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Identification of the Biomarkers and Pathological Process of Heterotopic Ossification: Weighted Gene Co-Expression Network Analysis

ABSTRACT: Heterotopic ossification (HO) is the formation of abnormal mature lamellar bone in extra-skeletal sites, including soft tissues and joints, which result in high rates of disability. The understanding of the mechanism of HO is insufficient. The aim of this study was to explore biomarkers and pathological processes in HO+ samples. The gene expression profile GSE94683 was downloaded from the Gene Expression Omnibus database. Sixteen samples from nine HO- and seven HO+ subjects were analyzed. After data preprocessing, 3,529 genes were obtained for weighted gene co-expression network analysis. Highly correlated genes were divided into 13 modules. Finally, the cyan and purple modules were selected for further study. Gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment indicated that the cyan module was enriched in a variety of components, including protein binding, membrane, nucleoplasm, cytosol, poly(A) RNA binding, biosynthesis of antibiotics, carbon metabolism, endocytosis, citrate cycle, and metabolic pathways. In addition, the purple module was enriched in cytosol, mitochondrion, protein binding, structural constituent of ribosome, rRNA processing, oxidative phosphorylation, ribosome, and non-alcoholic fatty liver disease. Finally, 10 hub genes in the cyan module [actin related protein 3 (ACTR3), ADP ribosylation factor 4 (ARF4), progesterone receptor membrane component 1 (PGRMC1), ribosomal protein S23 (RPS23), mannose-6-phosphate receptor (M6PR), WD repeat domain 12 (WDR12), synaptosome associated protein 23 (SNAP23), actin related protein 2 (ACTR2), siah E3 ubiquitin protein ligase 1 (SIAH1), and glomulin (GLMN)] and 2 hub genes in the purple module [proteasome 20S subunit alpha 3 (PSMA3) and ribosomal protein S27 like (RPS27L)] were identified. Hub genes were validated through quantitative real-time polymerase chain reaction. In summary, 12 hub genes were identified in two modules that were associated with HO. These hub genes could provide new biomarkers, therapeutic ideas, and targets in HO.

SUBMITTER: Wang S

PROVIDER: S-EPMC7774600 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:PurposeIntracerebral hemorrhage (ICH) is a serious public health hazard due to its high morbidity, disability, and mortality. Currently, the exact molecular mechanisms of ICH are unknown. We tried to identify the ICH-related candidate blood messenger RNA (mRNA) biomarkers by microarray analysis and weighted gene co-expression network analysis (WGCNA).Materials and methodsWe collected the blood samples from patients with ICH (n = 4) and from vascular risk factor (VRF) controls (n = 4) and analyzed the mRNA expression profiles by competitive endogenous RNA (ceRNA) microarray. Differentially expressed genes (DEGs) were identified and then a weighted gene co-expression network was constructed. Modules with clinical significance were distinguished. Then, we downloaded two Gene Expression Omnibus (GEO) datasets (GSE24265 and GSE125512). Candidate mRNAs were identified by taking the intersection of the DEGs in our microarray, the interesting genes in the key module, and the DEGs in GSE24265. Functional analysis involving Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and construction of a protein-protein interaction (PPI) network were conducted.ResultsA total of 340 DEGs in our microarray were identified between the ICH group and the control group. Among the eight gene modules established by WGCNA, the yellow module containing 191 genes was the most strongly associated with ICH. Four candidate mRNAs (C3AR1, PAWR, ARNTL2, and LDLRAD4) were identified. In the early stage of ICH (within 24 h), C3AR1, PAWR, and ARNTL2 were highly expressed in the perihematomal tissue, but with low expressions in peripheral blood; in the late stage (72 h after the first blood draw), an obvious upward trend of C3AR1 and PAWR in peripheral blood was seen. Functional analysis showed that candidate mRNAs were concerned with multiple pathways, such as the Wnt signaling pathway and calcium signaling pathway. They might affect the process of ICH through neuroinflammation, cell apoptosis, and pyroptosis.ConclusionWe identified four candidate blood mRNAs (C3AR1, PAWR, ARNTL2, and LDLRAD4) related to ICH. They showed different expression patterns in peripheral blood and perihematomal tissues and changed with time. They might play important roles in ICH through neuroinflammation, cell apoptosis, and pyroptosis and might shed new light to novel biomarkers or therapeutic targets in ICH.

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Identification of the Biomarkers and Pathological Process of Heterotopic Ossification: Weighted Gene Co-Expression Network Analysis

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