DNA N6-methyladenine methylase N6AMT1 controls neuropathic pain through epigenetically modifying Kcnj16 in dorsal horn neurons.

Abstract

ABSTRACT:

Nerve injury-induced aberrant changes in gene expression in spinal dorsal horn neurons are critical for the genesis of neuropathic pain. N6-methyladenine (m 6 A) modification of DNA represents an additional layer of gene regulation. Here, we report that peripheral nerve injury significantly decreased the level of m 6 A-specific DNA methyltransferase 1 ( N6amt1 ) in dorsal horn neurons. This decrease was attributed, at least partly, to a reduction in transcription factor Nr2f6 . Rescuing the decrease in N6amt1 reversed the loss of m 6 A at the promoter for inwardly rectifying potassium channel subfamily J member 16 ( Kcnj16 ), mitigating the nerve injury-induced upregulation of Kcnj16 expression in the dorsal horn and alleviating neuropathic pain hypersensitivities. Conversely, mimicking the downregulation of N6amt1 in naive mice erased DNA m 6 A at the Kcnj16 promoter, elevated Kcnj16 expression, and led to neuropathic pain-like behaviors. Therefore, decreased N6amt1 caused by NR2F6 is required for neuropathic pain, likely through its regulation of m 6 A-controlled KCNJ16 in dorsal horn neurons, suggesting that DNA m 6 A modification may be a potential new target for analgesic and treatment strategies.

• Authors: Hui-Min Zhou, Heng-Jun Xu, Run-Hang Sun, Ming Zhang, Xiao-Tong Li, Ya-Xuan Zhao, Kehui Yang, Runa Wei, Qiaoqiao Liu, Siyuan Li, Zhouya Xue, Ling-Yun Hao, Li Yang, Qi-Hui Wang, Hong-Jun Wang, Fang Gao, Jun-Li Cao, Zhiqiang Pan
• Journal: Pain (Pain) Vol. 165 Issue 1 Pg. 75-91 (Jan 01 2024) ISSN: 1872-6623 [Electronic] United States
• PMID: 37624905 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 International Association for the Study of Pain.

Chemical References

• Site-Specific DNA-Methyltransferase (Adenine-Specific)
• Kcnj16 protein, mouse

Topics

• Animals
• Mice
• Down-Regulation
• Hyperalgesia (metabolism)
• Neuralgia (genetics, metabolism)
• Posterior Horn Cells (metabolism)
• Spinal Cord Dorsal Horn (metabolism)
• Up-Regulation
• Site-Specific DNA-Methyltransferase (Adenine-Specific) (metabolism)