Journal of Molecular Neuroscience

, Volume 46, Issue 2, pp 420–426 | Cite as

Increased Expression of DNA methyltransferase 1 and 3a in Human Temporal Lobe Epilepsy

  • Qiong Zhu
  • Liang Wang
  • Ying Zhang
  • Feng-hua Zhao
  • Jing Luo
  • Zheng Xiao
  • Guo-jun Chen
  • Xue-feng Wang
Article
First Online:
Received:
Accepted:

Abstract

DNA methylation is a key epigenetic modification of DNA that is catalyzed by DNA methyltransferase (DNMT). Increasing evidence suggests that DNA methylation in neurons regulates synaptic plasticity as well as neuronal network activity. Here, we evaluated DNA methyltransferase 1 (Dnmt1) and Dnmt3a expression in brain tissues of epileptic patients to explore their possible role in epileptogenesis. Tissue samples from temporal neocortices of 25 patients with intractable temporal lobe epilepsy (TLE) and ten histologically normal temporal lobes from control patients were used to detect Dnmt1 and Dnmt3a expression through immunohistochemistry, immunofluorescence, and Western blotting analysis. We found that both Dnmt1 and Dnmt3a expression were principally expressed in the nucleus and the cytoplasm of NeuN-positive neurons, but not in GFAP-positive astrocytes. Levels of the two DNMT proteins were significantly increased in patients with TLE. Our study suggests that DNMT1 and DNMT3a may play a role in the pathogenesis of TLE.

Keywords

Temporal lobe epilepsy DNA methyltransferase 1 DNA methyltransferase 3a 
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Notes

Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (no. 81071039, 81071040). We sincerely thank the patients and their families for their participation in this study.

References

  1. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302:885–889PubMedCrossRefGoogle Scholar
  2. Chen Y, Sharma RP, Costa RH, Costa E, Grayson DR (2002) On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res 30:2930–2939PubMedCrossRefGoogle Scholar
  3. Detich N, Bovenzi V, Szyf M (2003) Valproate induces replication-independent active DNA demethylation. J Biol Chem 278:27586–27592PubMedCrossRefGoogle Scholar
  4. Feng J, Chang H, Li E, Fan G (2005) Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res 79:734–746PubMedCrossRefGoogle Scholar
  5. Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13:423–430PubMedCrossRefGoogle Scholar
  6. Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A, Costa E (2005) Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A 102:9341–9346PubMedCrossRefGoogle Scholar
  7. Grayson DR, Chen Y, Costa E, Dong E, Guidotti A, Kundakovic M, Sharma RP (2006) The human reelin gene: transcription factors (+), repressors (−) and the methylation switch (+/−) in schizophrenia. Pharmacol Ther 111:272–286PubMedCrossRefGoogle Scholar
  8. Haas CA, Frotscher M (2010) Reelin deficiency causes granule cell dispersion in epilepsy. Exp Brain Res 200:141–149PubMedCrossRefGoogle Scholar
  9. Huang Y, Doherty JJ, Dingledine R (2002) Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. J Neurosci 22:8422–8428PubMedGoogle Scholar
  10. Kobow K, Jeske I, Hildebrandt M, Hauke J, Hahnen E, Buslei R, Buchfelder M, Weigel D, Stefan H, Kasper B, Pauli E, Blumcke I (2009) Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. J Neuropathol Exp Neurol 68:356–364PubMedCrossRefGoogle Scholar
  11. LaPlant Q, Vialou V, Covington HE, Dumitriu D, Feng J, Warren BL, Maze I, Dietz DM, Watts EL, Iniguez SD, Koo JW, Mouzon E, Renthal W, Hollis F, Wang H, Noonan MA, Ren Y, Eisch AJ, Bolanos CA, Kabbaj M, Xiao G, Neve RL, Hurd YL, Oosting RS, Fan G, Morrison JH, Nestler EJ (2010) Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci 13:1137–1143PubMedCrossRefGoogle Scholar
  12. Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, Malone LM, Sweatt JD (2006) Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 281:15763–15773PubMedCrossRefGoogle Scholar
  13. Liu ZJ, Maekawa M, Horii T, Morita M (2003) The multiple promoter methylation profile of PR gene and ERalpha gene in tumor cell lines. Life Sci 73:1963–1972PubMedCrossRefGoogle Scholar
  14. Lundberg J, Karimi M, von Gertten C, Holmin S, Ekstrom TJ, Sandberg-Nordqvist AC (2009) Traumatic brain injury induces relocalization of DNA-methyltransferase 1. Neurosci Lett 457:8–11PubMedCrossRefGoogle Scholar
  15. McKinney RA, Capogna M, Durr R, Gahwiler BH, Thompson SM (1999) Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat Neurosci 2:44–49PubMedCrossRefGoogle Scholar
  16. Mehler MF (2008) Epigenetics and the nervous system. Ann Neurol 64:602–617PubMedCrossRefGoogle Scholar
  17. Nelson ED, Kavalali ET, Monteggia LM (2008) Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J Neurosci 28:395–406PubMedCrossRefGoogle Scholar
  18. Newell-Price J, Clark AJ, King P (2000) DNA methylation and silencing of gene expression. Trends Endocrinol Metab 11:142–148PubMedCrossRefGoogle Scholar
  19. Noh JS, Sharma RP, Veldic M, Salvacion AA, Jia X, Chen Y, Costa E, Guidotti A, Grayson DR (2005) DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci U S A 102:1749–1754PubMedCrossRefGoogle Scholar
  20. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257PubMedCrossRefGoogle Scholar
  21. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741PubMedCrossRefGoogle Scholar
  22. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610PubMedCrossRefGoogle Scholar
  23. Sng JC, Taniura H, Yoneda Y (2006) Histone modifications in kainate-induced status epilepticus. Eur J Neurosci 23:1269–1282PubMedCrossRefGoogle Scholar
  24. Tsankova NM, Kumar A, Nestler EJ (2004) Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J Neurosci 24:5603–5610PubMedCrossRefGoogle Scholar
  25. Zhubi A, Veldic M, Puri NV, Kadriu B, Caruncho H, Loza I, Sershen H, Lajtha A, Smith RC, Guidotti A, Davis JM, Costa E (2009) An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes. Schizophr Res 111:115–122PubMedCrossRefGoogle Scholar
  26. Zucker RS (2005) Minis: whence and wherefore? Neuron 45:482–484PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Qiong Zhu
    • 1
  • Liang Wang
    • 1
  • Ying Zhang
    • 1
  • Feng-hua Zhao
    • 1
  • Jing Luo
    • 1
  • Zheng Xiao
    • 1
  • Guo-jun Chen
    • 1
  • Xue-feng Wang
    • 1
  1. 1.Department of NeurologyThe First Affiliated Hospital, Chongqing Medical UniversityChongqingChina

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