Abstract
Nerve injury induces changes in gene transcription in dorsal root ganglion (DRG) neurons, which may contribute to nerve injury-induced neuropathic pain. DNA methylation represses gene expression. Here, we report that peripheral nerve injury increases expression of the DNA methyltransferase DNMT3a in the injured DRG neurons via the activation of the transcription factor octamer transcription factor 1. Blocking this increase prevents nerve injury-induced methylation of the voltage-dependent potassium (Kv) channel subunit Kcna2 promoter region and rescues Kcna2 expression in the injured DRG and attenuates neuropathic pain. Conversely, in the absence of nerve injury, mimicking this increase reduces the Kcna2 promoter activity, diminishes Kcna2 expression, decreases Kv current, increases excitability in DRG neurons and leads to spinal cord central sensitization and neuropathic pain symptoms. These findings suggest that DNMT3a may contribute to neuropathic pain by repressing Kcna2 expression in the DRG.
Highlights
Nerve injury induces changes in gene transcription in dorsal root ganglion (DRG) neurons, which may contribute to nerve injury-induced neuropathic pain
Using double labelling for DNMT3a and NeuN or triple labelling for DNMT3a, glutamine synthetase (GS, a marker for satellite glial cells) and 40, 6-diamidino-2phenylindole (DAPI, a marker for cellular nuclei), we found that DNMT3a co-expressed with NeuN in cellular nuclei (Fig. 1a) and was not detected in the cellular nuclei of GS-labelled cells (Fig. 1b), indicating that DNMT3a is expressed exclusively in the neurons of DRG
In this study, we demonstrated that peripheral nerve injury led to an increase in DNMT3a expression through an activation of the transcription factor octamer transcription factor 1 (OCT1) in the injured DRG neurons
Summary
Nerve injury induces changes in gene transcription in dorsal root ganglion (DRG) neurons, which may contribute to nerve injury-induced neuropathic pain. We report that peripheral nerve injury increases expression of the DNA methyltransferase DNMT3a in the injured DRG neurons via the activation of the transcription factor octamer transcription factor 1. Blocking this increase prevents nerve injury-induced methylation of the voltage-dependent potassium (Kv) channel subunit Kcna promoter region and rescues Kcna expression in the injured DRG and attenuates neuropathic pain. We report here that the de novo methyltransferase DNMT3a, but not DNMT3b, is significantly increased in the injured DRG neurons after peripheral nerve injury This increase contributes to injury-induced epigenetic silencing of the Kcna gene in the DRG. Our findings indicate that transactivation of Dnmt3a mRNA and subsequent production of DNMT3a protein occur exclusively in the injured DRG neurons, in the early period post injury
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