ALKBH5-mediated m6A modification of 5-HT3A mRNA in primary sensory neurons promotes neuropathic pain behaviors
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE226989 | GEO | 2024/01/16
REPOSITORIES: GEO
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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: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 | GSE337672 | 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 | 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:ALKBH5-mediated m6A modification of 5-HT3A mRNA in primary sensory neurons promotes neuropathic pain behaviors
| PRJNA942619 | ENA
Project description:The cerebral cortex plays a key role in the multi-dimensional human pain experience. However, the neural mechanisms mediating pain-related cortical activity remain largely unknown, particularly in primary somatosensory cortex (S1). We therefore developed a new animal model of trigeminal neuralgia, a prototypical neuropathic pain, which allowed us to evaluate pain-related cortical dynamics with unprecedented translational relevance. Our novel model (FLIT: Foramen Lacerum Impingement of Trigeminal-nerve) displayed robust clinically relevant trigeminal neuralgia-like behaviors, including asymmetric facial grimacing, dental pain-like behaviors, anxiety-like behavior, and sexual dysfunction, capturing many features of the human pain experience. Awake FLIT mice exhibited highly synchronized spontaneous population activity in S1, due to GABAergic interneuron hypoactivity. Remarkably, clinically effective treatments including carbamazepine and trigeminal nerve root decompression abrogated S1 synchronization and alleviated trigeminal neuralgia-like behaviors. These results reveal synchronized S1 activity as a new and important cortical substrate of neuropathic pain, which can be clinically targeted to provide effective therapy.
2023-02-10 | GSE162284 | GEO
Project description:Purpose: In this study, we aimed to analyze lncRNA expression in the whole transcriptome of trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) in a chronic inflammatory TMJ pain mouse model. Chronic inflammatory TMJ pain was induced by intra-TMJ injection of complete Freund's adjuvant (CFA). The lncRNA expression patterns in the whole transcriptome of TG and Sp5C were profiled with RNA sequencing.
2022-06-01 | GSE188922 | GEO
Project description:Trigeminal neuropathic pain (TNP) is one of the most debilitating forms of neuropathic pain, with its underlying mechanisms not yet fully understood. Urocortins (UCNs), a family of peptides within the corticotropin-releasing factor (CRF) family, have been implicated in various functions, including stress, anxiety, and social behaviors. In this study, we demonstrate that UCN1 in the trigeminal ganglion (TG) plays a pivotal role in partial infraorbital nerve transection (pIONT)-induced TNP in mice. pIONT induced UCN1 upregulation in large-diameter TG neurons, and silencing Ucn1 using siRNA or adeno-associated virus (AAV)-mediated shRNA effectively attenuated pIONT-induced orofacial mechanical allodynia. Furthermore, the transcription factor BTB-and-CNC homology 1 (BACH1) was identified as a direct regulator of Ucn1 expression, and knockdown of Bach1 reduced Ucn1 expression and alleviated pIONT-induced TNP. Mechanistically, pIONT increased the expression of corticotropin-releasing hormone receptor 1 (CRHR1), and intra-TG injection of UCN1 induced CRHR1-dependent mechanical allodynia, accompanied by activation of extracellular signal-regulated kinase (ERK) and cyclic-AMP responsive element binding protein (CREB), as well as upregulation of heat shock protein-1 (HSPB1). Finally, HSPB1, released from neurons via extracellular vesicles, activated satellite glial cells and macrophages through TLR2/TLR4 signaling, thereby promoting neuroinflammation. Collectively, our results suggest that BACH1-regulated UCN1 contributes to TNP by activating CRHR1/ERK/CREB/HSPB1 signaling pathway in the TG, and targeting this signaling axis may present a promising therapeutic strategy for TNP.
2026-08-05 | GSE342076 | GEO
Project description:Orofacial inflammation could lead to transcriptional alterations in the trigeminal ganglion (TG). In this study, we performed single-cell RNA-sequencing (scRNA-seq) analysis of mouse TG to identify all cell types and profile transcriptomic alterations of TG cells under inflammatory conditions. A total of 7 types of cells including endothelial cells, fibroblasts, glial cells, granulocytes, lymphocytes, monocyte-macrophages and several subtypes of neurons were identified. In addition, we performed annotation of neuronal subtypes and differential gene expression analysis among TG neurons, identifying several differential genes involved in pain modulation such as Scn10a, Zbtb20 and Runx1. Collectively, our study revealed the heterogeneity of TG cells and diverse neuronal transcriptomic responses to orofacial inflammation, which aids in the development of novel therapeutics for orofacial inflammatory pain.
2022-05-24 | GSE186421 | GEO
Project description:Neuropathic pain (NP), defined as a complex chronic pain state caused by somatosensory nervous system lesions or diseases, is currently the most challenging clinical neurological disorder in the world. The main signs and symptoms of NP include spontaneous pain, abnormal pain and hyperalgesia. It is generally believed that the specific pathological causes of NP include spinal cord or peripheral spinal cord injury, postherpetic neuralgia, trigeminal neuralgia, and tumor invasion. While the critical role of mRNA in NP is well recognized, the involvement of mRNA in the development of NP remains to be elucidated. Therefore, in this study, we explored changes in mRNA expression profiles through transcriptome sequencing to provide a landscape of mRNA dysregulation in the NP spinal cord.
2024-09-01 | GSE256472 | GEO