title: G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition.
abstract: Neuropathic pain is a debilitating clinical problem and difficult to treat. Nerve injury causes a long-lasting reduction in K(+) channel expression in the dorsal root ganglion (DRG), but little is known about the epigenetic mechanisms involved. We found that nerve injury increased dimethylation of Lys9 on histone H3 (H3K9me2) at Kcna4, Kcnd2, Kcnq2 and Kcnma1 promoters but did not affect levels of DNA methylation on these genes in DRGs. Nerve injury increased activity of euchromatic histone-lysine N-methyltransferase-2 (G9a), histone deacetylases and enhancer of zeste homolog-2 (EZH2), but only G9a inhibition consistently restored K(+) channel expression. Selective knockout of the gene encoding G9a in DRG neurons completely blocked K(+) channel silencing and chronic pain development after nerve injury. Remarkably, RNA sequencing analysis revealed that G9a inhibition not only reactivated 40 of 42 silenced genes associated with K(+) channels but also normalized 638 genes down- or upregulated by nerve injury. Thus G9a has a dominant function in transcriptional repression of K(+) channels and in acute-to-chronic pain transition after nerve injury.
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Laumet
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Garriga
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Li
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Smith
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Anesthesiology, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Issa
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D059787:Acute Pain / Q000235:genetics* / Q000473:pathology; D000818:Animals; D059350:Chronic Pain / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015221:Potassium Channels; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase