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N6-Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons.
Advanced Science ( IF 14.3 ) Pub Date : 2020-05-27 , DOI: 10.1002/advs.201902402
Yize Li 1 , Xinying Guo 1 , Linlin Sun 1 , Jifang Xiao 1 , Songxue Su 2 , Shibin Du 1 , Zhen Li 1 , Shaogen Wu 1 , Weili Liu 1 , Kai Mo 1 , Shangzhou Xia 1 , Yun-Juan Chang 3 , Daniel Denis 1 , Yuan-Xiang Tao 1, 2, 4
Affiliation  

Nerve injury‐induced change in gene expression in primary sensory neurons of dorsal root ganglion (DRG) is critical for neuropathic pain genesis. N6‐methyladenosine (m6A) modification of RNA represents an additional layer of gene regulation. Here, it is reported that peripheral nerve injury increases the expression of the m6A demethylase fat‐mass and obesity‐associated proteins (FTO) in the injured DRG via the activation of Runx1, a transcription factor that binds to the Fto gene promoter. Mimicking this increase erases m6A in euchromatic histone lysine methyltransferase 2 (Ehmt2 ) 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 m6A sites in Ehmt2 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.

中文翻译:


N6-甲基腺苷脱甲基酶 FTO 通过稳定初级感觉神经元中的 G9a 表达来缓解神经性疼痛。



神经损伤引起的背根神经节(DRG)初级感觉神经元基因表达的变化对于神经病理性疼痛的发生至关重要。 RNA 的 N 6 -甲基腺苷 (m 6 A) 修饰代表了额外的基因调控层。据报道,周围神经损伤通过激活 Runx1(一种与Fto基因启动子结合的转录因子),增加受损 DRG 中 m 6 A 去甲基化酶脂肪量和肥胖相关蛋白 (FTO) 的表达。模仿这种增加会消除常染色质组蛋白赖氨酸甲基转移酶 2 ( Ehmt​​2 ) mRNA(编码组蛋白甲基转移酶 G9a)中的 m 6 A,并提高 DRG 中 G9a 的水平,并导致神经性疼痛症状。相反,阻断这种增加可逆转Ehmt2 mRNA 中 m 6 A 位点的丢失,并破坏受损 DRG 中神经损伤诱导的 G9a 上调的稳定性,并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引起的初级感觉神经元中 G9a(一种神经病理性疼痛引发剂)的上调而导致神经病理性疼痛。
更新日期:2020-07-08
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