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. 2022 Mar 4:16:794342.
doi: 10.3389/fninf.2022.794342. eCollection 2022.

The Involvement of Long Non-coding RNA and Messenger RNA Based Molecular Networks and Pathways in the Subacute Phase of Traumatic Brain Injury in Adult Mice

Zhaoyu Yang  1   2 , Xuexuan Li  1   2 , Weikang Luo  1   2 , Yao Wu  1   2 , Tao Tang  1   2 , Yang Wang  1   2
Affiliations

The Involvement of Long Non-coding RNA and Messenger RNA Based Molecular Networks and Pathways in the Subacute Phase of Traumatic Brain Injury in Adult Mice

Zhaoyu Yang et al. Front Neuroinform. .

Abstract

Traumatic brain injury (TBI) is a complex injury with a multi-faceted recovery process. Long non-coding RNAs (lncRNAs) are demonstrated to be involved in central nervous system (CNS) disorders. However, the roles of lncRNAs in long-term neurological deficits post-TBI are poorly understood. The present study depicted the microarray's lncRNA and messenger RNA (mRNA) profiles at 14 days in TBI mice hippocampi. LncRNA and mRNA microarray was used to identify differentially expressed genes. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the microarray results. Bioinformatics analysis [including Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, lncRNA-mRNA co-expression network, and lncRNA-miRNA-mRNA network] were applied to explore the underlying mechanism. A total of 264 differentially expressed lncRNAs and 232 expressed mRNAs were identified (fold change > 1.5 and P-value < 0.05). Altered genes were enriched in inflammation, immune response, blood-brain barrier, glutamatergic neurological effects, and neuroactive ligand-receptor, which may be associated with TBI-induced pathophysiologic changes in the long-term neurological deficits. The lncRNAs-mRNAs co-expression network was generated for 74 lncRNA-mRNA pairs, most of which are positive correlations. The lncRNA-miRNA-mRNA interaction network included 12 lncRNAs, 59 miRNAs, and 25 mRNAs. Numerous significantly altered lncRNAs and mRNAs in mice hippocampi were enriched in inflammation and immune response. Furthermore, these dysregulated lncRNAs and mRNAs may be promising therapeutic targets to overcome obstacles in long-term recovery following TBI.

Keywords: immune response; inflammation; lncRNA and mRNA microarray; subacute phase; traumatic brain injury.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Traumatic brain injury (TBI)-induced neurological and brain tissue deficits. (A) Overview of experimental design and timeline for the experiment. Neurological deficits were evaluated with the modified neurological score (mNSS) and corner turn test from day 0 to day 14. The hippocampus was obtained on day 14. Using Modified neurological severity score (mNSS) test (B) and corner turn test (C) assess the neurological function of sham and TBI groups. The data are displayed as the mean ± SD, n = 5 per group. **P < 0.01, two-way ANOVA and two-tailed unpaired Student’s t-test. (D) The pathological analysis of sham and TBI groups (scar bar = 1,000 μm).
FIGURE 2
FIGURE 2
Expression profiles of DE lncRNAs and mRNAs in TBI and sham groups. Volcano maps of differentially expressed lncRNAs (A) and mRNAs (B). The x- and y-axes have values of log2 (fold change) and -log10 (P-value). With a fold change > 1.5 and a P-value < 0.05, red/blue dots indicate statistically considerable differentially expressed lncRNAs and mRNAs (red depicts elevated expression while blue indicates decreased expression). No differentially expressed lncRNAs and mRNAs are indicated by gray dots. The hierarchical cluster analysis generated heat maps of DE lncRNAs (C) and mRNAs (D) (fold change > 1.5 and P < 0.05). DE, differentially expressed.
FIGURE 3
FIGURE 3
Validation of different expressed mRNAs and lncRNAs. The data are defined as the mean ± SD, n = 5 per group. **P < 0.01, One-way ANOVA, and two-tailed unpaired Student’s t-test.
FIGURE 4
FIGURE 4
GO cluster plot showing a chord dendrogram of clustering of the expression spectrum of significantly DE genes. DE, differentially expressed; GO, Gene Ontology.
FIGURE 5
FIGURE 5
The KEGG enrichment analysis of up-regulated genes. The y-axis represents KEGG-enriched terms. The x-axis represents the Gene Ratio. The dot size stands for the number of genes under a specific time. The color of the dots represents the P-value. The left cluster plot shows a chord dendrogram of clustering the expression spectrum of significantly DE genes. DE, differentially expressed; KEGG, Kyoto Encyclopedia of Genes and Genomes.
FIGURE 6
FIGURE 6
The KEGG enrichment analysis of down-regulated genes. The y-axis represents KEGG-enriched terms. The x-axis represents the Gene Ratio. The size of the dot demonstrates the number of genes under a specific term. The color of the dots represents the P-value. The left cluster plot shows a chord dendrogram of clustering the expression spectrum of significantly DE genes. DE, differentially expressed; KEGG, Kyoto Encyclopedia of Genes and Genomes.
FIGURE 7
FIGURE 7
Co-expression network analysis. Red nodes represent lncRNAs; purple nodes represent mRNAs. A positive correlation is solid lines; a negative correlation is dashed lines.
FIGURE 8
FIGURE 8
GO and KEGG pathway analyses based on the CNC network. The x-axis represents the number of genes. The color of the bars depicts the P-value. GO, Gene Ontology. KEGG, Kyoto Encyclopedia of Genes and Genomes.
FIGURE 9
FIGURE 9
The ceRNA network between lncRNAs, mRNAs, and predicted miRNAs. Purple nodes, lncRNAs; green nodes, mRNAs; Pink nodes, miRNA.
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References

    1. Ang C. E., Trevino A. E., Chang H. Y. (2020). Diverse lncRNA mechanisms in brain development and disease. Curr. Opin. Genet. Dev. 65 42–46. 10.1016/j.gde.2020.05.006 - DOI - PubMed
    1. Atkins C. M., Oliva A. A., Jr., Alonso O. F., Pearse D. D., Bramlett H. M., Dietrich W. D. (2007). Modulation of the cAMP signaling pathway after traumatic brain injury. Exp. Neurol. 208 145–158. 10.1016/j.expneurol.2007.08.011 - DOI - PMC - PubMed
    1. Banoei M. M., Casault C., Metwaly S. M., Winston B. W. (2018). Metabolomics and biomarker discovery in traumatic brain injury. J. Neurotrauma 35 1831–1848. 10.1089/neu.2017.5326 - DOI - PubMed
    1. Barha C. K., Ishrat T., Epp J. R., Galea L. A., Stein D. G. (2011). Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury. Exp. Neurol. 231 72–81. 10.1016/j.expneurol.2011.05.016 - DOI - PMC - PubMed
    1. Birney E., Stamatoyannopoulos J. A., Dutta A., Guigó R., Gingeras T. R., Margulies E. H., et al. (2007). Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447 799–816. 10.1038/nature05874 - DOI - PMC - PubMed

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