Tet1-dependent epigenetic modification of BDNF expression in dorsal horn neurons mediates neuropathic pain in rats

Sci Rep. 2016 Nov 18:6:37411. doi: 10.1038/srep37411.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism
  • Animals
  • Brain-Derived Neurotrophic Factor / genetics*
  • Cytosine / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA Methylation / genetics
  • DNA Methyltransferase 3B
  • Dioxygenases / genetics*
  • Epigenesis, Genetic
  • Gene Expression Regulation / genetics
  • Humans
  • Neuralgia / genetics*
  • Neuralgia / pathology
  • Posterior Horn Cells / metabolism
  • Posterior Horn Cells / pathology*
  • Promoter Regions, Genetic
  • Rats
  • Spinal Nerves / metabolism
  • Spinal Nerves / pathology


  • Brain-Derived Neurotrophic Factor
  • 5-Methylcytosine
  • Cytosine
  • TET1 protein, rat
  • Dioxygenases
  • DNA (Cytosine-5-)-Methyltransferases