Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Neuroscience. 2010 Mar 10;166(1):1-4. doi: 10.1016/j.neuroscience.2009.12.021. Epub 2009 Dec 13.
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.
周围神经损伤导致初级传入神经元中与疼痛相关的基因表达发生多种改变，这是神经性疼痛神经元可塑性的基础。其中一个特征性改变是背根神经节（DRG）中电压门控钾（Kv）通道（包括 Kv4.3）的长期下调。本研究表明，神经损伤降低了包含保守的神经元限制沉默元件（NRSE）的 Kv4.3 基因的信使 RNA（mRNA）表达水平，该元件是神经元限制沉默因子（NRSF）的结合位点。此外，我们发现，使用染色质免疫沉淀（ChIP）分析，损伤导致 DRG 中 K(v)4.3-NRSE 与 NRSF 的直接结合增加。ChIP 分析进一步表明，K(v)4.3-NRSE 处的组蛋白 H4 乙酰化，而不是 H3，在损伤后 7 天明显减少。最后，通过 NRSF 的反义敲低，显著阻断了损伤诱导的 Kv4.3 下调。总之，这些数据表明，神经损伤通过 DRG 中的转录抑制因子 NRSF 引起 K(v)4.3 基因的表观遗传沉默。
