Neuron-restrictive silencer factor causes epigenetic silencing of Kv4.3 gene after peripheral nerve injury.

Peripheral nerve injury causes a variety of alterations in pain-related gene expression in primary afferent, which underlie the neuronal plasticity in neuropathic pain. One of the characteristic alterations is a long-lasting downregulation of voltage-gated potassium (K(v)) channel, including K(v)4.3, in the dorsal root ganglion (DRG). The present study showed that nerve injury reduces the messenger RNA (mRNA) expression level of K(v)4.3 gene, which contains a conserved neuron-restrictive silencer element (NRSE), a binding site for neuron-restrictive silencer factor (NRSF). Moreover, we found that injury causes an increase in direct NRSF binding to K(v)4.3-NRSE in the DRG, using chromatin immunoprecipitation (ChIP) assay. ChIP assay further revealed that acetylation of histone H4, but not H3, at K(v)4.3-NRSE is markedly reduced at day 7 post-injury. Finally, the injury-induced K(v)4.3 downregulation was significantly blocked by antisense-knockdown of NRSF. Taken together, these data suggest that nerve injury causes an epigenetic silencing of K(v)4.3 gene mediated through transcriptional suppressor NRSF in the DRG.