title: DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons.
abstract: Nerve injury induces changes in gene transcription in dorsal root ganglion (DRG) neurons, which may contribute to nerve injury-induced neuropathic pain. DNA methylation represses gene expression. Here, we report that peripheral nerve injury increases expression of the DNA methyltransferase DNMT3a in the injured DRG neurons via the activation of the transcription factor octamer transcription factor 1. Blocking this increase prevents nerve injury-induced methylation of the voltage-dependent potassium (Kv) channel subunit Kcna2 promoter region and rescues Kcna2 expression in the injured DRG and attenuates neuropathic pain. Conversely, in the absence of nerve injury, mimicking this increase reduces the Kcna2 promoter activity, diminishes Kcna2 expression, decreases Kv current, increases excitability in DRG neurons and leads to spinal cord central sensitization and neuropathic pain symptoms. These findings suggest that DNMT3a may contribute to neuropathic pain by repressing Kcna2 expression in the DRG.
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.|State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Jian-Yuan
authors.initials: JY
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Lingli
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Xiyao
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.|Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Shaogen
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.|Department of Anatomy, College of Medicine, Howard University, Washington DC 20059, USA.
authors.forename: Fidelis E
authors.initials: FE
authors.lastname: Atianjoh
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Mo
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Shushan
authors.initials: S
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Brianna Marie
authors.initials: BM
authors.lastname: Lutz
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Bekker
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.|Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.|Departments of Cell Biology &Molecular Medicine and Physiology, Pharmacology &Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
mesh_terms: D000818:Animals; D059333:Central Nervous System Sensitization / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation; D051663:Kv1.2 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008026:Ligation; D008297:Male; D009437:Neuralgia / Q000235:genetics*; D009475:Neurons, Afferent / Q000378:metabolism*; D050811:Octamer Transcription Factor-1 / Q000235:genetics; D059348:Peripheral Nerve Injuries / Q000235:genetics*; D051381:Rats; D013127:Spinal Nerves / Q000293:injuries
chemical_list: C496972:Kcna2 protein, rat; D051663:Kv1.2 Potassium Channel; D050811:Octamer Transcription Factor-1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A