G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons.
G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons.
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DOI：
10.1038/srep37704
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发表时间：
2016-11-22
影响因子：
4.6
通讯作者：
Tao YX
中科院分区：
文献类型：
--
作者：
Liang L;Gu X;Zhao JY;Wu S;Miao X;Xiao J;Mo K;Zhang J;Lutz BM;Bekker A;Tao YX
神经损伤引起的背根神经节（DRG）电压门控钾通道亚基Kcna 2的下调对DRG神经元兴奋性和神经病理性疼痛的发生至关重要。然而，神经损伤如何导致这种下调仍然是难以捉摸的。常染色质组蛋白-赖氨酸N-甲基转移酶2，也称为G9 a，使组蛋白H3在赖氨酸残基9上甲基化，以主要产生动态组蛋白二甲基化，导致染色质浓缩和基因转录抑制。我们发现，阻断神经损伤诱导的G9 a增加可以挽救轴突切断的DRG中Kcna 2 mRNA和蛋白的表达，并减弱神经损伤诱导的疼痛超敏反应的发展。模拟这种增加降低了Kcna 2 mRNA和蛋白表达，降低了Kv电流，并增加了DRG神经元的兴奋性，导致脊髓中枢敏化和神经性疼痛样症状。G9 a mRNA与Kcna 2 mRNA在DRG神经元中共定位。这些发现表明G9 a通过轴突切断的DRG中Kcna 2的表观遗传沉默促进神经性疼痛的发展。
Nerve injury-induced downregulation of voltage-gated potassium channel subunit Kcna2 in the dorsal root ganglion (DRG) is critical for DRG neuronal excitability and neuropathic pain genesis. However, how nerve injury causes this downregulation is still elusive. Euchromatic histone-lysine N-methyltransferase 2, also known as G9a, methylates histone H3 on lysine residue 9 to predominantly produce a dynamic histone dimethylation, resulting in condensed chromatin and gene transcriptional repression. We showed here that blocking nerve injury-induced increase in G9a rescued Kcna2 mRNA and protein expression in the axotomized DRG and attenuated the development of nerve injury-induced pain hypersensitivity. Mimicking this increase decreased Kcna2 mRNA and protein expression, reduced Kv current, and increased excitability in the DRG neurons and led to spinal cord central sensitization and neuropathic pain-like symptoms. G9a mRNA is co-localized with Kcna2 mRNA in the DRG neurons. These findings indicate that G9a contributes to neuropathic pain development through epigenetic silencing of Kcna2 in the axotomized DRG.