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Molecular Neurobiology

, Volume 56, Issue 4, pp 2542–2550 | Cite as

Inhibition of the Epigenetic Regulator REST Ameliorates Ischemic Brain Injury

  • Kahlilia C. Morris-Blanco
  • TaeHee Kim
  • Mario J. Bertogliat
  • Suresh L. Mehta
  • Anil K. Chokkalla
  • Raghu VemugantiEmail author
Article

Abstract

Cerebral ischemia is known to activate the repressor element-1 (RE1)-silencing transcription factor (REST) which silences neural genes via epigenetic remodeling and promotes neurodegeneration. We presently determined if REST inhibition derepresses target genes involved in synaptic plasticity and promotes functional outcome after experimental stroke. Following transient focal ischemia induced by middle cerebral artery occlusion (MCAO) in adult rats, REST expression was upregulated significantly from 12 h to 1 day of reperfusion compared to sham control. At 1 day of reperfusion, REST protein levels were increased and observed in the nuclei of neurons in the peri-infarct cortex. REST knockdown by intracerebral REST siRNA injection significantly reduced the post-ischemic expression of REST and increased the expression of several REST target genes, compared to control siRNA group. REST inhibition also decreased post-ischemic markers of apoptosis, reduced cortical infarct volume, and improved post-ischemic functional recovery on days 5 and 7 of reperfusion compared to the control siRNA group. REST knockdown resulted in a global increase in synaptic plasticity gene expression at 1 day of reperfusion compared to the control siRNA group and significantly increased several synaptic plasticity genes containing RE-1 sequences in their regulatory regions. These results demonstrate that direct inhibition of the epigenetic remodeler REST prevents secondary brain damage in the cortex and improves functional outcome potentially via de-repression of plasticity-related genes after stroke.

Keywords

Cerebral ischemia Transcription factor Synaptic plasticity Neurodegeneration BDNF Neuron-restrictive silencing factor 

Notes

Funding Information

This study was funded by the National Institute of Health grant no. R21NS095192, RO1 NS099531, and RO1 NS101960.

Compliance with Ethical Standards

Human and Animal Rights and Informed Consent

All surgical procedures were approved by the Research Animal Resources and Care Committee of the University of Wisconsin-Madison, and the rats were cared for in accordance with the Guide for the Care and Use of Laboratory Animals (U.S. Department of Health and Human Services Publication 86-23, revised).

References

  1. 1.
    Hu Z, Zhong B, Tan J, Chen C, Lei Q, Zeng L (2016) The emerging role of epigenetics in cerebral ischemia. Mol Neurobiol 54:1887–1905.  https://doi.org/10.1007/s12035-016-9788-3 CrossRefPubMedGoogle Scholar
  2. 2.
    Calderone A, Jover T, Noh KM, Tanaka H, Yokota H, Lin Y, Grooms SY, Regis R et al (2003) Ischemic insults derepress the gene silencer REST in neurons destined to die. J Neurosci 23(6):2112–2121CrossRefGoogle Scholar
  3. 3.
    Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MV, Zukin RS (2012) Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci U S A 109(16):E962–E971.  https://doi.org/10.1073/pnas.1121568109 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mehta SL, Kim T, Vemuganti R (2015) Long noncoding RNA FosDT promotes ischemic brain injury by interacting with REST-associated chromatin-modifying proteins. J Neurosci 35(50):16443–16449.  https://doi.org/10.1523/jneurosci.2943-15.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Liu Z, Liu M, Niu G, Cheng Y, Fei J (2009) Genome-wide identification of target genes repressed by the zinc finger transcription factor REST/NRSF in the HEK 293 cell line. Acta Biochim Biophys Sin Shanghai 41(12):1008–1017CrossRefGoogle Scholar
  6. 6.
    Schoenherr CJ, Paquette AJ, Anderson DJ (1996) Identification of potential target genes for the neuron-restrictive silencer factor. Proc Natl Acad Sci U S A 93(18):9881–9886CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Huang Y, Myers SJ, Dingledine R (1999) Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nat Neurosci 2(10):867–872.  https://doi.org/10.1038/13165 CrossRefPubMedGoogle Scholar
  8. 8.
    Qureshi IA, Mehler MF (2009) Regulation of non-coding RNA networks in the nervous system—what’s the REST of the story? Neurosci Lett 466(2):73–80.  https://doi.org/10.1016/j.neulet.2009.07.093 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wu J, Xie X (2006) Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol 7(9):R85.  https://doi.org/10.1186/gb-2006-7-9-r85 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G (2005) REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121(4):645–657.  https://doi.org/10.1016/j.cell.2005.03.013 CrossRefPubMedGoogle Scholar
  11. 11.
    Abrajano JJ, Qureshi IA, Gokhan S, Molero AE, Zheng D, Bergman A, Mehler MF (2010) Corepressor for element-1-silencing transcription factor preferentially mediates gene networks underlying neural stem cell fate decisions. Proc Natl Acad Sci U S A 107(38):16685–16690.  https://doi.org/10.1073/pnas.0906917107 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR et al (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35(1):76–83.  https://doi.org/10.1038/ng1219 CrossRefPubMedGoogle Scholar
  13. 13.
    Paquette AJ, Perez SE, Anderson DJ (2000) Constitutive expression of the neuron-restrictive silencer factor (NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors in vivo. Proc Natl Acad Sci U S A 97(22):12318–12323.  https://doi.org/10.1073/pnas.97.22.12318 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Baldelli P, Meldolesi J (2015) The transcription repressor REST in adult neurons: physiology, pathology, and diseases (1,2,3). eNeuro 2(4). doi: https://doi.org/10.1523/eneuro.0010-15.2015
  15. 15.
    Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM et al (2014) REST and stress resistance in ageing and Alzheimer’s disease. Nature 507(7493):448–454.  https://doi.org/10.1038/nature13163 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zuccato C, Belyaev N, Conforti P, Ooi L, Tartari M, Papadimou E, MacDonald M, Fossale E et al (2007) Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease. J Neurosci 27(26):6972–6983.  https://doi.org/10.1523/jneurosci.4278-06.2007 CrossRefPubMedGoogle Scholar
  17. 17.
    Ooi L, Wood IC (2007) Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet 8(7):544–554.  https://doi.org/10.1038/nrg2100 CrossRefPubMedGoogle Scholar
  18. 18.
    McClelland S, Flynn C, Dube C, Richichi C, Zha Q, Ghestem A, Esclapez M, Bernard C et al (2011) Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. Ann Neurol 70(3):454–464.  https://doi.org/10.1002/ana.22479 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lin TP, Chang YT, Lee SY, Campbell M, Wang TC, Shen SH, Chung HJ, Chang YH et al (2016) REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling. Oncotarget 7(18):26137–26151.  https://doi.org/10.18632/oncotarget.8433 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cavadas MA, Mesnieres M, Crifo B, Manresa MC, Selfridge AC, Scholz CC, Cummins EP, Cheong A et al (2015) REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia. Sci Rep 5:17851.  https://doi.org/10.1038/srep17851 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cavadas MA, Mesnieres M, Crifo B, Manresa MC, Selfridge AC, Keogh CE, Fabian Z, Scholz CC et al (2016) REST is a hypoxia-responsive transcriptional repressor. Sci Rep 6:31355.  https://doi.org/10.1038/srep31355 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pandi G, Nakka VP, Dharap A, Roopra A, Vemuganti R (2013) MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage. PLoS One 8(3):e58039.  https://doi.org/10.1371/journal.pone.0058039 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Formisano L, Guida N, Valsecchi V, Cantile M, Cuomo O, Vinciguerra A, Laudati G, Pignataro G et al (2015) Sp3/REST/HDAC1/HDAC2 complex represses and Sp1/HIF-1/p300 complex activates ncx1 gene transcription, in brain ischemia and in ischemic brain preconditioning, by epigenetic mechanism. J Neurosci 35(19):7332–7348.  https://doi.org/10.1523/jneurosci.2174-14.2015 CrossRefPubMedGoogle Scholar
  24. 24.
    Formisano L, Guida N, Valsecchi V, Pignataro G, Vinciguerra A, Pannaccione A, Secondo A, Boscia F et al (2013) NCX1 is a new rest target gene: role in cerebral ischemia. Neurobiol Dis 50:76–85.  https://doi.org/10.1016/j.nbd.2012.10.010 CrossRefPubMedGoogle Scholar
  25. 25.
    Nakka VP, Lang BT, Lenschow DJ, Zhang DE, Dempsey RJ, Vemuganti R (2011) Increased cerebral protein ISGylation after focal ischemia is neuroprotective. J Cereb Blood Flow Metab 31(12):2375–2384.  https://doi.org/10.1038/jcbfm.2011.103 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mehta SL, Pandi G, Vemuganti R (2017) Circular RNA expression profiles alter significantly in mouse brain after transient focal ischemia. Stroke 48(9):2541–2548.  https://doi.org/10.1161/strokeaha.117.017469 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shyu WC, Lin SZ, Chiang MF, Chen DC, Su CY, Wang HJ, Liu RS, Tsai CH et al (2008) Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke. J Clin Invest 118(1):133–148.  https://doi.org/10.1172/jci32723 CrossRefPubMedGoogle Scholar
  28. 28.
    Murphy TH, Corbett D (2009) Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci 10(12):861–872.  https://doi.org/10.1038/nrn2735 CrossRefPubMedGoogle Scholar
  29. 29.
    Pekna M, Pekny M, Nilsson M (2012) Modulation of neural plasticity as a basis for stroke rehabilitation. Stroke 43(10):2819–2828.  https://doi.org/10.1161/strokeaha.112.654228 CrossRefPubMedGoogle Scholar
  30. 30.
    Johnson DS, Mortazavi A, Myers RM, Wold B (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316(5830):1497–1502.  https://doi.org/10.1126/science.1141319 CrossRefGoogle Scholar
  31. 31.
    Mortazavi A, Leeper Thompson EC, Garcia ST, Myers RM, Wold B (2006) Comparative genomics modeling of the NRSF/REST repressor network: from single conserved sites to genome-wide repertoire. Genome Res 16(10):1208–1221.  https://doi.org/10.1101/gr.4997306 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bruce AW, Donaldson IJ, Wood IC, Yerbury SA, Sadowski MI, Chapman M, Gottgens B, Buckley NJ (2004) Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc Natl Acad Sci U S A 101(28):10458–10463.  https://doi.org/10.1073/pnas.0401827101 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Johnson R, Teh CH, Kunarso G, Wong KY, Srinivasan G, Cooper ML, Volta M, Chan SS et al (2008) REST regulates distinct transcriptional networks in embryonic and neural stem cells. PLoS Biol 6(10):e256.  https://doi.org/10.1371/journal.pbio.0060256 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Yu M, Cai L, Liang M, Huang Y, Gao H, Lu S, Fei J, Huang F (2009) Alteration of NRSF expression exacerbating 1-methyl-4-phenyl-pyridinium ion-induced cell death of SH-SY5Y cells. Neurosci Res 65(3):236–244.  https://doi.org/10.1016/j.neures.2009.07.006 CrossRefPubMedGoogle Scholar
  35. 35.
    Yu M, Suo H, Liu M, Cai L, Liu J, Huang Y, Xu J, Wang Y et al (2013) NRSF/REST neuronal deficient mice are more vulnerable to the neurotoxin MPTP. Neurobiol Aging 34(3):916–927.  https://doi.org/10.1016/j.neurobiolaging.2012.06.002 CrossRefPubMedGoogle Scholar
  36. 36.
    Posod A, Wechselberger K, Stanika RI, Obermair GJ, Wegleiter K, Huber E, Urbanek M, Kiechl-Kohlendorfer U et al (2017) Administration of secretoneurin is protective in hypoxic-ischemic neonatal brain injury predominantly in the hypoxic-only hemisphere. Neuroscience 352:88–96.  https://doi.org/10.1016/j.neuroscience.2017.03.055 CrossRefPubMedGoogle Scholar
  37. 37.
    Oguro K, Oguro N, Kojima T, Grooms SY, Calderone A, Zheng X, Bennett MV, Zukin RS (1999) Knockdown of AMPA receptor GluR2 expression causes delayed neurodegeneration and increases damage by sublethal ischemia in hippocampal CA1 and CA3 neurons. J Neurosci 19(21):9218–9227CrossRefGoogle Scholar
  38. 38.
    Naruse S, Aoki Y, Takei R, Horikawa Y, Ueda S (1991) Effects of atrial natriuretic peptide on ischemic brain edema in rats evaluated by proton magnetic resonance method. Stroke 22(1):61–65CrossRefGoogle Scholar
  39. 39.
    Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M (1999) NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med 5(5):554–559.  https://doi.org/10.1038/8432 CrossRefPubMedGoogle Scholar
  40. 40.
    Lenz M, Vlachos A, Maggio N (2015) Ischemic long-term-potentiation (iLTP): perspectives to set the threshold of neural plasticity toward therapy. Neural Regen Res 10(10):1537–1539.  https://doi.org/10.4103/1673-5374.165215 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Minatohara K, Akiyoshi M, Okuno H (2015) Role of immediate-early genes in synaptic plasticity and neuronal ensembles underlying the memory trace. Front Mol Neurosci 8:78. doi: https://doi.org/10.3389/fnmol.2015.00078
  42. 42.
    Lanahan A, Worley P (1998) Immediate-early genes and synaptic function. Neurobiol Learn Mem 70(1–2):37–43.  https://doi.org/10.1006/nlme.1998.3836 CrossRefPubMedGoogle Scholar
  43. 43.
    Schabitz WR, Berger C, Kollmar R, Seitz M, Tanay E, Kiessling M, Schwab S, Sommer C (2004) Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia. Stroke 35(4):992–997.  https://doi.org/10.1161/01.str.0000119754.85848.0d CrossRefPubMedGoogle Scholar
  44. 44.
    Schabitz WR, Sommer C, Zoder W, Kiessling M, Schwaninger M, Schwab S (2000) Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke 31(9):2212–2217CrossRefGoogle Scholar
  45. 45.
    Berretta A, Tzeng YC, Clarkson AN (2014) Post-stroke recovery: the role of activity-dependent release of brain-derived neurotrophic factor. Expert Rev Neurother 14(11):1335–1344.  https://doi.org/10.1586/14737175.2014.969242 CrossRefPubMedGoogle Scholar
  46. 46.
    Lu B, Nagappan G, Lu Y (2014) BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 220:223–250.  https://doi.org/10.1007/978-3-642-45106-5_9 CrossRefPubMedGoogle Scholar
  47. 47.
    Glorioso C, Sabatini M, Unger T, Hashimoto T, Monteggia LM, Lewis DA, Mirnics K (2006) Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood. Mol Psychiatry 11(7):633–648.  https://doi.org/10.1038/sj.mp.4001835 CrossRefPubMedGoogle Scholar
  48. 48.
    Jourdi H, Kabbaj M (2013) Acute BDNF treatment upregulates GluR1-SAP97 and GluR2-GRIP1 interactions: implications for sustained AMPA receptor expression. PLoS One 8(2):e57124.  https://doi.org/10.1371/journal.pone.0057124 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Sato M, Suzuki K, Nakanishi S (2001) NMDA receptor stimulation and brain-derived neurotrophic factor upregulate homer 1a mRNA via the mitogen-activated protein kinase cascade in cultured cerebellar granule cells. J Neurosci 21(11):3797–3805CrossRefGoogle Scholar
  50. 50.
    Wu CL, Yin JH, Hwang CS, Chen SD, Yang DY, Yang DI (2012) c-Jun-dependent sulfiredoxin induction mediates BDNF protection against mitochondrial inhibition in rat cortical neurons. Neurobiol Dis 46(2):450–462.  https://doi.org/10.1016/j.nbd.2012.02.010 CrossRefPubMedGoogle Scholar
  51. 51.
    Kuzniewska B, Rejmak E, Malik AR, Jaworski J, Kaczmarek L, Kalita K (2013) Brain-derived neurotrophic factor induces matrix metalloproteinase 9 expression in neurons via the serum response factor/c-Fos pathway. Mol Cell Biol 33(11):2149–2162.  https://doi.org/10.1128/mcb.00008-13 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, Nawa H (2004) Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 24(44):9760–9769.  https://doi.org/10.1523/jneurosci.1427-04.2004 CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Neurological SurgeryUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.William S. Middleton Veterans Administration HospitalMadisonUSA
  3. 3.Cellular and Molecular Pathology ProgramUniversity of Wisconsin-MadisonMadisonUSA

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