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Epitranscriptomic Analysis of m6A Methylome After Peripheral Nerve Injury.

ABSTRACT: N6-methyladenosine (m6A) is one of the most plentiful internal RNA modifications, especially in eukaryotic messenger RNA (mRNA), which plays pivotal roles in the regulation of mRNA life cycle and nerve development. However, the mRNA m6A methylation pattern in peripheral nervous injury (PNI) has not been investigated. In this study, sciatic nerve samples were collected from 7 days after sciatic nerve injury (SNI) and control rats. Quantitative real-time PCR demonstrated that m6A-related methyltransferase/demethylase genes were remarkably upregulated in SNI group compared with control group. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to reveal the m6A methylation landscape. The results showed that 4,014 m6A peaks were significantly altered, including 2,144 upregulated and 1,870 downregulated m6A peaks, which were corresponded to 1,858 genes. Moreover, 919 differentially expressed genes were identified by the conjoint analysis of MeRIP-seq and RNA-seq. GO and KEGG pathway analyses were performed to determine the biological functions and signaling pathways of the m6A-modified genes. Notably, these genes were mainly related to the immune system process, cell activation, and nervous system development in GO analysis. KEGG pathway analysis revealed that these genes were involved in the cell cycle, B cell receptor signaling pathway, axon guidance pathway, and calcium signaling pathway. Furthermore, the m6A methylation and protein expression levels of autophagy-related gene (Atg7) were increased, together with the activation of autophagy. These findings shed some light on the epigenetic regulation of gene expression, which may provide a new opinion to promote functional recovery after PNI.

SUBMITTER: Zhang L

PROVIDER: S-EPMC8301379 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Studies have shown that microRNAs (miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is hard to select key miRNAs with essential biological functions among a large number of differentially expressed miRNAs. Previously, we collected injured sciatic nerve stumps at multiple time points after nerve crush injury, examined gene changes at different stages (acute, sub-acute, and post-acute), and obtained mRNA expression profiles. Here, we jointly analyzed mRNAs and miRNAs, and investigated upstream miRNAs of differentially expressed mRNAs using Ingenuity Pathway Analysis bioinformatic software. A total of 31, 42, 30, and 23 upstream miRNAs were identified at 1, 4, 7, and 14 days after rat sciatic nerve injury, respectively. Temporal expression patterns and biological involvement of commonly involved upstream miRNAs (miR-21, let-7, miR-223, miR-10b, miR-132, miR-15b, miR-127, miR-29a, miR-29b, and miR-9) were then determined at multiple time points. Expression levels of miR-21, miR-132, miR-29a, and miR-29b were robustly increased after sciatic nerve injury. Biological processes involving these miRNAs include multicellular organismal response to stress, positive regulation of the epidermal growth factor receptor signaling pathway, negative regulation of epithelial cell differentiation, and regulation of myocardial tissue growth. Moreover, we constructed mechanistic networks of let-7, miR-21, and miR-223, the most significantly involved upstream miRNAs. Our findings reveal that multiple upstream miRNAs (i.e., let-7, miR-21, and miR-223) were associated with gene expression changes in rat sciatic nerve stumps after nerve injury, and these miRNAs play an important role in peripheral nerve regeneration. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China (approval No. 20190303-18) on March 3, 2019.

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Epitranscriptomic Analysis of m6A Methylome After Peripheral Nerve Injury.

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