Hydroxymethylation of microRNA-365-3p Regulates Nociceptive Behaviors via Kcnh2
Hydroxymethylation of microRNA-365-3p Regulates Nociceptive Behaviors via Kcnh2
复制标题
microRNA-365-3p 的羟甲基化通过 Kcnh2 调节伤害感受行为
DOI：
10.1523/jneurosci.3474-15.2016
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发表时间：
2016-03-02
影响因子：
5.3
通讯作者：
Cao, Jun-Li
中科院分区：
文献类型：
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作者：
Pan, Zhiqiang;Zhang, Ming;Cao, Jun-Li
DNA 5-羟基甲基胞嘧啶（5HMC）由十个易位甲基二氧酶（TET）催化的DNA（5HMC）大量发生在哺乳动物的神经元中。但是，尚未建立TET失调和伤害性调节之间的体内因果关系。在这里，我们发现在福尔马林诱导的急性炎性疼痛的模型中，脊柱TET1和TET3显着增加，伴随着脊髓中全基因组5HMC含量的增强。脊柱TET1或TET3的敲低减轻了福尔马林诱导的伤害性行为和天真小鼠中脊柱TET1或TET3的过表达，从而产生了类似疼痛的行为，从而证明了降低的热疼痛阈值。此外，我们发现TET1或TET3通过靶向MicroRNA-365-3P（miR-365-3p）来调节伤害性行为。福尔马林在miR-365-3p启动子中增加了5HMC，被TET1或TET3敲低抑制，并通过天真小鼠的TET1或TET3过表达模仿。通过下调miR-365-3p的下调，福尔马林或脊柱TET1或TET3的过表达引起的伤害性行为可以预防，并通过过度表达miR-365-3p模仿。最后，我们证明了钾通道，电压门控EAG相关的亚家族H成员2（KCNH2），被验证为miR-365-3p的靶标，在脊柱TET或miR-365-3p的伤害性调节中起着至关重要的作用。我们一起得出的结论是，TET介导的miR-365-3p的羟基甲基化通过KCNH2调节伤害性行为。
DNA 5-hydroxylmethylcytosine (5hmC) catalyzed by ten-eleven translocation methylcytosine dioxygenase (TET) occurs abundantly in neurons of mammals. However, the in vivo causal link between TET dysregulation and nociceptive modulation has not been established. Here, we found that spinal TET1 and TET3 were significantly increased in the model of formalin-induced acute inflammatory pain, which was accompanied with the augment of genome-wide 5hmC content in spinal cord. Knockdown of spinal TET1 or TET3 alleviated the formalin-induced nociceptive behavior and overexpression of spinal TET1 or TET3 in naive mice produced pain-like behavior as evidenced by decreased thermal pain threshold. Furthermore, we found that TET1 or TET3 regulated the nociceptive behavior by targeting microRNA-365-3p (miR-365-3p). Formalin increased 5hmC in the miR-365-3p promoter, which was inhibited by knockdown of TET1 or TET3 and mimicked by overexpression of TET1 or TET3 in naive mice. Nociceptive behavior induced by formalin or overexpression of spinal TET1 or TET3 could be prevented by downregulation of miR-365-3p, and mimicked by overexpression of spinal miR-365-3p. Finally, we demonstrated that a potassium channel, voltage-gated eag-related subfamily H member 2 (Kcnh2), validated as a target of miR-365-3p, played a critical role in nociceptive modulation by spinal TET or miR-365-3p. Together, we concluded that TET-mediated hydroxymethylation of miR-365-3p regulates nociceptive behavior via Kcnh2. SIGNIFICANCE STATEMENT Mounting evidence indicates that epigenetic modifications in the nociceptive pathway contribute to pain processes and analgesia response. Here, we found that the increase of 5hmC content mediated by TET1 or TET3 in miR-365-3p promoter in the spinal cord is involved in nociceptive modulation through targeting a potassium channel, Kcnh2. Our study reveals a new epigenetic mechanism underlying nociceptive information processing, which may be a novel target for development of antinociceptive drugs.