3,091
Views
7
CrossRef citations to date
0
Altmetric
Review

Epigenetic control of ion channel expression and cell-specific splicing in nociceptors: Chronic pain mechanisms and potential therapeutic targets

ORCID Icon &
Pages 155-163 | Received 25 Nov 2020, Accepted 03 Dec 2020, Published online: 08 Jan 2021

References

  • Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of chronic pain and high-impact chronic pain among adults - United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67:1001–1006.
  • Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123–2132.
  • Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16:425–434.
  • Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain - United States, 2016. MMWR Recomm Rep. 2016;65:1–49.
  • Lipscombe D, Andrade A. Calcium channel CaValpha(1) splice isoforms - Tissue specificity and drug action. Curr Mol Pharmacol. 2015;8:22–31.
  • von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012;73:638–652.
  • Waxman SG, Zamponi GW. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci. 2014;17:153–163.
  • Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–254.
  • Ma DK, Jang MH, Guo JU, et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science. 2009;323:1074–1077.
  • Shulha HP, Cheung I, Guo Y, et al. Coordinated cell type-specific epigenetic remodeling in prefrontal cortex begins before birth and continues into early adulthood. PLoS Genet. 2013;9:e1003433.
  • Corces MR, Shcherbina A, Kundu S, et al. Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer’s and Parkinson’s diseases. Nat Genet. 2020;52:1158–1168.
  • Marshall LL, Killinger BA, Ensink E, et al. Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective. Nat Neurosci. 2020;23:1203–1214.
  • Beaver M, Bhatnagar A, Panikker P, et al. Disruption of Tip60 HAT mediated neural histone acetylation homeostasis is an early common event in neurodegenerative diseases. Sci Rep. 2020;10:18265.
  • Ramaswami G, Won H, Gandal MJ, et al. Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism. Nat Commun. 2020;11:4873.
  • Li CH, Coffey EL, Dall’Agnese A, et al. MeCP2 links heterochromatin condensates and neurodevelopmental disease. Nature. 2020;586:440–444.
  • Laumet G, Garriga J, Chen SR, et al. G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition. Nat Neurosci. 2015;18:1746–1755.
  • Berdasco M, Esteller M. Clinical epigenetics: seizing opportunities for translation. Nat Rev Genet. 2019;20:109–127.
  • Xiong S, Feng Y, Cheng L. Cellular reprogramming as a therapeutic target in cancer. Trends Cell Biol. 2019;29:623–634.
  • Garriga J, Laumet G, Chen SR, et al. Nerve injury-induced chronic pain is associated with persistent DNA methylation reprogramming in dorsal root ganglion. J Neurosci. 2018;38:6090–6101.
  • Golzenleuchter M, Kanwar R, Zaibak M, et al. Plasticity of DNA methylation in a nerve injury model of pain. Epigenetics. 2015;10:200–212.
  • Palmisano I, Danzi MC, Hutson TH, et al. Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons. Nat Neurosci. 2019;22:1913–1924.
  • Donlin LT, Park SH, Giannopoulou E, et al. Insights into rheumatic diseases from next-generation sequencing. Nat Rev Rheumatol. 2019;15:327–339.
  • Liang L, Gu X, Zhao JY, et al. G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons. Sci Rep. 2016;6:37704.
  • Zhang J, Chen SR, Chen H, et al. RE1-silencing transcription factor controls the acute-to-chronic neuropathic pain transition and Chrm2 receptor gene expression in primary sensory neurons. J Biol Chem. 2018;293:19078–19091.
  • Lopez Soto EJ, Lipscombe D. Cell-specific exon methylation and CTCF binding in neurons regulate calcium ion channel splicing and function. Elife. 2020;9:e54879
  • Sun L, Zhao JY, Gu X, et al. Nerve injury-induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons. Pain. 2017;158:1153–1165.
  • Weng YL, An R, Cassin J, et al. An intrinsic epigenetic barrier for functional axon regeneration. Neuron. 2017;94:337–346 e336.
  • Zhao X, Tang Z, Zhang H, et al. A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat Neurosci. 2013;16:1024–1031.
  • Pan Z, Xue ZY, Li GF, et al. DNA hydroxymethylation by ten-eleven translocation methylcytosine dioxygenase 1 and 3 regulates nociceptive sensitization in a chronic inflammatory pain model. Anesthesiology. 2017;127:147–163.
  • Meadows JP, Guzman-Karlsson MC, Phillips S, et al. Dynamic DNA methylation regulates neuronal intrinsic membrane excitability. Sci Signal. 2016;9:ra83.
  • Gregoire S, Millecamps M, Naso L, et al. Therapeutic benefits of the methyl donor S-adenosylmethionine on nerve injury-induced mechanical hypersensitivity and cognitive impairment in mice. Pain. 2017;158:802–810.
  • Iskandar BJ, Rizk E, Meier B, et al. Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. J Clin Invest. 2010;120:1603–1616.
  • Rashid MH, Inoue M, Toda K, et al. Loss of peripheral morphine analgesia contributes to the reduced effectiveness of systemic morphine in neuropathic pain. J Pharmacol Exp Ther. 2004;309:380–387.
  • Altier C, Dale CS, Kisilevsky AE, et al. Differential role of N-type calcium channel splice isoforms in pain. J Neurosci. 2007;27:6363–6373.
  • Andrade A, Denome S, Jiang YQ, et al. Opioid inhibition of N-type Ca2+ channels and spinal analgesia couple to alternative splicing. Nat Neurosci. 2010;13:1249–1256.
  • Jiang YQ, Andrade A, Lipscombe D. Spinal morphine but not ziconotide or gabapentin analgesia is affected by alternative splicing of voltage-gated calcium channel CaV2.2 pre-mRNA. Mol Pain. 2013;9:67.
  • Bannister K, Kucharczyk M, Dickenson AH. Hopes for the future of pain control. Pain Ther. 2017;6:117–128.
  • Bowersox S, Mandema J, Tarczy-Hornoch K, et al. Pharmacokinetics of SNX-111, a selective N-type calcium channel blocker, in rats and cynomolgus monkeys. Drug Metab Dispos. 1997;25:379–383.
  • Miljanich GP. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem. 2004;11:3029–3040.
  • Miljanich GP, Ramachandran J. Antagonists of neuronal calcium channels: structure, function, and therapeutic implications. Annu Rev Pharmacol Toxicol. 1995;35:707–734.
  • Nieto-Rostro M, Ramgoolam K, Pratt WS, et al. Ablation of alpha2delta-1 inhibits cell-surface trafficking of endogenous N-type calcium channels in the pain pathway in vivo. Proc Natl Acad Sci U S A. 2018;115:E12043–E12052.
  • Bell TJ, Thaler C, Castiglioni AJ, et al. Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron. 2004;41:127–138.
  • Castiglioni AJ, Raingo J, Lipscombe D. Alternative splicing in the C-terminus of CaV2.2 controls expression and gating of N-type calcium channels. J Physiol. 2006;576:119–134.
  • Lopez Soto EJ, Raingo J. A118G Mu opioid receptor polymorphism increases inhibitory effects on CaV2.2 channels. Neurosci Lett. 2012;523:190–194.
  • Macabuag N, Dolphin AC. Alternative splicing in Ca(V)2.2 regulates neuronal trafficking via adaptor protein complex-1 adaptor protein motifs. J Neurosci. 2015;35:14636–14652.
  • Raingo J, Castiglioni AJ, Lipscombe D. Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors. Nat Neurosci. 2007;10:285–292.
  • Mayer DJ, Mao J, Holt J, et al. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci U S A. 1999;96:7731–7736.
  • Ossipov MH, Lopez Y, Nichols ML, et al. The loss of antinociceptive efficacy of spinal morphine in rats with nerve ligation injury is prevented by reducing spinal afferent drive. Neurosci Lett. 1995;199:87–90.
  • Zhang X, Bao L, Shi TJ, et al. Down-regulation of mu-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy. Neuroscience. 1998;82:223–240.
  • Gandal MJ, Zhang P, Hadjimichael E, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362.(6420):eaat8127.
  • Li Q, Lee JA, Black DL. Neuronal regulation of alternative pre-mRNA splicing. Nat Rev Neurosci. 2007;8:819–831.
  • Lopez Soto EJ, Gandal MJ, Gonatopoulos-Pournatzis T, et al. Mechanisms of neuronal alternative splicing and strategies for therapeutic interventions. J Neurosci. 2019;39:8193–8199.
  • Ong CT, Corces VG. CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet. 2014;15:234–246.
  • Shukla S, Kavak E, Gregory M, et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature. 2011;479:74–79.
  • Renthal W, Tochitsky I, Yang L, et al. Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury. Neuron. 2020;108:128–144 e129.
  • Zhao JY, Liang L, Gu X, et al. DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nat Commun. 2017;8:14712.
  • Agirre E, Bellora N, Allo M, et al. A chromatin code for alternative splicing involving a putative association between CTCF and HP1alpha proteins. BMC Biol. 2015;13:31.
  • Ruiz-Velasco M, Kumar M, Lai MC, et al. CTCF-mediated chromatin loops between promoter and gene body regulate alternative splicing across individuals. Cell Syst. 2017;5:628–637 e626.
  • Descalzi G, Ikegami D, Ushijima T, et al. Epigenetic mechanisms of chronic pain. Trends Neurosci. 2015;38:237–246.
  • Pollema-Mays SL, Centeno MV, Apkarian AV, et al. Expression of DNA methyltransferases in adult dorsal root ganglia is cell-type specific and up regulated in a rodent model of neuropathic pain. Front Cell Neurosci. 2014;8:217.
  • Sharma N, Flaherty K, Lezgiyeva K, et al. The emergence of transcriptional identity in somatosensory neurons. Nature. 2020;577:392–398.
  • Zheng Y, Liu P, Bai L, et al. Deep sequencing of somatosensory neurons reveals molecular determinants of intrinsic physiological properties. Neuron. 2019;103:598–616 e597.
  • Mo K, Wu S, Gu X, et al. MBD1 contributes to the genesis of acute pain and neuropathic pain by epigenetic silencing of Oprm1 and Kcna2 genes in primary sensory neurons. J Neurosci. 2018;38:9883–9899.
  • Kurihara M, Kato K, Sanbo C, et al. Genomic profiling by ALaP-Seq reveals transcriptional regulation by PML bodies through DNMT3A exclusion. Mol Cell. 2020;78:493–505 e498.
  • Aneichyk T, Hendriks WT, Yadav R, et al. Dissecting the causal mechanism of X-linked dystonia-parkinsonism by integrating genome and transcriptome assembly. Cell. 2018;172:897–909 e821.
  • Bautista DM. Spicy science: David Julius and the discovery of temperature-sensitive TRP channels. Temperature (Austin). 2015;2:135–141.
  • Gu T, Lin X, Cullen SM, et al. DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells. Genome Biol. 2018;19:88.
  • Marina RJ, Sturgill D, Bailly MA, et al. TET-catalyzed oxidation of intragenic 5-methylcytosine regulates CTCF-dependent alternative splicing. Embo J. 2016;35:335–355.
  • d’Ydewalle C, Ramos DM, Pyles NJ, et al. The antisense transcript SMN-AS1 regulates SMN expression and is a novel therapeutic target for spinal muscular atrophy. Neuron. 2017;93:66–79.
  • Hua Y, Sahashi K, Hung G, et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010;24:1634–1644.
  • Passini MA, Bu J, Richards AM, et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med. 2011;3:72ra18.
  • Singh NK, Singh NN, Androphy EJ, et al. Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol. 2006;26:1333–1346.
  • Gapinske M, Luu A, Winter J, et al. CRISPR-SKIP: programmable gene splicing with single base editors. Genome Biol. 2018;19:107.
  • Konermann S, Lotfy P, Brideau NJ, et al. Transcriptome engineering with RNA-targeting type VI-D CRISPR effectors. Cell. 2018;173:665–676 e614.
  • Yuan J, Ma Y, Huang T, et al. Genetic modulation of RNA splicing with a CRISPR-guided cytidine deaminase. Mol Cell. 2018;72:380–394 e387.
  • Liu XS, Jaenisch R. Editing the epigenome to tackle brain disorders. Trends Neurosci. 2019;42:861–870.