The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Oxidative stress-induced aberrant G9a activation disturbs RE-1-containing neuron-specific genes expression, leading to degeneration in human SH-SY5Y neuroblastoma cells

  • Kim, Ho-Tae (Department of Biology, College of Natural Science, Chosun University) ;
  • Ohn, Takbum (Department of Cellular and Molecular Medicine, College of Medicine, Chosun University) ;
  • Jeong, Sin-Gu (Department of Biology, College of Natural Science, Chosun University) ;
  • Song, Anji (Department of Biology, College of Natural Science, Chosun University) ;
  • Jang, Chul Ho (Department of Otolaryngology, Chonnam National University Medical School) ;
  • Cho, Gwang-Won (Department of Biology, College of Natural Science, Chosun University)
  • Received : 2020.06.18
  • Accepted : 2020.10.12
  • Published : 2021.01.01
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Abstract

Oxidative stress-induced neurodegeneration is one of several etiologies underlying neurodegenerative disease. In the present study, we investigated the functional role of histone methyltransferase G9a in oxidative stress-induced degeneration in human SH-SY5Y neuroblastoma cells. Cell viability significantly decreased on H2O2 treatment; however, treatment with the G9a inhibitor BIX01294 partially attenuated this effect. The expression of neuron-specific genes also decreased in H2O2-treated cells; however, it recovered on G9a inhibition. H2O2-treated cells showed high levels of H3K9me2 (histone H3 demethylated at the lysine 9 residue), which is produced by G9a activation; BIX01294 treatment reduced aberrant activation of G9a. H3K9me2 occupancy of the RE-1 site in neuron-specific genes was significantly increased in H2O2-treated cells, whereas it was decreased in BIX01294-treated cells. The differentiation of H2O2-treated cells also recovered on G9a inhibition by BIX01294. Consistent results were observed when used another G9a inhibitor UCN0321. These results demonstrate that oxidative stress induces aberrant activation of G9a, which disturbs the expression of neuron-specific genes and progressively mediates neuronal cell death. Moreover, a G9a inhibitor can lessen aberrant G9a activity and prevent neuronal damage. G9a inhibition may therefore contribute to the prevention of oxidative stress-induced neurodegeneration.

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References

  1. Kauser H, Sahu S, Panjwani U. Guanfacine promotes neuronal survival in medial prefrontal cortex under hypobaric hypoxia. Brain Res. 2016;1636:152-160. https://doi.org/10.1016/j.brainres.2016.01.053
  2. Pradhan SS, Salinas K, Garduno AC, Johansson JU, Wang Q, Manning-Bog A, Andreasson KI. Anti-inflammatory and neuroprotective effects of PGE2 EP4 signaling in models of Parkinson's disease. J Neuroimmune Pharmacol. 2017;12:292-304. https://doi.org/10.1007/s11481-016-9713-6
  3. Neniskyte U, Fricker M, Brown GC. Amyloid β induces microglia to phagocytose neurons via activation of protein kinase Cs and NADPH oxidase. Int J Biochem Cell Biol. 2016;81(Pt B):346-355. https://doi.org/10.1016/j.biocel.2016.06.005
  4. Olney JW, Tenkova T, Dikranian K, Qin YQ, Labruyere J, Ikonomidou C. Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res. 2002;133:115-126. https://doi.org/10.1016/S0165-3806(02)00279-1
  5. Wang X, Hu X, Yang Y, Takata T, Sakurai T. Nicotinamide mononucleotide protects against -amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016;1643:1-9. https://doi.org/10.1016/j.brainres.2016.04.060
  6. Ramesh G, Meisner OC, Philipp MT. Anti-inflammatory effects of dexamethasone and meloxicam on Borrelia burgdorferi-induced inflammation in neuronal cultures of dorsal root ganglia and myelinating cells of the peripheral nervous system. J Neuroinflammation. 2015;12:240. https://doi.org/10.1186/s12974-015-0461-y
  7. Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, Kellis M, Marra MA, Beaudet AL, Ecker JR, Farnham PJ, Hirst M, Lander ES, Mikkelsen TS, Thomson JA. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol. 2010;28:1045-1048. https://doi.org/10.1038/nbt1010-1045
  8. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57-74. https://doi.org/10.1038/nature11247
  9. Sedivy JM, Banumathy G, Adams PD. Aging by epigenetics--a consequence of chromatin damage? Exp Cell Res. 2008;314:1909-1917. https://doi.org/10.1016/j.yexcr.2008.02.023
  10. Landgrave-Gomez J, Mercado-Gomez O, Guevara-Guzman R. Epigenetic mechanisms in neurological and neurodegenerative diseases. Front Cell Neurosci. 2015;9:58. https://doi.org/10.3389/fncel.2015.00058
  11. Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MV, Zukin RS. Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci U S A. 2012;109:E962-E971. https://doi.org/10.1073/pnas.1121568109
  12. Liu H, Le W. Epigenetic modifications of chronic hypoxia-mediated neurodegeneration in Alzheimer's disease. Transl Neurodegener. 2014;3:7. https://doi.org/10.1186/2047-9158-3-7
  13. Subbanna S, Nagre NN, Shivakumar M, Umapathy NS, Psychoyos D, Basavarajappa BS. Ethanol induced acetylation of histone at G9a exon1 and G9a-mediated histone H3 dimethylation leads to neurodegeneration in neonatal mice. Neuroscience. 2014;258:422-432. https://doi.org/10.1016/j.neuroscience.2013.11.043
  14. Thiel G, Ekici M, Rossler OG. RE-1 silencing transcription factor (REST): a regulator of neuronal development and neuronal/endocrine function. Cell Tissue Res. 2015;359:99-109. https://doi.org/10.1007/s00441-014-1963-0
  15. Zheng D, Zhao K, Mehler MF. Profiling RE1/REST-mediated histone modifications in the human genome. Genome Biol. 2009;10:R9. https://doi.org/10.1186/gb-2009-10-1-r9
  16. Ding N, Zhou H, Esteve PO, Chin HG, Kim S, Xu X, Joseph SM, Friez MJ, Schwartz CE, Pradhan S, Boyer TG. Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation. Mol Cell. 2008;31:347-359. https://doi.org/10.1016/j.molcel.2008.05.023
  17. Ding N, Tomomori-Sato C, Sato S, Conaway RC, Conaway JW, Boyer TG. MED19 and MED26 are synergistic functional targets of the RE1 silencing transcription factor in epigenetic silencing of neuronal gene expression. J Biol Chem. 2009;284:2648-2656. https://doi.org/10.1074/jbc.M806514200
  18. Wang Z, Yang D, Zhang X, Li T, Li J, Tang Y, Le W. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS One. 2011;6:e19229. https://doi.org/10.1371/journal.pone.0019229
  19. Subbanna S, Shivakumar M, Umapathy NS, Saito M, Mohan PS, Kumar A, Nixon RA, Verin AD, Psychoyos D, Basavarajappa BS. G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain. Neurobiol Dis. 2013;54:475-485. https://doi.org/10.1016/j.nbd.2013.01.022
  20. Kubicek S, O'Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, Rea S, Mechtler K, Kowalski JA, Homon CA, Kelly TA, Jenuwein T. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell. 2007;25:473-481. https://doi.org/10.1016/j.molcel.2007.01.017
  21. Ahn MJ, Jeong SG, Cho GW. Antisenescence activity of G9a inhibitor BIX01294 on human bone marrow mesenchymal stromal cells. Turk J Biol. 2016;40:443-451. https://doi.org/10.3906/biy-1507-11
  22. Kim HT, Jeong SG, Cho GW. G9a inhibition promotes neuronal differentiation of human bone marrow mesenchymal stem cells through the transcriptional induction of RE-1 containing neuronal specific genes. Neurochem Int. 2016;96:77-83. https://doi.org/10.1016/j.neuint.2016.03.002
  23. Shankar SR, Bahirvani AG, Rao VK, Bharathy N, Ow JR, Taneja R. G9a, a multipotent regulator of gene expression. Epigenetics. 2013;8:16-22. https://doi.org/10.4161/epi.23331
  24. Schweizer S, Harms C, Lerch H, Flynn J, Hecht J, Yildirim F, Meisel A, Marschenz S. Inhibition of histone methyltransferases SUV39H1 and G9a leads to neuroprotection in an in vitro model of cerebral ischemia. J Cereb Blood Flow Metab. 2015;35:1640-1647. https://doi.org/10.1038/jcbfm.2015.99
  25. Zhou Q, Obana EA, Radomski KL, Sukumar G, Wynder C, Dalgard CL, Doughty ML. Inhibition of the histone demethylase Kdm5b promotes neurogenesis and derepresses Reln (reelin) in neural stem cells from the adult subventricular zone of mice. Mol Biol Cell. 2016;27:627-639. https://doi.org/10.1091/mbc.E15-07-0513
  26. Chen X, Du Z, Shi W, Wang C, Yang Y, Wang F, Yao Y, He K, Hao A. 2-Bromopalmitate modulates neuronal differentiation through the regulation of histone acetylation. Stem Cell Res. 2014;12:481-491. https://doi.org/10.1016/j.scr.2013.12.010
  27. Jeong SG, Ohn T, Kim SH, Cho GW. Valproic acid promotes neuronal differentiation by induction of neuroprogenitors in human bone-marrow mesenchymal stromal cells. Neurosci Lett. 2013;554:22-27. https://doi.org/10.1016/j.neulet.2013.08.059
  28. Joe IS, Jeong SG, Cho GW. Resveratrol-induced SIRT1 activation promotes neuronal differentiation of human bone marrow mesenchymal stem cells. Neurosci Lett. 2015;584:97-102. https://doi.org/10.1016/j.neulet.2014.10.024
  29. Oh YS, Kim SH, Cho GW. Functional restoration of amyotrophic lateral sclerosis patient-derived mesenchymal stromal cells through inhibition of DNA methyltransferase. Cell Mol Neurobiol. 2016;36:613-620. https://doi.org/10.1007/s10571-015-0242-2
  30. Roopra A, Qazi R, Schoenike B, Daley TJ, Morrison JF. Localized domains of G9a-mediated histone methylation are required for silencing of neuronal genes. Mol Cell. 2004;14:727-738. https://doi.org/10.1016/j.molcel.2004.05.026
  31. Subbanna S, Basavarajappa BS. Pre-administration of G9a/GLP inhibitor during synaptogenesis prevents postnatal ethanol-induced LTP deficits and neurobehavioral abnormalities in adult mice. Exp Neurol. 2014;261:34-43. https://doi.org/10.1016/j.expneurol.2014.07.003
  32. Sharma M, Dierkes T, Sajikumar S. Epigenetic regulation by G9a/GLP complex ameliorates amyloid-beta 1-42 induced deficits in long-term plasticity and synaptic tagging/capture in hippocampal pyramidal neurons. Aging Cell. 2017;16:1062-1072. https://doi.org/10.1111/acel.12634
  33. Fang Q, Strand A, Law W, Faca VM, Fitzgibbon MP, Hamel N, Houle B, Liu X, May DH, Poschmann G, Roy L, Stühler K, Ying W, Zhang J, Zheng Z, Bergeron JJ, Hanash S, He F, Leavitt BR, Meyer HE, et al. Brain-specific proteins decline in the cerebrospinal fluid of humans with Huntington disease. Mol Cell Proteomics. 2009;8:451-466. https://doi.org/10.1074/mcp.M800231-MCP200
  34. Merienne N, Meunier C, Schneider A, Seguin J, Nair SS, Rocher AB, Le Gras S, Keime C, Faull R, Pellerin L, Chatton JY, Neri C, Merienne K, Deglon N. Cell-type-specific gene expression profiling in adult mouse brain reveals normal and disease-state signatures. Cell Rep. 2019;26:2477-2493.e9. https://doi.org/10.1016/j.celrep.2019.02.003
  35. Pearl JR, Colantuoni C, Bergey DE, Funk CC, Shannon P, Basu B, Casella AM, Oshone RT, Hood L, Price ND, Ament SA. Genomescale transcriptional regulatory network models of psychiatric and neurodegenerative disorders. Cell Syst. 2019;8:122-135.e7. https://doi.org/10.1016/j.cels.2019.01.002