2. Academic Validation
  3. H3K27 Trimethylation-Mediated Downregulation of miR-216a-3p in Sensory Neurons Regulates Neuropathic Pain Behaviors via Targeting STIM1

H3K27 Trimethylation-Mediated Downregulation of miR-216a-3p in Sensory Neurons Regulates Neuropathic Pain Behaviors via Targeting STIM1

  • J Neurosci. 2025 Jan 1;45(1):e0607242024. doi: 10.1523/JNEUROSCI.0607-24.2024.
Yufang Sun 1 2,  Yu Tao 2,  Junping Cao 3,  Yaqun Zhang 2,  Zitong Huang 2,  Shoupeng Wang 2,  Weiwei Lu 2,  Qi Zhu 2,  Lidong Shan 2,  Dongsheng Jiang 4 5,  Yuan Zhang 6 7 8,  Jin Tao 9 7 8
Affiliations

Affiliations

  • 1 Department of Geriatrics, Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
  • 2 Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Suzhou Medical College of Soochow University, Suzhou 215123, China.
  • 3 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, China.
  • 4 Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
  • 5 Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Munich 81377, Germany.
  • 6 Department of Geriatrics, Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China taoj@suda.edu.cn yuanzhang@suda.edu.cn.
  • 7 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou 215123, China.
  • 8 MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China.
  • 9 Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Suzhou Medical College of Soochow University, Suzhou 215123, China taoj@suda.edu.cn yuanzhang@suda.edu.cn.
PMID: 39592234 DOI: 10.1523/JNEUROSCI.0607-24.2024
Abstract

Although the therapeutic potential of microRNA-mediated gene regulation has been investigated, its precise functional regulatory mechanism in neuropathic pain remains incompletely understood. In this study, we elucidate that miR-216a-3p serves as a critical noncoding RNA involved in the modulation of trigeminal-mediated neuropathic pain. By conducting RNA-seq and qPCR analysis, we observed a notable decrease of miR-216a-3p in the injured trigeminal ganglia (TG) of male rats. Intra-TG administration of miR-216a-3p agomir or lentiviral-mediated overexpression of miR-216a-3p specifically in sensory neurons of injured TGs alleviated established neuropathic pain behaviors, while downregulation of miR-216a-3p (pharmacologically or genetically) in naive rats induced pain behaviors. Moreover, nerve injury significantly elevated the histone H3 lysine-27 (H3K27) trimethylation (H3K27me3) levels in the ipsilateral TG, thereby suppressing the SRY-box TF 10 (SOX10) binding to the miR-216a-3p promoter and resulting in the reduction of miR-216a-3p. Inhibiting the Enzymes responsible for catalyzing H3K27me3 restored the nerve injury-induced reduction in miR-216a-3p expression and markedly ameliorated neuropathic pain behaviors. Furthermore, miR-216a-3p targeted stromal interaction molecule 1 (STIM1), and the decreased miR-216a-3p associated with neuropathic pain caused a significant upregulation in the protein abundance of STIM1. Conversely, overexpression of miR-216a-3p in the injured TG suppressed the upregulation of STIM1 expression and reversed the mechanical allodynia. Together, the mechanistic understanding of H3K27me3-dependent SOX10/miR-216a-3p/STIM1 signaling axial in sensory neurons may facilitate the discovery of innovative therapeutic strategies for neuropathic pain management.

Keywords

histone methylation; miR-216a-3p; neuropathic pain; stromal interaction molecule 1; trigeminal ganglion neurons.

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