Identification of Epigenetic Interactions between MicroRNA-30c-5p and DNA Methyltransferases in Neuropathic Pain

• Published in: International journal of molecular sciences Vol. 23; no. 22; p. 13994
• Main Authors: Francés, Raquel, Mata-Garrido, Jorge, de la Fuente, Roberto, Carcelén, María, Lafarga, Miguel, Berciano, María Teresa, García, Raquel, Hurlé, María A, Tramullas, Mónica
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.11.2022; MDPI
• Subjects: Animals; Chromosome 5; Chronic pain; Cytokines; Deoxyribonucleic acid; DNA; DNA methylation; DNA Modification Methylases - genetics; DNMTs; Dorsal horn; Dorsal root ganglia; Epigenesis, Genetic; epigenetic; Epigenetics; Gene expression; Inhibitors; Injuries; Methylation; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-30c-5p; miRNA; Nerves; Nervous system; Neuralgia - metabolism; neuropathic pain; Pain; Pain perception; Peripheral Nerve Injuries - metabolism; Rats; Rats, Sprague-Dawley; Rodents; Sciatic nerve; Sciatic Neuropathy - genetics; Surgery; TGF-β1; Therapeutic targets; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; DNMTs; DNA methylation; miR-30c-5p; TGF-β1; neuropathic pain; epigenetic
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232213994

Neuropathic pain is a prevalent and severe chronic syndrome, often refractory to treatment, whose development and maintenance may involve epigenetic mechanisms. We previously demonstrated a causal relationship between miR-30c-5p upregulation in nociception-related neural structures and neuropathic pain in rats subjected to sciatic nerve injury. Furthermore, a short course of an miR-30c-5p inhibitor administered into the cisterna magna exerts long-lasting antiallodynic effects via a TGF-β1-mediated mechanism. Herein, we show that miR-30c-5p inhibition leads to global DNA hyper-methylation of neurons in the lumbar dorsal root ganglia and spinal dorsal horn in rats subjected to sciatic nerve injury. Specifically, the inhibition of miR-30-5p significantly increased the expression of the novo DNA methyltransferases DNMT3a and DNMT3b in those structures. Furthermore, we identified the mechanism and found that miR-30c-5p targets the mRNAs of DNMT3a and DNMT3b. Quantitative methylation analysis revealed that the promoter region of the antiallodynic cytokine TGF-β1 was hypomethylated in the spinal dorsal horn of nerve-injured rats treated with the miR-30c-5p inhibitor, while the promoter of Nfyc, the host gene of miR-30c-5p, was hypermethylated. These results are consistent with long-term protection against neuropathic pain development after nerve injury. Altogether, our results highlight the key role of miR-30c-5p in the epigenetic mechanisms' underlying neuropathic pain and provide the basis for miR-30c-5p as a therapeutic target.