Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (11): 2545-2552.doi: 10.4103/1673-5374.371374

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Epigenetic combined with transcriptomic analysis of the m6A methylome after spared nerve injury-induced neuropathic pain in mice

Fanning Zeng1, 2, Jun Cao1, 3, Zexuan Hong1, 2, Yitian Lu1, Zaisheng Qin1, *, Tao Tao2, *   

  1. 1Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China; 2Department of Anesthesiology, Central People’s Hospital of Zhanjiang, Zhanjiang, Guangdong Province, China; 3Department of Anesthesiology, Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong Province, China
  • Online:2023-11-15 Published:2023-05-05
  • Contact: Tao Tao, MD, taotaomzk@smu.edu.cn; Zaisheng Qin, MD, mzkqzs@smu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81973305 (to ZQ); Science and Technology Planning Project of Guangzhou of China, No. 201904010487 (to ZQ); the Natural Science Foundation of Guangdong Province, China, No. 2021A1515010897 (to TT); and the Discipline Construction Fund of Central People’s Hospital of Zhanjiang, Nos. 2020A01 (to TT) and 2020A02 (to TT).

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Abstract: Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuropathic pain. N6-methyladenosine (m6A) is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases. However, the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown. In this study, we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve. High-throughput methylated RNA immunoprecipitation sequencing results showed that after spared nerve injury, there were 55 m6A methylated and differentially expressed genes in the spinal cord. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury. Over time, the differential gene function at postoperative day 7 was enriched in “positive regulation of neurogenesis” and “positive regulation of neural precursor cell proliferation.” These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance. Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes, such as “very-low-density lipoprotein particle clearance,” “negative regulation of cholesterol transport” and “membrane lipid catabolic process.” We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling. We speculate that m6A reader enzymes also have an important role in neuropathic pain. These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at different stages after injury.

Key words: epigenetic, m6A reader, m6A, MeRIP-Seq, Nlrp1b, neuropathic pain, RNA methylation, spared nerve injury, Ythdf2