ZBTB18 dysfunction promotes neuropathic pain via CHD4-based epigenetic disinhibition of CLIC1 channels in sensory neurons
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE337672 | GEO | 2026/09/02
REPOSITORIES: GEO
Similar Datasets
Project description:Nerve injury-induced alterations in trigeminal ganglion (TG) gene expression are critical for the development of neuropathic pain, yet the underlying regulatory mechanisms remain largely unknown. This study identifies a significant downregulation of ZBTB18 (zinc finger and BTB domain containing 18) in injured TG neurons following nerve injury. Restoring ZBTB18 expression alleviated nerve injury-induced mechanical allodynia, whereas its knockdown in intact TGs produces neuropathic pain symptoms. Mechanistically, ZBTB18 transcriptionally represses Clic1 by binding to a specific cis-acting silencer within the Clic1 promoter region; disruption of this binding abolished both the suppression of CLIC1 and the associated antinociceptive effects. Furthermore, ZBTB18 recruits the NuRD (nucleosome remodeling and deacetylase) complex through direct interaction between its BTB domain and CHD4. Dysfunction of this recruitment attenuates histone H3K27ac deacetylation, and enhances RNA polymerase II enrichment at the Clic1 promoter, thereby facilitating Clic1 transcription. Consequently, ZBTB18 downregulation after nerve injury led to increased CLIC1 expression and channel activity, enhancing TG neuronal excitability, while in the TG of intact rats, downregulation of ZBTB18 increased CLIC1 expression and induced mechanical hypersensitivity.
2026-09-02 | GSE310187 | GEO
Project description:Nerve injury-induced alterations in trigeminal ganglion (TG) gene expression are critical for the development of neuropathic pain, yet the underlying regulatory mechanisms remain largely unknown. This study identifies a significant downregulation of ZBTB18 (zinc finger and BTB domain containing 18) in injured TG neurons following nerve injury. Restoring ZBTB18 expression alleviated nerve injury-induced mechanical allodynia, whereas its knockdown in intact TGs produces neuropathic pain symptoms. Mechanistically, ZBTB18 transcriptionally represses Clic1 by binding to a specific cis-acting silencer within the Clic1 promoter region; disruption of this binding abolished both the suppression of CLIC1 and the associated antinociceptive effects. Furthermore, ZBTB18 recruits the NuRD (nucleosome remodeling and deacetylase) complex through direct interaction between its BTB domain and CHD4. Dysfunction of this recruitment attenuates histone H3K27ac deacetylation, and enhances RNA polymerase II enrichment at the Clic1 promoter, thereby facilitating Clic1 transcription. Consequently, ZBTB18 downregulation after nerve injury led to increased CLIC1 expression and channel activity, enhancing TG neuronal excitability, while in the TG of intact rats, downregulation of ZBTB18 increased CLIC1 expression and induced mechanical hypersensitivity.
2026-09-02 | GSE310186 | GEO
Project description:Although miRNA-mediated epigenetic regulation has been investigated as a potential therapeutic strategy for diseases, its exact functional regulatory contributions to neuropathic pain have not yet been fully elucidated. Herein, we revealed miR-323-3p as a key functional noncoding RNA in modulating trigeminal neuropathic pain. Through combined high-throughput sequencing and qPCR analysis, we revealed that miR-323-3p was most significantly upregulated in the injured trigeminal ganglion (TG). The administration of a miR-323-3p antagomir via intra-TG injection or blockade of miR-323-3p through lentiviral delivery specifically targeting neurons in injured TGs suppressed established trigeminal neuropathic pain. While miR-323-3p inhibition had no effect on inflammatory pain, local induction of miR-323-3p in naive TGs directly elicited pain hypersensitivity. Mechanistically, nerve injury caused upregulated protein expression of arginine methyltransferase 2 (PRMT2), which promotes asymmetric demethylation of H3R8 (H3R8me2a), thereby facilitating the binding of the forkhead box A2 (FOXA2) transcription factor to the miR-323-3p promoter and resulting in the upregulation of miR-323-3p expression. Furthermore, the increase in miR-323-3p expression induced significant reductions in Kv2.1 protein expression and channel currents, resulting in TG neuronal hyperexcitability. Conversely, downregulation of miR-323-3p in the injured TG reversed the decrease in Kv2.1 expression and attenuated nerve injury-induced mechanical allodynia. Thus, miR-323-3p upregulation is causally involved in the development of trigeminal neuropathic pain through the regulation of Kv2.1 channels in the TG. The mechanistic understanding of the PRMT2/FOXA2/miR-323-3p/Kv2.1 signaling axis in sensory neurons may enable the discovery of new therapeutic targets for neuropathic pain management.
2025-06-08 | GSE224814 | GEO
Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).
2014-09-29 | E-GEOD-60033 | biostudies-arrayexpress
Project description:Nerve injury-induced changes in gene expression in primary sensory neurons, such as trigeminal ganglion (TG) neurons, play a critical role in the genesis of neuropathic pain. Therefore, understanding the molecular mechanisms underlying these changes in the TGs following peripheral nerve injury will enable us to develop a new avenue for managing trigeminal-mediated neuropathic pain. Studies have highlighted the involvement of miRNA-mediated modulation in a wide range of diseases, leading to the exploration of miRNA-based therapeutics as a potential treatment strategy. Here, in this RNA-seq database, we have found that microRNA-216a-3p (miR-216a-3p) and miR-32-5p (miR-32-5p), which are downregulated in injured TGs, are novel functional RNAs involved in regulating trigeminal-mediated neuropathic pain. Histone methylation-mediated miRNA downregulation in TG neurons regulates trigeminal neuropathic pain by targeting either STIM1 (H3K27me3/SOX10/miR-216a-3p/STIM1) or Cav3.2 (GR/miR-32-5p/Cav3.2) channels. Moreover, we found that miR-323-3p exhibited the most significant upregulation in the injured TG. Understanding the mechanistic role of the PRMT2/FOXA2/miR-323-3p/Kv2.1 signaling axis in sensory neurons may advance the discovery of novel therapeutic strategies for neuropathic pain.
2025-01-08 | GSE192803 | GEO
Project description:Spinal microglia play a pivotal role in the development of neuropathic pain. Peripheral nerve injury induces changes in the transcriptional profile of microglia, including increased expression of components of translational machinery. Whether microglial protein synthesis is stimulated following nerve injury and has a functional role in mediating pain hypersensitivity is unknown. Here, we show that nascent protein synthesis is upregulated in spinal microglia following peripheral nerve injury. Stimulating mRNA translation in microglia, via selective ablation of the translational repressor, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), promoted the transition of microglia to a reactive state and induced mechanical hypersensitivity. Conversely, inhibiting microglial translation by expressing mutant 4E-BP1 in microglia attenuated their peripheral nerve injury-induced activation and alleviated neuropathic pain. Thus, the stimulation of 4E-BP1-dependent translation promotes microglia reactivity and mechanical hypersensitivity, whereas its inhibition alleviates neuropathic pain.
2024-01-31 | GSE254472 | GEO
Project description:Neuropathic pain is an apparently spontaneous experience triggered by abnormal physiology of the peripheral or central nervous system, which evolves with time. Neuropathic pain arising from peripheral nerve injury is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. There is no evidence of this type of pain in human infants or rat pups; brachial plexus avulsion, which causes intense neuropathic pain in adults, is not painful when the injury is sustained at birth. Since infants are capable of nociception from before birth and display both acute and chronic inflammatory pain behaviour from an early neonatal age, it appears that the mechanisms underlying neuropathic pain are differentially regulated over a prolonged postnatal period. We used microarrays to detail the global programme of gene expression underlying the differences in nerve injury between along the postnatal development and identified distinct classes of regulated genes during the injury Experiment Overall Design: We have performed a microarray analysis of the rat L4/L5 dorsal root ganglia, 7 days post spared nerve injury, a model of neuropathic pain. Genes that are regulated in adult rats displaying neuropathic behaviour were compared to those regulated in young rats (10 days old) that did not show the same neuropathic behaviour.
2010-01-30 | E-GEOD-15041 | biostudies-arrayexpress
Project description:Spinal microglia play a pivotal role in the development of neuropathic pain. Peripheral nerve injury induces changes in the transcriptional profile of microglia, including increased expression of components of translational machinery. Whether microglial protein synthesis is stimulated following nerve injury and has a functional role in mediating pain hypersensitivity is unknown. Here, we show that nascent protein synthesis is upregulated in spinal microglia following peripheral nerve injury in both male and female mice. Stimulating mRNA translation in microglia, by selectively ablating the translational repressor eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), promoted the transition of microglia to a reactive state and induced mechanical hypersensitivity in both sexes, whereas spontaneous pain was increased only in males. Conversely, inhibiting microglial translation by expressing a mutant form of 4E-BP1 in microglia attenuated their activation following peripheral nerve injury and alleviated neuropathic pain in both sexes. Thus, stimulating 4E-BP1-dependent translation promotes microglial reactivity and mechanical hypersensitivity, whereas inhibiting it alleviates neuropathic pain.
2025-02-25 | GSE285677 | GEO
Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries.
2014-09-29 | GSE60033 | GEO
Project description:Background: Neuropathic pain is a complex, chronic condition affecting 7% to 10% of the general population. Current neuropathic pain treatments fail to provide adequate relief in at least ~40% of patients and are usually accompanied by side effects that are sometimes severe. In this study, we investigated the effect of boldine, a natural occurring alkaloid, in attenuating peripheral nerve injury-induced neuropathic pain symptoms and transcriptomic changes. Methods: Male C57BL6 mice were subjected to chronic constriction injury (CCI) to the sciatic nerve. Customized chow containing boldine or control chow was administered right after surgery. Mechanical pain responses were assessed by Von Frey filament test. Spontaneous pain-like weight bearing behavior was measured using the dynamic weight bearing system. Spinal cords were collected at 15 days post injury and subjected to quantitative PCR and bulk RNA sequencing. Results: CCI led to ipsilateral hypersensitivity of mechanical pain responses and weight bearing deficits including reduced rearing duration, ipsilateral/contralateral weight support ratio, and ipsilateral hind paw posed duration. Boldine treatment substantially attenuated CCI-induced mechanical allodynia, but not the weight bearing deficits. Gene expression analysis showed that boldine inhibited CCI-induced upregulation of inflammatory markers in the spinal cord. RNA sequencing analysis revealed several pain-related canonical pathways and upstream factors after CCI, and boldine treatment markedly reversed these CCI-induced transcriptomic changes. Conclusions: In a mouse model of CCI, oral administration of boldine reduced nerve injury-induced mechanical allodynia and counter-regulated injury-associated transcriptomic changes in the spinal cord, possibly through regulating inflammation and immune responses.
2026-08-26 | GSE344718 | GEO