Epigenetic Repression of miR-216a-3p via H3K27me3 Drives STIM1-Mediated Neuronal Excitability in Neuropathic Pain

Neuropathic pain affects ∼7–10% of the global population and is notoriously resistant to conventional analgesic therapies. Elucidation of the molecular mechanisms that contribute to pain development might lead to novel treatments. Among these mechanisms, central and peripheral sensitization play prominent roles. Sensitization occurs when peripheral or central nociceptive neurons become hyperexcitable, resulting in increased responsiveness to both noxious stimuli (hyperalgesia) and non-noxious stimuli (allodynia). Peripheral sensitization arises from functional and molecular alterations in primary afferent nociceptors, often mediated by inflammatory cytokines, prostaglandins, or nerve injury. These alterations include changes in ion channel expression and function, increased peripheral synaptic transmission, and intracellular signaling cascades that amplify excitability. In contrast, central sensitization involves activity-dependent plasticity in spinal dorsal horn and supraspinal circuits, characterized by increased synaptic efficacy, receptor trafficking, intracellular signaling, and transcriptional reprogramming (Ma et al., 2024). Recent studies have highlighted the contributions of epigenetic regulation in sustaining maladaptive gene expression changes that underpin chronic pain states. Epigenetic mechanisms, such as DNA methylation, histone modification, and non-coding RNA interactions, enable heritable changes in gene expression without altering the underlying DNA sequence (Penas and Navarro, 2018). Post-translational modifications of histones—highly conserved proteins around which DNA is wrapped to form nucleosomes—modify chromatin structure and modulate transcriptional accessibility. Acetylation by histone acetyltransferases (HATs) generally promotes gene expression by loosening chromatin, whereas histone deacetylases (HDACs) reverse this effect and can repress transcription. Notably, the balance of HAT and HDAC activity influences pain-relevant gene expression (Wang et al., 2018). In contrast, histone methylation can either activate or repress transcription, depending on the specific lysine residue modified. A well-characterized repressive modification is trimethylation of histone H3 at lysine 27 (referred to asH3K27me3), catalyzed by the polycomb complex component enhancer of zeste homolog 2 (EZH2; Jiang et al., 2023 … Correspondence should be addressed to Sapphire Newman-Fogel at 19snf3{at}queensu.ca.