Contribution of DNMT1 to Neuropathic Pain Genesis Partially through Epigenetically Repressing <i>Kcna2</i> in Primary Afferent Neurons

Abstract

Expressional changes of pain-associated genes in primary sensory neurons of DRG are critical for neuropathic pain genesis. DNA methyltransferase (DNMT)-triggered DNA methylation silences gene expression. We show here that DNMT1, a canonical maintenance methyltransferase, acts as the <i>de novo</i> DNMT and is required for neuropathic pain genesis likely through repressing at least DRG <i>Kcna2</i> gene expression in male mice. Peripheral nerve injury upregulated DNMT1 expression in the injured DRG through the transcription factor cAMP response element binding protein-triggered transcriptional activation of <i>Dnmt1</i> gene. Blocking this upregulation prevented nerve injury-induced DNA methylation within the promoter and 5'-untranslated region of <i>Kcna2</i> gene, rescued <i>Kcna2</i> expression and total Kv current, attenuated hyperexcitability in the injured DRG neurons, and alleviated nerve injury-induced pain hypersensitivities. Given that <i>Kcna2</i> is a key player in neuropathic pain, our findings suggest that DRG DNMT1 may be a potential target for neuropathic pain management.<b>SIGNIFICANCE STATEMENT</b> In the present study, we reported that DNMT1, a canonical DNA maintenance methyltransferase, is upregulated via the activation of the transcription factor CREB in the injured DRG after peripheral nerve injury. This upregulation was responsible for nerve injury-induced <i>de novo</i> DNA methylation within the promoter and 5'-untranslated region of the <i>Kcna2</i> gene, reductions in <i>Kcna2</i> expression and Kv current and increases in neuronal excitability in the injured DRG. Since pharmacological inhibition or genetic knockdown of DRG DNMT1 alleviated nerve injury-induced pain hypersensitivities, DRG DNMT1 contributes to neuropathic pain genesis partially through repression of DRG <i>Kcna2</i> gene expression.