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Nociceptor HDAC4 regulates inflammatory pain

ABSTRACT: Transcriptional alterations are characteristic of persistent pain states but the key regulators remain elusive. Using a conditional knockout (cKO) strategy in mice we sought to determine whether loss of the transcriptional co-repressor histone deacetylase four (HDAC4) would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely dispensable for transcriptional regulation of naïve sensory neurons but was required for transcriptional responses after injury, with Calca and Trpv1 expression consistently downregulated in HDAC4 cKO compared to littermate controls (0.2-0.44 fold). This downregulation corresponded to reduced sensitivity to capsaicin in vitro (76% +/- 4.4% wildtype capsaicin responders vs 56.9% +/- 4.7% cKO responders) and to reduced thermal hypersensitivity in the complete Freund’s adjuvant model of inflammatory pain (1.3-1.4 fold improvement). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors.

ORGANISM(S): Mus musculus

PROVIDER: GSE62405 | GEO | 2015/04/23

SECONDARY ACCESSION(S): PRJNA264050

REPOSITORIES: GEO

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Nociceptor HDAC4 regulates inflammatory pain

Project description:Transcriptional alterations are characteristic of persistent pain states but the key regulators remain elusive. Using a conditional knockout (cKO) strategy in mice we sought to determine whether loss of the transcriptional co-repressor histone deacetylase four (HDAC4) would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely dispensable for transcriptional regulation of naïve sensory neurons but was required for transcriptional responses after injury, with Calca and Trpv1 expression consistently downregulated in HDAC4 cKO compared to littermate controls (0.2-0.44 fold). This downregulation corresponded to reduced sensitivity to capsaicin in vitro (76% +/- 4.4% wildtype capsaicin responders vs 56.9% +/- 4.7% cKO responders) and to reduced thermal hypersensitivity in the complete Freund’s adjuvant model of inflammatory pain (1.3-1.4 fold improvement). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors. Total RNA was extracted from HDAC4 cKO and HDAC4 fl/fl naïve adult lumbar dorsal root ganglia (n=3/group). mRNA expression was compared using Affymetrix Mouse Gene Arrays (Mouse Gene 2.0ST) run on a GeneChip Fluidics Station 450. Chips were scanned on an Affymetrix GeneChip Scanner.

2015-04-23 | E-GEOD-62405 | biostudies-arrayexpress

Mus musculus

Project description:Nociceptor HDAC4 regulates inflammatory pain

| PRJNA264050 | ENA

NOCICEPTRA: Gene and microRNA signatures and their trajectories characterizing human iPSC-derived nociceptor maturation

Project description:Nociceptors are specialized sensory neurons implicated in the reception and transduction of painful stimuli. Many pain disorders directly affect nociceptors but mechanistic insight into underlying pathway regulations is limited by the translational paresis from animal models to human pain disorders. Although transcriptomic data are available for rodent and post-mortem patient samples, no comprehensive transcriptomic data are currently available for human nociceptor development. Here, we performed paired long and small RNA sequencing for six timepoints during nociceptor differentiation from three different human iPSC cell lines. Complex bioinformatics analyses for differential gene expression, protein-protein interactions and mRNA targeting by microRNAs revealed five distinct differentiation stages with critical hub genes and microRNAs guiding nociceptor development. The online resource platform NOCICEPTRA was specifically developed to visualize respective mRNA and microRNA trajectories, as well as query disease specific pathways, thereby enabling researchers to determine susceptibility windows for nociceptor-associated disorders as well as possible new treatment targets.

2021-09-06 | GSE161530 | GEO

Transcriptomic analysis of adult mouse spinal cord tissue in the control of HDAC4 during inflammatory pain

Project description:The goal of this study was to evaluate the role of HDAC4 in spinal sensitization. We analyzed gene expression changes associated with the subcellular localization of HDAC4 in the spinal cord dorsal horn following CFA-induced inflammatory pain. The analysis was performed in basal conditions and after intraplantar injection of CFA to the hind paw of mice that received intraspinal injection of rAAV-constructs influencing the subcellular localization of HDAC4.

2021-12-31 | GSE159895 | GEO

Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain [SmartSeq2]

Project description:Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

2021-01-27 | GSE165553 | GEO

Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain [Wafergen]

2021-01-27 | GSE165566 | GEO

Expression of receptors for inflammatory mediators in murine vagal nodose versus jugular capsaicin-sensitive (Trpv1-positive) C-fiber neurons

Project description:Capsaicin-sensitive (Trpv1-positive) sensory C-fibers derived from vagal ganglia innervate the visceral organs, and respond to inflammatory mediators and noxious stimuli. These neurons play an important role in maintenance of visceral homeostasis, and contribute to the symptoms of visceral inflammatory diseases. Vagal sensory neurons are located in two ganglia, the jugular ganglia (derived from the neural crest), and the nodose ganglia (from the epibranchial placodes). The functional difference, especially in response to immune mediators, between jugular and nodose neurons is not fully understood. In this study, we microscopically isolated murine nodose and jugular capsaicin-sensitive / Trpv1-expressing C-fiber neurons and performed transcriptome profiling using ultra-low input RNA sequencing.

2017-10-01 | GSE102123 | GEO

WT vs Hypomethylated DRG Gene Expression

Project description:Although DNA methylation plays a critical role in the development and function of mammalian central nervous system (CNS), its role in peripheral neurons has not been elucidated. To address this issue, we produced conditional knockout mice (CKO) specifically deleting the gene for maintenance DNA methyltransferase 1 (Dnmt1) during the development of neural crest cells. Despite global hypomethylation in the embryonic dorsal root ganglion (DRG) of the CKO mice, the number of sensory neurons was relatively unaffected. However, expression of many genes required for sensory neuron development was altered in embryonic mutant DRG, including down-regulation of Runx1 and TrkA genes as well as up-regulation of Id1 and Dtx1, two negative regulators for neurogenesis. Accompanied with the downregulation of an NGF receptor TrkA, the peripheral axonal projection and the branching of sensory neurons were impaired. Furthermore, the expression of the neuropeptide Galanin and several vanilloid receptors such as TrpV1 and TrpM8 were not detected in the DRG of the CKO mice during late embryonic and neonatal stages, suggesting that DNA methylation regulates the differentiation program for a subset of nociceptive sensory neurons. Taken together, our findings suggest that through transcriptional regulation of key developmental genes in sensory neurons, DNA methylation play a key role in the control of the axonal projection and fate specification of peripheral sensory neurons. We compared gene expression patterns in Wildtype and DNA methylation deficient (Wnt1-cre; Dnmt1 mutant) mouse dorsal cortex. We performed 4 replicates using different each individual mouse strain. The Sample GSM565172 table is the average log ratio for the 4 replicatesArrays were performed.

2011-12-01 | E-GEOD-23530 | biostudies-arrayexpress

Nociceptor translational profiling reveals the RagA-mTORC1 network as a critical generator of neuropathic pain

Project description:Pain sensing neurons, nociceptors, are key drivers of neuropathic pain. We used translating ribosome affinity purification (trap) to comprehensively characterize up- and down-regulated mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain. We provide evidence that an underlying mechanism driving these changes in gene expression is a sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling, demonstrating a new link between these distinct signaling pathways. Neuropathic pain and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We reveal a novel translational circuit for the genesis of neuropathic pain with important implications for next generation neuropathic pain therapeutics.

2018-08-01 | GSE113941 | GEO

Nociceptor differentiation from pluripotent cells

Project description:Here we performed the first combinatorial small molecule screen for the rapid conversion of hPSCs into postmitotic neurons. We identified a combination of five small molecule pathway inhibitors sufficient to yield neurons at > 75% efficiency within 10 days of differentiation in the absence of any recombinant growth factors. The resulting human neurons express canonical markers of nociceptive sensory fate. Two treatments (LSB and 3i) at days 2,3,5,7,9, and 15, in triplicate

2011-04-01 | E-GEOD-26867 | biostudies-arrayexpress

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