Threshold Inhibition of Methyltransferase G9a/Glp Exacerbates Neuropathic Hypersensitivity through Mediating GRIN2B Methylation
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Published
May 30, 2019
Abstract
Background In this study, we investigated whether G9a related DNA methylation and histone modification is involved in the transcription alteration of NR2B following peripheral nerve injury and subsequently contributes to pain facilitation of G9a inhibition.
Methods After approval by the institutional ethical committee on pain research in conscious animals, C57BL/6 mice were used to induce neuropathic pain with spared nerve injury (SNI). G9a/Glp expression, GRIN2B gene 5’-regulatory region CpG sites methylation profile, as well as NR2B expression in the spinal dorsal horn following SNI was detected with immunofluorescence, bisulfite sequencing, and western blot, respectively. For mechanism study, threshold doses of G9a/Glp inhibitors BIX01294/UNC0638 or direct DNA demethylation agent 5-Aza was intrathecal injected through the pre-buried catheter daily in bolus for 3 days, G9a/Glp and its enzymatic substrate H3K9me2/H3K9me3 expression, GRIN2B gene methylation alteration, as well as NR2B expression were observed. Nociceptive behavior was depicted in response to von Frey filaments following SNI with or without intrathecal BIX/UNC and 5-Aza treatments.
Results Ipsilateral mechanical withdrawal threshold rather than thermal withdrawal latency prominently decreased and peaked at day 7 to 14 post SNI. Besides, nerve injury consistently increased G9a/Glp, H3K9me2 expression, GRIN2B gene 5’-regulatory region CpG sites methylation, as well as NR2B expression in the spinal dorsal horn at day 7 post SNI. Furthermore, either G9a/Glp inhibition by BIX/UNC or H3K9me2 blockade by 5-Aza independently reversed GRIN2B gene high methylation, followed with disinhibition of NR2B transcription inhibition. Consistent with molecular changes, either BIX/UNC or 5-Aza further worsens nerve injury-induced allodynia.
Conclusion G9a/Glp contributes to the pathogenesis of neuropathic pain via methylating GRIN2B gene affecting NR2B transcription. G9a/Glp at an elevated setpoint may prevent the over-sensitization following peripheral nerve injury.
Methods After approval by the institutional ethical committee on pain research in conscious animals, C57BL/6 mice were used to induce neuropathic pain with spared nerve injury (SNI). G9a/Glp expression, GRIN2B gene 5’-regulatory region CpG sites methylation profile, as well as NR2B expression in the spinal dorsal horn following SNI was detected with immunofluorescence, bisulfite sequencing, and western blot, respectively. For mechanism study, threshold doses of G9a/Glp inhibitors BIX01294/UNC0638 or direct DNA demethylation agent 5-Aza was intrathecal injected through the pre-buried catheter daily in bolus for 3 days, G9a/Glp and its enzymatic substrate H3K9me2/H3K9me3 expression, GRIN2B gene methylation alteration, as well as NR2B expression were observed. Nociceptive behavior was depicted in response to von Frey filaments following SNI with or without intrathecal BIX/UNC and 5-Aza treatments.
Results Ipsilateral mechanical withdrawal threshold rather than thermal withdrawal latency prominently decreased and peaked at day 7 to 14 post SNI. Besides, nerve injury consistently increased G9a/Glp, H3K9me2 expression, GRIN2B gene 5’-regulatory region CpG sites methylation, as well as NR2B expression in the spinal dorsal horn at day 7 post SNI. Furthermore, either G9a/Glp inhibition by BIX/UNC or H3K9me2 blockade by 5-Aza independently reversed GRIN2B gene high methylation, followed with disinhibition of NR2B transcription inhibition. Consistent with molecular changes, either BIX/UNC or 5-Aza further worsens nerve injury-induced allodynia.
Conclusion G9a/Glp contributes to the pathogenesis of neuropathic pain via methylating GRIN2B gene affecting NR2B transcription. G9a/Glp at an elevated setpoint may prevent the over-sensitization following peripheral nerve injury.
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Keywords
G9a/Glp, NR2B, DNA Methylation, Spinal Cord, Neuropathic Pain
Supporting Agencies
This work was supported in part by the National Natural Scientific Foun- dation of China (NSFC, 81371248, 81560200,and 81600960), and the Nanjing Municipal Health Bureau Fund Project (YKK15162).
References
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23. Zhang Y, Chen SR, Laumet G, Chen H, Pan HL. Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of mu-Opioid Receptors in Primary Sensory Neurons. J Biol Chem 2016; 291: 8475-8485.
24. Liang L, Zhao JY, Gu X, Wu S, Mo K, Xiong M, et al. G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury. Mol Pain 2016; 12: 1-12.
25. Wang X, Shen X, Ma S, Liu Y, Xu S, Wu S, et al. Threshold Effect of G9a/Glp on Peripheral Nerve Injury Induced Hypersensitivity. Mol Pain 2017; 13: 1744806917729305.
26. Chang Y, Zhang X, Horton JR, Upadhyay AK, Spannhoff A, Liu J, et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol 2009; 16: 312-317.
27. Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, et al. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol 2011; 7: 566-574.
28. Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P, Tang C, et al. Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 2007; 67: 6400-6408.
29. Xu S, Wu H, Wang X, Shen X, Guo X, Shen R, et al. Tumor suppressor menin mediates peripheral nerve injury-induced neuropathic pain through potentiating synaptic plasticity. Neuroscience 2012; 223: 473-485.
30. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 2000; 87: 149-158.
31. Wang X, Feng SW, Wang F, Xu S. Modeled behavior of neuropathic pain with social defect in rats: a preliminary methodology evaluation. Med Sci Monit Basic Res 2014; 20: 164-169.
32. Shen X, Liu Y, Xu S, Zhao Q, Wu H, Guo X, et al. Menin regulates spinal glutamate-GABA balance through GAD65 contributing to neuropathic pain. Pharmacol Rep 2014; 66: 49-55.
33. Liang DY, Sun Y, Shi XY, Sahbaie P, Clark JD. Epigenetic regulation of spinal cord gene expression controls opioid-induced hyperalgesia. Mol Pain 2014; 10: 59.
34. Qiang M, Denny A, Chen J, Ticku MK, Yan B, Henderson G. The site specific demethylation in the 5'-regulatory area of NMDA receptor 2B subunit gene associated with CIE-induced up-regulation of transcription. PLoS One 2010; 5: e8798.
35. Dupont JM, Tost J, Jammes H, Gut IG. De novo quantitative bisulfite sequencing using the pyrosequencing technology. Anal Biochem 2004; 333: 119-127.
36. Brakensiek K, Wingen LU, Langer F, Kreipe H, Lehmann U. Quantitative high-resolution CpG island mapping with Pyrosequencing reveals disease-specific methylation patterns of the CDKN2B gene in myelodysplastic syndrome and myeloid leukemia. Clin Chem 2007; 53: 17-23.
37. Nguyen CT, Weisenberger DJ, Velicescu M, Gonzales FA, Lin JC, Liang G, et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. Cancer Res 2002; 62: 6456-6461.
38. Zhang Z, Tao W, Hou YY, Wang W, Kenny PJ, Pan ZZ. MeCP2 repression of G9a in regulation of pain and morphine reward. J Neurosci 2014; 34: 9076-9087.
39. Qiang M, Ticku MK. Role of AP-1 in ethanol-induced N-methyl-D-aspartate receptor 2B subunit gene up-regulation in mouse cortical neurons. J Neurochem 2005; 95: 1332-1341.
40. Khan S, Shehzad O, Chun J, Kim YS. Mechanism underlying anti-hyperalgesic and anti-allodynic properties of anomalin in both acute and chronic inflammatory pain models in mice through inhibition of NF-kappaB, MAPKs and CREB signaling cascades. Eur J Pharmacol 2013; 718: 448-458.
41. Khan S, Shehzad O, Chun J, Choi RJ, Park S, Islam MN, et al. Anti-hyperalgesic and anti-allodynic activities of capillarisin via suppression of inflammatory signaling in animal model. J Ethnopharmacol 2014; 152: 478-486.
42. Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH. Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 1997; 51: 23-32.
43. Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, et al. Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci 2005; 25: 11107-11116.
44. Chen L, Liu JC, Zhang XN, Guo YY, Xu ZH, Cao W, et al. Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain. Neuropharmacology 2008; 54: 1175-1181.
2. Jones RC, 3rd, Lawson E, Backonja M. Managing Neuropathic Pain. Med Clin North Am 2016; 100: 151-167.
3. Cohen SP, Mao J. Neuropathic pain: mechanisms and their clinical implications. BMJ 2014; 348: f7656.
4. Sullivan R, Dailey T, Duncan K, Abel N, Borlongan CV. Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer. Int J Mol Sci 2016; 17.
5. Xie JD, Chen SR, Chen H, Zeng WA, Pan HL. Presynaptic N-Methyl-d-aspartate (NMDA) Receptor Activity Is Increased Through Protein Kinase C in Paclitaxel-induced Neuropathic Pain. J Biol Chem 2016; 291: 19364-19373.
6. Lefevre Y, Amadio A, Vincent P, Descheemaeker A, Oliet SH, Dallel R, et al. Neuropathic pain depends upon D-serine co-activation of spinal NMDA receptors in rats. Neurosci Lett 2015; 603: 42-47.
7. Kiyoyuki Y, Taniguchi W, Okubo M, Yamanaka H, Kobayashi K, Nishio N, et al. Leukotriene enhances NMDA-induced inward currents in dorsal horn neurons of the rat spinal cord after peripheral nerve injury. Mol Pain 2015; 11: 53.
8. Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur J Neurosci 2011; 33: 1351-1365.
9. Xia T, Cui Y, Qian Y, Chu S, Song J, Gu X, et al. Regulation of the NR2B-CREB-CRTC1 Signaling Pathway Contributes to Circadian Pain in Murine Model of Chronic Constriction Injury. Anesth Analg 2016; 122: 542-552.
10. Liu S, Liu YP, Huang ZJ, Zhang YK, Song AA, Ma PC, et al. Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats. Pain 2015; 156: 2572-2584.
11. Qu XX, Cai J, Li MJ, Chi YN, Liao FF, Liu FY, et al. Role of the spinal cord NR2B-containing NMDA receptors in the development of neuropathic pain. Exp Neurol 2009; 215: 298-307.
12. Miwa H, Fukaya M, Watabe AM, Watanabe M, Manabe T. Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long-term potentiation in the adult mouse CNS. J Physiol 2008; 586: 2539-2550.
13. Lei Y, Sun Y, Lu C, Ma Z, Gu X. Activated Glia Increased the Level of Proinflammatory Cytokines in a Resiniferatoxin-Induced Neuropathic Pain Rat Model. Reg Anesth Pain Med 2016; 41: 744-749.
14. Ferrari LF, Lotufo CM, Araldi D, Rodrigues MA, Macedo LP, Ferreira SH, et al. Inflammatory sensitization of nociceptors depends on activation of NMDA receptors in DRG satellite cells. Proc Natl Acad Sci U S A 2014; 111: 18363-18368.
15. Wu F, Pan R, Chen J, Sugita M, Chen C, Tao Y, et al. Lentivirus mediated siRNA against GluN2B subunit of NMDA receptor reduces nociception in a rat model of neuropathic pain. Biomed Res Int 2014; 2014: 871637.
16. Gabra BH, Kessler FK, Ritter JK, Dewey WL, Smith FL. Decrease in N-methyl-D-aspartic acid receptor-NR2B subunit levels by intrathecal short-hairpin RNA blocks group I metabotropic glutamate receptor-mediated hyperalgesia. J Pharmacol Exp Ther 2007; 322: 186-194.
17. Descalzi G, Ikegami D, Ushijima T, Nestler EJ, Zachariou V, Narita M. Epigenetic mechanisms of chronic pain. Trends Neurosci 2015; 38: 237-246.
18. Machelska H, Celik MO. Recent advances in understanding neuropathic pain: glia, sex differences, and epigenetics. F1000Res 2016; 5: 2743.
19. Tachibana M, Matsumura Y, Fukuda M, Kimura H, Shinkai Y. G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO J 2008; 27: 2681-2690.
20. Wang N, Shen X, Bao S, Feng SW, Wang W, Liu Y, et al. Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity. Mol Pain 2016; 12: 1-10.
21. Laumet G, Garriga J, Chen SR, Zhang Y, Li DP, Smith TM, et al. G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition. Nat Neurosci 2015; 18: 1746-1755.
22. Liang L, Gu X, Zhao JY, Wu S, Miao X, Xiao J, et al. G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons. Sci Rep 2016; 6: 37704.
23. Zhang Y, Chen SR, Laumet G, Chen H, Pan HL. Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of mu-Opioid Receptors in Primary Sensory Neurons. J Biol Chem 2016; 291: 8475-8485.
24. Liang L, Zhao JY, Gu X, Wu S, Mo K, Xiong M, et al. G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury. Mol Pain 2016; 12: 1-12.
25. Wang X, Shen X, Ma S, Liu Y, Xu S, Wu S, et al. Threshold Effect of G9a/Glp on Peripheral Nerve Injury Induced Hypersensitivity. Mol Pain 2017; 13: 1744806917729305.
26. Chang Y, Zhang X, Horton JR, Upadhyay AK, Spannhoff A, Liu J, et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol 2009; 16: 312-317.
27. Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, et al. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol 2011; 7: 566-574.
28. Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P, Tang C, et al. Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 2007; 67: 6400-6408.
29. Xu S, Wu H, Wang X, Shen X, Guo X, Shen R, et al. Tumor suppressor menin mediates peripheral nerve injury-induced neuropathic pain through potentiating synaptic plasticity. Neuroscience 2012; 223: 473-485.
30. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 2000; 87: 149-158.
31. Wang X, Feng SW, Wang F, Xu S. Modeled behavior of neuropathic pain with social defect in rats: a preliminary methodology evaluation. Med Sci Monit Basic Res 2014; 20: 164-169.
32. Shen X, Liu Y, Xu S, Zhao Q, Wu H, Guo X, et al. Menin regulates spinal glutamate-GABA balance through GAD65 contributing to neuropathic pain. Pharmacol Rep 2014; 66: 49-55.
33. Liang DY, Sun Y, Shi XY, Sahbaie P, Clark JD. Epigenetic regulation of spinal cord gene expression controls opioid-induced hyperalgesia. Mol Pain 2014; 10: 59.
34. Qiang M, Denny A, Chen J, Ticku MK, Yan B, Henderson G. The site specific demethylation in the 5'-regulatory area of NMDA receptor 2B subunit gene associated with CIE-induced up-regulation of transcription. PLoS One 2010; 5: e8798.
35. Dupont JM, Tost J, Jammes H, Gut IG. De novo quantitative bisulfite sequencing using the pyrosequencing technology. Anal Biochem 2004; 333: 119-127.
36. Brakensiek K, Wingen LU, Langer F, Kreipe H, Lehmann U. Quantitative high-resolution CpG island mapping with Pyrosequencing reveals disease-specific methylation patterns of the CDKN2B gene in myelodysplastic syndrome and myeloid leukemia. Clin Chem 2007; 53: 17-23.
37. Nguyen CT, Weisenberger DJ, Velicescu M, Gonzales FA, Lin JC, Liang G, et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. Cancer Res 2002; 62: 6456-6461.
38. Zhang Z, Tao W, Hou YY, Wang W, Kenny PJ, Pan ZZ. MeCP2 repression of G9a in regulation of pain and morphine reward. J Neurosci 2014; 34: 9076-9087.
39. Qiang M, Ticku MK. Role of AP-1 in ethanol-induced N-methyl-D-aspartate receptor 2B subunit gene up-regulation in mouse cortical neurons. J Neurochem 2005; 95: 1332-1341.
40. Khan S, Shehzad O, Chun J, Kim YS. Mechanism underlying anti-hyperalgesic and anti-allodynic properties of anomalin in both acute and chronic inflammatory pain models in mice through inhibition of NF-kappaB, MAPKs and CREB signaling cascades. Eur J Pharmacol 2013; 718: 448-458.
41. Khan S, Shehzad O, Chun J, Choi RJ, Park S, Islam MN, et al. Anti-hyperalgesic and anti-allodynic activities of capillarisin via suppression of inflammatory signaling in animal model. J Ethnopharmacol 2014; 152: 478-486.
42. Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH. Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 1997; 51: 23-32.
43. Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, et al. Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci 2005; 25: 11107-11116.
44. Chen L, Liu JC, Zhang XN, Guo YY, Xu ZH, Cao W, et al. Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain. Neuropharmacology 2008; 54: 1175-1181.
How to Cite
Wang, F., Wang, X., Wu, H., Ma, J., Xu, S., Li, S., & Bao, S. (2019). Threshold Inhibition of Methyltransferase G9a/Glp Exacerbates Neuropathic Hypersensitivity through Mediating GRIN2B Methylation. Science Insights, 29(1), 33–47. https://doi.org/10.15354/si.19.ar910
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