Dataset Information

Bioinformatics analysis of ferroptosis in spinal cord injury.

ABSTRACT: Ferroptosis plays a key role in aggravating the progression of spinal cord injury (SCI), but the specific mechanism remains unknown. In this study, we constructed a rat model of T10 SCI using a modified Allen method. We identified 48, 44, and 27 ferroptosis genes that were differentially expressed at 1, 3, and 7 days after SCI induction. Compared with the sham group and other SCI subgroups, the subgroup at 1 day after SCI showed increased expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 and the oxidative stress marker malondialdehyde in the injured spinal cord while glutathione in the injured spinal cord was lower. These findings with our bioinformatics results suggested that 1 day after SCI was the important period of ferroptosis progression. Bioinformatics analysis identified the following top ten hub ferroptosis genes in the subgroup at 1 day after SCI: STAT3, JUN, TLR4, ATF3, HMOX1, MAPK1, MAPK9, PTGS2, VEGFA, and RELA. Real-time polymerase chain reaction on rat spinal cord tissue confirmed that STAT3, JUN, TLR4, ATF3, HMOX1, PTGS2, and RELA mRNA levels were up-regulated and VEGFA, MAPK1 and MAPK9 mRNA levels were down-regulated. Ten potential compounds were predicted using the DSigDB database as potential drugs or molecules targeting ferroptosis to repair SCI. We also constructed a ferroptosis-related mRNA-miRNA-lncRNA network in SCI that included 66 lncRNAs, 10 miRNAs, and 12 genes. Our results help further the understanding of the mechanism underlying ferroptosis in SCI.

SUBMITTER: Li JZ

PROVIDER: S-EPMC9727440 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Bioinformatics analysis of ferroptosis in spinal cord injury.

Li Jin-Ze JZ Fan Bao-You BY Sun Tao T Wang Xiao-Xiong XX Li Jun-Jin JJ Zhang Jian-Ping JP Gu Guang-Jin GJ Shen Wen-Yuan WY Liu De-Rong DR Wei Zhi-Jian ZJ Feng Shi-Qing SQ

Neural regeneration research 20230301 3

Ferroptosis plays a key role in aggravating the progression of spinal cord injury (SCI), but the specific mechanism remains unknown. In this study, we constructed a rat model of T10 SCI using a modified Allen method. We identified 48, 44, and 27 ferroptosis genes that were differentially expressed at 1, 3, and 7 days after SCI induction. Compared with the sham group and other SCI subgroups, the subgroup at 1 day after SCI showed increased expression of the ferroptosis marker acyl-CoA synthetase ...[more]

PMID: 36018187

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Project description:Background: Spinal cord injury (SCI) is a severe neurological deficit affecting both young and older people worldwide. The potential role of key enhancer RNAs (eRNAs) in SCI remains elusive, which is a prominent challenge in the trauma repair process. This study aims to investigate the roles of key eRNAs, transcription factors (TFs), signaling pathways, and small-molecule inhibitors in SCI using multi-omics bioinformatics analysis. Methods: Microarray data of peripheral blood mononuclear cell (PBMC) samples from 27 healthy volunteers and 25 chronic-phase SCI patients were retrieved from the Gene Expression Omnibus database. Differentially expressed transcription factors (DETFs), differentially expressed enhancer RNAs (DEeRNAs), and differentially expressed target genes (DETGs) were identified using the Linear Models for Microarray Data (limma) package. Fraction of immune cells was estimated using CIBERSORT algorithm. Gene Set Variation Analysis (GSVA) was applied to identify the downstream signaling pathways. The eRNA regulatory network was constructed based on the correlation results. Connectivity Map (CMap) database was used to find potential drugs for SCI patients. The cellular communication analysis was performed to explore the molecular regulation mechanism of SCI based on single-cell RNA sequencing (scRNA-seq) data. Chromatin immunoprecipitation sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) data were used to validate the key regulatory mechanisms. scRNA-seq dataset was used to validate the cell subtype localization of the key eRNAs. Results: In total, 21 DETFs, 24 DEeRNAs, and 829 DETGs were identified. A regulatory network of 13 DETFs, six DEeRNAs, seven DETGs, two hallmark pathways, two immune cells, and six immune pathways was constructed. The link of Splicing factor proline and glutamine rich (SFPQ) (TF) and vesicular overexpressed in cancer prosurvival protein 1 (VOPP1) (eRNA) (R = 0.990, p < 0.001, positive), VOPP1 (eRNA) and epidermal growth factor receptor (EGFR) (target gene) (R = 0.974, p < 0.001, positive), VOPP1, and T helper (Th) cells (R = -0.987, p < 0.001, negative), and VOPP1 and hallmark coagulation (R = 0.937, p < 0.001, positive) was selected. Trichostatin A was considered the best compound target to SCI-related eRNAs (specificity = 0.471, p < 0.001). Conclusion: VOPP1, upregulated by SFPQ, strengthened the transient expression of EGFR. Th cells and coagulation were the potential downstream pathways of VOPP1. This regulatory network and potential inhibitors provide novel diagnostic biomarkers and therapeutic targets for SCI.

Project description:Spinal cord injury (SCI) is mostly caused by trauma. As primary mechanical injury is unavoidable in SCI, a focus on the pathophysiology and underlying molecular mechanisms of SCI-induced secondary injury is necessary to develop promising treatments for SCI patients. Circular RNAs (circRNAs) are associated with various diseases. Nevertheless, studies to date have not yet determined the functional roles of circRNAs in traumatic SCI. We examined circRNA expression profiles in the contused spinal cords of rats using microarray and quantitative reverse transcription-PCR (qRT-PCR) then predict their potential roles in post-SCI pathophysiology with bioinformatics. We found a total of 1676 differentially expressed circRNAs (fold change ≥ 2.0; P < 0.05) in spinal cord 3 days after contusion using circRNA microarray; 1261 circRNAs were significantly downregulated, whereas the remaining 415 were significantly upregulated. Then, five selected circRNAs, namely, rno_circRNA_005342, rno_circRNA_015513, rno_circRNA_002948, rno_circRNA_006096, and rno_circRNA_013017 were all significantly downregulated in the SCI group after verification by qRT-PCR, demonstrating a similar expression pattern in both microarray and PCR data. The next section of the study was concerned with the prediction of circRNA/miRNA/mRNA interactions using bioinformatics analysis. In the final part of the study, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses indicated carbohydrate metabolic process was one of the most significant enrichments and meaningful terms after GO analysis, and the top two signaling pathways affected by the circRNAs-miRNAs axes were the AMP-activated protein kinase signaling pathway and the peroxisome related pathway. In summary, this study showed an altered circRNA expression pattern that may be involved in physiological and pathological processes in rats after traumatic SCI, providing deep insights into numerous possibilities for SCI treatment targets by regulating circRNAs.

Dataset Information

Bioinformatics analysis of ferroptosis in spinal cord injury.

Publications

Bioinformatics analysis of ferroptosis in spinal cord injury.

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