Li Yize, Guo Xinying, Sun Linlin, Xiao Jifang, Su Songxue, Du Shibin, Li Zhen, Wu Shaogen, Liu Weili, Mo Kai, Xia Shangzhou, Chang Yun-Juan, Denis Daniel, Tao Yuan-Xiang
Department of Anesthesiology New Jersey Medical School, Rutgers The State University of New Jersey 185 S. Orange Ave., MSB E594 Newark NJ 07103 USA.
Department of Physiology, Pharmacology & Neuroscience New Jersey Medical School, Rutgers The State University of New Jersey 185 S. Orange Ave., MSB E661 Newark NJ 07103 USA.
Adv Sci (Weinh). 2020 May 27;7(13):1902402. doi: 10.1002/advs.201902402. eCollection 2020 Jul.
Nerve injury-induced change in gene expression in primary sensory neurons of dorsal root ganglion (DRG) is critical for neuropathic pain genesis. N-methyladenosine (mA) modification of RNA represents an additional layer of gene regulation. Here, it is reported that peripheral nerve injury increases the expression of the mA demethylase fat-mass and obesity-associated proteins (FTO) in the injured DRG via the activation of Runx1, a transcription factor that binds to the gene promoter. Mimicking this increase erases mA in euchromatic histone lysine methyltransferase 2 () mRNA (encoding the histone methyltransferase G9a) and elevates the level of G9a in DRG and leads to neuropathic pain symptoms. Conversely, blocking this increase reverses a loss of mA sites in mRNA and destabilizes the nerve injury-induced G9a upregulation in the injured DRG and alleviates nerve injury-associated pain hypersensitivities. FTO contributes to neuropathic pain likely through stabilizing nerve injury-induced upregulation of G9a, a neuropathic pain initiator, in primary sensory neurons.
神经损伤诱导的背根神经节（DRG）初级感觉神经元基因表达变化对于神经性疼痛的发生至关重要。RNA的N-甲基腺苷（mA）修饰代表了基因调控的另一个层面。在此报告中，外周神经损伤通过激活Runx1（一种与基因启动子结合的转录因子）增加了损伤的DRG中mA去甲基化酶脂肪量和肥胖相关蛋白（FTO）的表达。模拟这种增加会消除常染色质组蛋白赖氨酸甲基转移酶2（）mRNA（编码组蛋白甲基转移酶G9a）中的mA，并提高DRG中G9a的水平，导致神经性疼痛症状。相反，阻断这种增加会逆转mRNA中mA位点的丢失，并使损伤的DRG中神经损伤诱导的G9a上调不稳定，减轻神经损伤相关的疼痛超敏反应。FTO可能通过稳定神经损伤诱导的初级感觉神经元中神经性疼痛引发剂G9a的上调来促成神经性疼痛。
