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Huang, Z.* ; Zhang, Y.* ; Wang, S.* ; Qi, R.* ; Tao, Y.* ; Sun, Y.* ; Jiang, D. ; Jiang, X.* ; Tao, J.*

FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain via m6A-dependent stabilization of 5-HT3A mRNA in sensory neurons.

Proc. Natl. Acad. Sci. U.S.A. 121:e2312861121 (2024)
DOI PMC
Creative Commons Lizenzvertrag
The N6-methyladenosine (m6A) modification of RNA is an emerging epigenetic regulatory mechanism that has been shown to participate in various pathophysiological processes. However, its involvement in modulating neuropathic pain is still poorly understood. In this study, we elucidate a functional role of the m6A demethylase alkylation repair homolog 5 (ALKBH5) in modulating trigeminal-mediated neuropathic pain. Peripheral nerve injury selectively upregulated the expression level of ALKBH5 in the injured trigeminal ganglion (TG) of rats. Blocking this upregulation in injured TGs alleviated trigeminal neuropathic pain, while mimicking the upregulation of ALKBH5 in intact TG neurons sufficiently induced pain-related behaviors. Mechanistically, histone deacetylase 11 downregulation induced by nerve injury increases histone H3 lysine 27 acetylation (H3K27ac), facilitating the binding of the transcription factor forkhead box protein D3 (FOXD3) to the Alkbh5 promoter and promoting Alkbh5 transcription. The increased ALKBH5 erases m6A sites in Htr3a messenger RNA (mRNA), resulting in an inability of YT521-B homology domain 2 (YTHDF2) to bind to Htr3a mRNA, thus causing an increase in 5-HT3A protein expression and 5-HT3 channel currents. Conversely, blocking the increased expression of ALKBH5 in the injured TG destabilizes nerve injury-induced 5-HT3A upregulation and reverses mechanical allodynia, and the effect can be blocked by 5-HT3A knockdown. Together, FOXD3-mediated transactivation of ALKBH5 promotes neuropathic pain through m6A-dependent stabilization of Htr3a mRNA in TG neurons. This mechanistic understanding may advance the discovery of new therapeutic targets for neuropathic pain management.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Alkbh5 ; N6-methyladenosine ; Histone Acetylation ; Neuropathic Pain ; Trigeminal Ganglion Neurons; Spinal Nerve Ligation; Histone Acetylation; Inflammatory Pain; Gene-expression; Contributes; Ondansetron; Complex; Hdac1
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 121, Issue: 6, Pages: , Article Number: e2312861121 Supplement: ,
Publisher National Academy of Sciences
Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Regenerative Biology (IRBM)
Grants Natural Science Foundation of Jiangsu Province
Clinical Research Center of Neurological Disease
Science and Technology Bureau of Suzhou
Priority Academic Program Development of Jiangsu Higher Education