Abstract
Ten-eleven translocation methylcytosine dioxygenase 1 (Tet1) mediates the conversion of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC), hence promoting DNA demethylation. Although recent studies have linked the DNA demethylation of specific genes to pain hypersensitivity, the role of spinal Tet1-dependent DNA demethylation in nociception hypersensitivity development remains elusive. Here, we report correlated with behavioral allodynia, spinal nerve ligation (SNL) upregulated Tet1 expression in dorsal horn neurons that hydroxylate 5 mC to 5 hmC at CpG dinucleotides in the bdnf promoter to promote spinal BDNF expression at day 7 after operation. Focal knockdown of spinal Tet1 expression decreased Tet1 binding and 5 hmC enrichment, further increased 5 mC enrichment at CpG sites in the bdnf promoter and decreased spinal BDNF expression accompanied by the alleviation of the developed allodynia. Moreover, at day 7 after operation, SNL-enhanced Tet1 expression also inhibited the binding of DNA methyltransferases (DNMTs, i.e., DNMT1, DNMT3a, and DNMT3b) to the bdnf promoter, a requirement for transcriptional silencing by catalysing 5-cytosine (5C) to 5 mC. Together, these data suggest at CpG sites of the bdnf promoter, SNL-enhanced Tet1 expression promotes DNA demethylation both by converting 5 mC to 5 hmC and inhibiting DNMT binding to regulate spinal BDNF expression, hence contributing to behavioral allodynia development.
Highlights
Tet[1] overexpression leads to increased 5 hmC but decreased 5 mC enrichment at CpG sites in the bdnf promoter; Tet[1] downregulation is associated with reduced levels of 5 hmC enrichment at CpG sites in the bdnf promoter to decrease BDNF expression[10]
In line with the above global data, we found that 5 hmC enrichment at the CpG sites in the bdnf promoter in the ipsilateral dorsal horn was time dependently increased at day 3 and day 7 post spinal nerve ligation (SNL) (Fig. 5a), time points presumed to reflect the induction[20] and maintenance[21] phases of neuropathic pain, respectively
We explored the role of Tet1-mediated DNA demethylation in neuropathic pain development
Summary
Tet[1] overexpression leads to increased 5 hmC but decreased 5 mC enrichment at CpG sites in the bdnf promoter; Tet[1] downregulation is associated with reduced levels of 5 hmC enrichment at CpG sites in the bdnf promoter to decrease BDNF expression[10]. Numerous studies have linked bdnf transcription to the spinal plasticity underlying neuropathic pain in rat models[11,12]. These observations imply that Tet1-mediated DNA demethylation at CpG sites in the bdnf promoter could underlie the spinal plasticity causing the neuropathic pain. Spinal Tet1-achieved demethylation likely represents one mechanism to negatively modulate DNMTs-mediated methylation at the bdnf promoter to mediate neuropathic pain development. We investigated the contribution of spinal Tet[1] to the epigenetic machinery underlying neuropathic pain and the possible involvement of Tet1-promoted 5 mC/5 hmC conversion-associated gene modification
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