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Transcriptome sequencing reveals key role of ceRNA in regulating inflammation response after intracerebral hemorrhage
Na Hu1, Yufang Yan2, Leihong Deng3
1Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China.
Insights
This study reveals competing endogenous RNA networks in human intracerebral hemorrhage (ICH), identifying the NORAD/miR-924-5p/MAPK10 axis as a key regulator of neuroinflammation and a potential therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genomics
Background:
- Intracerebral hemorrhage (ICH) causes significant mortality and disability.
- Secondary inflammatory injury critically impacts ICH outcomes.
- Regulatory mechanisms of neuroinflammation, especially competing endogenous RNA (ceRNA) networks, are poorly understood.
Purpose of the Study:
- To comprehensively characterize ceRNA networks in human ICH.
- To identify key pathways and interactions driving post-ICH neuroinflammation.
- To uncover potential therapeutic targets for mitigating neuroinflammation.
Main Methods:
- Total RNA sequencing on human ICH and control brain tissues.
- Bioinformatics analysis including differential expression, functional enrichment, and ceRNA network construction.
- Experimental validation using qPCR, FISH, and luciferase reporter assays in microglia.
Main Results:
- Identified 3789 differentially expressed genes, including 1288 lncRNAs and 394 miRNAs.
- Revealed enrichment in immune response and neuronal pathways.
- Confirmed the NORAD/miR-924-5p/MAPK10 ceRNA axis, with NORAD and MAPK10 downregulated and miR-924-5p upregulated in ICH.
Conclusions:
- ceRNA-mediated regulatory networks are implicated in human ICH pathogenesis.
- The NORAD/miR-924-5p/MAPK10 axis is a critical player in post-hemorrhagic neuroinflammation.
- This axis represents a promising therapeutic target for managing ICH-induced inflammation.
Abstract:
Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high mortality and disability rates. The secondary inflammatory injury is a critical determinant of clinical outcomes, yet its regulatory mechanisms, particularly those involving competing endogenous RNA (ceRNA) networks, remain poorly understood. This study aimed to comprehensively characterize the ceRNA networks to identify key pathways and interactions driving neuroinflammation post-ICH. Total RNA sequencing was performed on brain tissues from three ICH patients and three surgical controls. Differential expression analysis identified significantly altered lncRNAs, miRNAs, and mRNAs. Bioinformatics approaches including functional enrichment analysis, co-expression network construction, and miRNA-target prediction were employed to elucidate potential biological functions and interactions. A stringent computational pipeline integrating multiple prediction tools and expression correlations was used to construct the ceRNA network. Key findings were validated using quantitative real-time PCR, fluorescence in situ hybridization, and luciferase reporter assays in primary microglia. RNA-seq analysis revealed 3789 differentially expressed genes, including 1288 lncRNAs and 394 miRNAs. Functional annotation showed enrichment in immune response pathways (TNF signaling, cytokine-cytokine interaction) among upregulated genes and neuronal processes (axon development, synaptic transmission) among downregulated genes. Integration of these findings revealed three significant pathways-TNF signaling, glutamatergic synapse, and Rap1 signaling-within the ceRNA network. Experimental validation confirmed the NORAD/miR-924-5p/MAPK10 ceRNA axis, showing NORAD and MAPK10 downregulation and miR-924-5p upregulation in ICH. In all, this study reveals ceRNA-mediated regulatory networks in human ICH, highlighting the NORAD/miR-924-5p/MAPK10 axis as a potential therapeutic target for modulating post-hemorrhagic inflammation.
