Tao Yuanxiang revealed a new mechanism for RNA methylation modification to participate in neuropathic pain.

Neuropathic pain caused by neurologic injury is a chronic and refractory disease. In the United States alone, more than 6 million people suffer from neuropathic pain for a long time every year.due to the poor efficacy of current drugs (such as opioids and non steroidal anti-inflammatory drugs) in most patients with neuropathic pain, it is urgent to explore new pathogenesis and develop new treatment methods.peripheral nerve injury causes changes in the expression of pain related genes in the primary sensory neurons of the dorsal root ganglion (DRG) at the transcription and translation levels. These changes have been confirmed to be related to the development and maintenance of neuropathic pain.further study on how peripheral nerve injury leads to changes in the expression of these pain related genes in DRG may provide a new way for the treatment of neuropathic pain.recent studies have shown that RNA methylation plays an important role in the regulation of gene expression [1].Tao Yuanxiang, Department of Anesthesiology, Rutgers University, New Jersey State Medical College, USA, published on May 27, 2020 an online issue entitled N6 methyladenosine demethylase FTO contributions to neuropathic pain by stabilizing G9a expression in primary sensor Neurons (N6 methyladenosine demethylase FTO participates in neuropathic pain by stabilizing G9a expression in primary sensory neurons).this study used a variety of techniques to elucidate for the first time the role of RNA methylation modification in neuropathic pain at different levels from molecular, cellular and animal levels.firstly, the expression of RNA m6A demethylase FTO was relatively low in normal DRG neurons.after peripheral nerve injury, the expression of FTO in DRG increased significantly, while the expression of other RNA methyltransferases and related molecules (mettl3, mettl14 and wtap), demethylase (alkbh5) and RNA m6A binding protein (ythdf2) did not change significantly.the increased expression of FTO may be due to the activation of Runx1, a transcription factor in DRG neurons, which is bound to the promoter region of FTO gene to promote its up-regulation.one of the main functions of FTO is to remove m6A from RNA.in this study, we used the m6A eclip sequencing technology to find that about 56% of the RNA in DRG neurons after nerve injury showed the loss of m6A site.among them, the loss of m6A on the mRNA of one histone lysine N-methyltransferase 2 (EHMT2) was the most obvious.EHMT2 mRNA encodes G9a protein and participates in the down regulation of pain related genes such as opioid receptor and voltage-dependent potassium channel on the membrane of DRG neurons caused by nerve injury, resulting in enhanced excitability of DRG neurons and increased release of primary afferent neurotransmitters, thus participating in the occurrence of neuropathic pain [2-4].the study further confirmed that after nerve injury, a large number of FTO in DRG neurons bound to the 3 'end of EHMT2 mRNA and eliminated m6A.it lost the binding with ythdf2, which caused protein degradation, and stabilized the expression of EHMT2 mRNA, so as to increase the expression of G9a protein and down regulate the expression of mu opioid receptor (MOR).in vivo and cell culture experiments confirmed that FTO was highly expressed in DRG neurons, up regulating G9a and down regulating mor. patch clamp electrophysiological records showed that high expression of FTO in DRG neurons resulted in increased release of MOR controlled neurotransmitters in the superficial layer of spinal dorsal horn. Br / > high expression of DRG can cause behavioral pain. the authors further used a variety of gene knockout techniques (including FTO siRNA, CRISPR / cas9 technology and conditional FTO transgenic mice) to specifically inhibit the up regulation of FTO expression in DRG induced by nerve injury, significantly reverse the loss of m6A in EHMT2 mRNA, block the up regulation of G9a and reverse the down regulation of MOR. behaviorally, it not only alleviates neuropathic pain, but also improves the analgesic effect of morphine under neuropathic pain and delays the formation of morphine tolerance. in this paper, the role and mechanism of RNA m6A modification in the pathogenesis of chronic neuropathic pain were discussed from the perspective of RNA methylation, which provided a new idea for the development of drugs for the treatment of neuropathic pain. moreover, the FTO inhibitor melofennacid has been approved by FDA as a non steroidal anti-inflammatory drug [5,6]. therefore, targeting DRG FTO as a target may provide a new means in clinical neuropathic pain management. Professor Tao Yuanxiang of Rutgers University is the corresponding author of the paper. The main team members of this paper, Dr. Li Yize (now anesthesiology department of General Hospital of Tianjin Medical University), postdoctoral doctor Guo Xinying, postdoctoral sun Linlin, postdoctoral Xiao Jifang, Dr. Su Songxue, and Mr. Du Shibin are the co authors of the paper. < br / < br / < br / < br / < br / < br / < br / < br / original link: platemaker: old wings, references 1. Wang x, Lu Z, Gomez a, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 2014; 2014; 2015; 505 (7481): 117-120.2. Liang L, Gu x, Zhao JY, et al. G9a participants in nerve injury-induced kcna2 downregulation in primary sensory neurons. SCI Rep. 2016; 6:37704.3 3 3:37704.3 3 3; 6:37704.3.3; 6:37704.3.3; 6:37704.3.3.3.3, 2016; 6:37704.3.3.3.3.3.. Liang L, Zhao JY, Gu X, et al. G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury. Mol Pain.2016;12:1744806916682242.4. Laumet G, Garriga J, Chen SR, et al. G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition. Nat Neurosci. 2015; 18(12):1746-1755.5. Chen B, Li Y, Song R, et al. Functions of RNA N6-methyladenosine modification in cancer progression. Mol Biol Rep. 2019;46(1):1383-1391.6. Huang Y, Yan J, Li Q, et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res. 2015;43(1):373-384.