title: Tet1-dependent epigenetic modification of BDNF expression in dorsal horn neurons mediates neuropathic pain in rats.
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.
authors.affiliation: Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Ming-Chun
authors.initials: MC
authors.lastname: Hsieh
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.|Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Lai
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Ho
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Hsueh-Hsiao
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.|Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Jen-Kun
authors.initials: JK
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Yat-Pang
authors.initials: YP
authors.lastname: Chau
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Hsien-Yu
authors.initials: HY
authors.lastname: Peng
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003596:Cytosine / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D049308:Dioxygenases / Q000235:genetics*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D009437:Neuralgia / Q000235:genetics* / Q000473:pathology; D020671:Posterior Horn Cells / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D051381:Rats; D013127:Spinal Nerves / Q000378:metabolism / Q000473:pathology; D000097584:DNA Methyltransferase 3B
chemical_list: D044503:5-Methylcytosine; D019208:Brain-Derived Neurotrophic Factor; D003596:Cytosine; D004248:DNA (Cytosine-5-)-Methyltransferases; D049308:Dioxygenases; D000097584:DNA Methyltransferase 3B; C000601821:TET1 protein, rat