Epigenetic Repression of miR-216a-3p via H3K27me3 Drives STIM1-Mediated Neuronal Excitability in Neuropathic Pain
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".