Abstract
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.
Highlights
N6-methyladenosine (m6A) modification of RNA represents an additional steroidal anti-inflammatory drugs are ineflayer of gene regulation
We provide the first evidence to our knowledge that peripheral nerve injury leads to an increase in fat-mass and obesity-associated proteins (FTO) expression through an activation of the transcription factor Runx1 in the injured dorsal root ganglia (DRG) neurons
This increase correlates with a loss of m6A sites in euchromatic histone lysine methyltransferase 2 (Ehmt2) mRNA and an elevation of G9a protein in the DRG and leads to neuropathic pain symptoms
Summary
To examine the role of DRG RNA m6A modification in neuropathic pain, we first analyzed the expression of methyltransferases and associated proteins, demethylases, and the m6Abinding proteins in the DRG after the fifth lumbar (L5) spinal nerve ligation (SNL) in rats, a preclinical animal model that mimics nerve trauma-induced neuropathic pain in clinical cases.[30] Unilateral SNL increased the expression of Fto mRNA and FTO protein in a time-dependent manner (Figure 1a,b), but not METTL3, METTL14, WTAP, and YTHDF2 (Figure 1c), in the ipsilateral L5 DRG. Given that all FTO-labeled neurons were exclusively positive for Runx in rat DRG (Figure 2l), our findings strongly support that Runx participates in the nerve injury-induced increase of DRG FTO
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