Dataset Information

Gene Regulatory Network Analysis of Perivascular Adipose Tissue of Abdominal Aortic Aneurysm Identifies Master Regulators of Key Pathogenetic Pathways.

ABSTRACT: The lack of medical therapy to treat abdominal aortic aneurysm (AAA) stems from our inadequate understanding of the mechanisms underlying AAA pathogenesis. To date, the only available treatment option relies on surgical intervention, which aims to prevent AAA rupture. Identifying specific regulators of pivotal pathogenetic mechanisms would allow the development of novel treatments. With this work, we sought to identify regulatory factors associated with co-expressed genes characterizing the diseased perivascular adipose tissue (PVAT) of AAA patients, which is crucially involved in AAA pathogenesis. We applied a reverse engineering approach to identify cis-regulatory elements of diseased PVAT genes, the associated transcription factors, and upstream regulators. Finally, by analyzing the topological properties of the reconstructed regulatory disease network, we prioritized putative targets for AAA interference treatment options. Overall, we identified NFKB1, SPIB, and TBP as the most relevant transcription factors, as well as MAPK1 and GSKB3 protein kinases and RXRA nuclear receptor as key upstream regulators. We showed that these factors could regulate different co-expressed gene subsets in AAA PVAT, specifically associated with both innate and antigen-driven immune response pathways. Inhibition of these factors may represent a novel option for the development of efficient immunomodulatory strategies to treat AAA.

SUBMITTER: Piacentini L

PROVIDER: S-EPMC7459520 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Gene Regulatory Network Analysis of Perivascular Adipose Tissue of Abdominal Aortic Aneurysm Identifies Master Regulators of Key Pathogenetic Pathways.

Piacentini Luca L Chiesa Mattia M Colombo Gualtiero Ivanoe GI

Biomedicines 20200814 8

The lack of medical therapy to treat abdominal aortic aneurysm (AAA) stems from our inadequate understanding of the mechanisms underlying AAA pathogenesis. To date, the only available treatment option relies on surgical intervention, which aims to prevent AAA rupture. Identifying specific regulators of pivotal pathogenetic mechanisms would allow the development of novel treatments. With this work, we sought to identify regulatory factors associated with co-expressed genes characterizing the dise ...[more]

PMID: 32823940

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Project description:Objective: Abdominal aortic aneurysm (AAA) refers to unusual permanent dilation of the abdominal aorta, and gradual AAA expansion can lead to fatal rupture. However, we lack clear understanding of the pathogenesis of this disease. The effect of perivascular adipose tissue (PVAT) on vascular functional status has attracted increasing attention. Here, we try to identify the potential mechanisms linking AAA and PVAT. Methods: We downloaded dataset GSE119717, including 30 dilated AAA PVAT samples and 30 non-dilated aorta PVAT samples from AAA cases, from Gene Expression Omnibus to identify differentially expressed genes (DEGs). We performed pathway enrichment analysis by Metascape, ClueGo and DAVID to annotate PVAT functional status according to the DEGs. A protein-protein interaction network, the support vector machine (SVM)-recursive feature elimination and the least absolute shrinkage and selection operator regression model were constructed to identify feature genes. Immune infiltration analysis was explored by CIBERSORT. And the correlation between feature gene and immune cells was also calculated. Finally, we used the angiotensin II (Ang II)-ApoE-/- mouse model of AAA to verify the effect of feature gene expression by confirming protein expression using immunohistochemistry and western blot. Results: We identified 22 DEGs, including 21 upregulated genes and 1 downregulated gene. The DEGs were mainly enriched in neutrophil chemotaxis and IL-17 signaling pathway. FOS was identified as a good diagnostic feature gene (AUC = 0.964). Immune infiltration analysis showed a higher level of T cells follicular helper, activated NK cells, Monocytes, activated Mast cells in AAA group. And FOS was correlated with immune cells. Immunohistochemistry and western blot confirmed higher FOS expression in PVAT of the AAA mouse model compared to control group. Conclusion: The differentially expressed genes and pathways identified in this study provide further understanding of how PVAT affects AAA development. FOS was identified as the diagnostic gene. There was an obvious difference in immune cells infiltration between normal and AAA groups.

Project description:BackgroundAberrant expression of N6-methyladenosine (m6A) RNA modification regulators plays a critical role in a variety of human diseases. However, their implication in abdominal aortic aneurysm (AAA) remains largely unknown. Herein, we sought to explore the general expression pattern and potential functions of m6A regulators in AAA.MethodsWe analyzed gene expression data of m6A regulators in human AAA and normal tissues from public GEO database. The R package and other tools such as m6A2Target database, Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses, gene set variation analysis (GSVA), Search Tool for the Retrieval of Interacting Genes (STRING), starBase, miRDB and Cytoscape software were applied for bioinformatics analysis to investigate the downstream molecular mechanisms and upstream regulatory mechanisms for distinctly expressed regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to validate the expression of key m6A regulators in our collected human AAA specimens.ResultsWe found that METTL14 and HNRNPC were the downregulated m6A regulators, and RBM15B was the upregulated methylation transferase in human AAA. The modified genes were primarily enriched in RNA catabolic process, regulation of translation, focal adhesion, transcription coregulator activity, ribosome, RNA transport, cell cycle, et al. METTL14, HNRNPC and RBM15B levels were correlated with the immune infiltration degree of Tcm, macrophages, mast cells, Tgd and NK CD56bright cells. A total of 154 and 76 target genes of three regulators were separately involved in body metabolism and autophagy in AAA disease, and their interactive relationships and hub genes were identified. The lncRNA-miRNA-mRNA interaction regulatory networks were also constructed for METTL14, HNRNPC and RBM15B. Based on our clinical tissue and serum samples, METTL14 exhibited lower expression levels in AAA and its rupture type, and low METTL14 expression was associated with high levels of WBC and CRP (all P < 0.05).ConclusionOur study presents an overview of the expression pattern and functional significance of m6A regulators in human AAA. Our findings will provide a valuable resource that may guide both mechanistic and therapeutic analyses about the role of key m6A regulators in AAA.

Project description:BackgroundWith a mortality rate of 65-85%, a ruptured abdominal aortic aneurysm (AAA) can have catastrophic consequences for patients. However, few effective pharmaceutical treatments are available to treat this condition. Therefore, elucidating the pathogenesis of AAA and finding the potential molecular targets for medical therapies are vital lines of research.MethodsAn mRNA microarray dataset of perivascular adipose tissue (PVAT) in AAA patients was downloaded and differentially expressed gene (DEG) screening was performed. Weighted gene co-expression networks for dilated and non-dilated PVAT samples were constructed via weighted correlation network analysis (WGCNA) and used to detect gene modules. Functional annotation analysis was performed for the DEGs and gene modules. We identified the hub genes of the modules and created a DEG co-expression network. We then mined crucial genes based on this network using Molecular Complex Detection (MCODE) in Cytoscape. Crucial genes with top-6 degree in the crucial gene cluster were visualized, and their potential clinical significance was determined.ResultsOf the 173 DEGs screened, 99 were upregulated and 74 were downregulated. Co-expression networks were built and we detected 6 and 5 modules for dilated and non-dilated PVAT samples, respectively. The turquoise and black modules for dilated PVAT samples were related to inflammation and immune response. MAP4K1 and PROK2 were the hub genes of these 2 modules, respectively. Then a DEG co-expression network with 112 nodes and 953 edges was created. PLAU was the crucial gene with the highest connectivity and showed potential clinical significance.ConclusionsUsing WGCNA, gene modules were detected and hub genes and crucial genes were identified. These crucial genes might be potential targets for pharmaceutic therapies and have potential clinical significance. Future in vitro and in vivo experiments are required to more comprehensively explore the biological mechanisms by which these genes affect AAA pathogenesis.

Dataset Information

Gene Regulatory Network Analysis of Perivascular Adipose Tissue of Abdominal Aortic Aneurysm Identifies Master Regulators of Key Pathogenetic Pathways.

Publications

Gene Regulatory Network Analysis of Perivascular Adipose Tissue of Abdominal Aortic Aneurysm Identifies Master Regulators of Key Pathogenetic Pathways.

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