecular characterization of different types of AS, we retrieved two datasets composed of 151 AS samples and 32 normal samples from the Gene Expression Omnibus database. Using the non-negative matrix factorization (NMF) algorithm, we successfully divided the 151 AS samples into two subgroups. We then compared the molecular characteristics between the two groups using weighted gene co-expression analysis (WGCNA) and identified six key modules associated with the two subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis were used to identify the potential functions and pathways associated with the modules. In addition, we used the cytoscape software to construct and visualize protein-protein networks so as to identify key genes in the modules of interest. Three hub genes including PTGER3, GNAI1, and IGFBP5 were further screened using the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms. Since the modules were associated with immune pathways, we performed immune cell infiltration analysis. We discovered a significant difference in the level of immune cell infiltration by naïve B cells, CD8 T cells, T regulatory cells (Tregs), resting NK cells, Monocytes, Macrophages M0, Macrophages M1, and Macrophages M2 between the two subgroups. In addition, we observed the three hub genes were positively correlated with Tregs but negatively correlated with Macrophages M0. We also found that the three key genes are differentially expressed between normal and diseased tissue, as well as in the different subgroups. Receiver operating characteristic (ROC) results showed a good performance in the validation dataset. These results may provide novel insight into cellular and molecular characteristics of AS and potential markers for diagnosis and targeted therapy.

Project description:Sepsis is a life-threatening condition in which an uncontrolled inflammatory host response is triggered. The exact pathogenesis of sepsis remains unclear. The aim of the present study was to identify key genes that may aid in the diagnosis and treatment of sepsis. mRNA expression data from blood samples taken from patients with sepsis and healthy individuals was downloaded from the Gene Expression Omnibus database and differentially expressed genes (DEGs) between the two groups were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and protein‑protein interaction (PPI) network construction, was performed to investigate the function of the identified DEGs. Furthermore, for validation of these results, the expression levels of several DEGs were analyzed by reverse transcription quantitative‑polymerase chain reaction (RT‑qPCR) in three patients with sepsis and three healthy blood samples to support the results obtained from the bioinformatics analysis. Receiver operating characteristic analyses were also used to analyze the diagnostic ability of the identified DEGs for sepsis. The results demonstrated that a total of 4,402 DEGs, including 1,960 upregulated and 2,442 downregulated genes, were identified between patients with sepsis and healthy individuals. KEGG pathway analysis revealed that 39 DEGs were significantly enriched in toll‑like receptor signaling pathways. The top 20 upregulated and downregulated DEGs were used to construct the PPI network. Hub genes with high degrees, including interleukin 1 receptor‑associated kinase 3 (IRAK3), S100 calcium‑binding protein (S100)A8, angiotensin II receptor‑associated protein (AGTRAP) and S100A9, were demonstrated to be associated sepsis. Furthermore, RT‑qPCR results demonstrated that IRAK3, adrenomedullin (ADM), arachidonate 5‑lipoxygenase (ALOX5), matrix metallopeptidase 9 (MMP9) and S100A8 were significantly upregulated, while ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) was upregulated but not significantly, in blood samples from patients with sepsis compared with healthy individuals, which was consistent with bioinformatics analysis results. Therefore, AGTRAP, IRAK3, ADM, ALOX5, MMP9, S100A8 and ENTPD1 were identified to have potential diagnostic value in sepsis. In conclusion, dysregulated levels of the AGTRAP, IRAK3, ADM, ALOX5, MMP9, S100A8 and ENTPD1 genes may be involved in sepsis pathophysiology and may be utilized as potential diagnostic biomarkers or therapeutic targets.

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Computational identification of key genes that may regulate gene expression reprogramming in Alzheimer's patients.

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Computational identification of key genes that may regulate gene expression reprogramming in Alzheimer's patients.

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