Skip to main content
Log in

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

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • 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 302:885–889

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Sharma RP, Costa RH, Costa E, Grayson DR (2002) On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res 30:2930–2939

    Article  PubMed  CAS  Google Scholar 

  • Detich N, Bovenzi V, Szyf M (2003) Valproate induces replication-independent active DNA demethylation. J Biol Chem 278:27586–27592

    Article  PubMed  CAS  Google Scholar 

  • 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 79:734–746

    Article  PubMed  CAS  Google Scholar 

  • 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 13:423–430

    Article  PubMed  CAS  Google Scholar 

  • 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 102:9341–9346

    Article  PubMed  CAS  Google Scholar 

  • 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 111:272–286

    Article  PubMed  CAS  Google Scholar 

  • Haas CA, Frotscher M (2010) Reelin deficiency causes granule cell dispersion in epilepsy. Exp Brain Res 200:141–149

    Article  PubMed  Google Scholar 

  • 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 22:8422–8428

    PubMed  CAS  Google Scholar 

  • 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 68:356–364

    Article  PubMed  CAS  Google Scholar 

  • 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 13:1137–1143

    Article  PubMed  CAS  Google Scholar 

  • 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 281:15763–15773

    Article  PubMed  CAS  Google Scholar 

  • 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 73:1963–1972

    Article  PubMed  CAS  Google Scholar 

  • 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 457:8–11

    Article  PubMed  CAS  Google Scholar 

  • McKinney RA, Capogna M, Durr R, Gahwiler BH, Thompson SM (1999) Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat Neurosci 2:44–49

    Article  PubMed  CAS  Google Scholar 

  • Mehler MF (2008) Epigenetics and the nervous system. Ann Neurol 64:602–617

    Article  PubMed  CAS  Google Scholar 

  • Nelson ED, Kavalali ET, Monteggia LM (2008) Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J Neurosci 28:395–406

    Article  PubMed  CAS  Google Scholar 

  • Newell-Price J, Clark AJ, King P (2000) DNA methylation and silencing of gene expression. Trends Endocrinol Metab 11:142–148

    Article  PubMed  CAS  Google Scholar 

  • 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 102:1749–1754

    Article  PubMed  CAS  Google Scholar 

  • Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257

    Article  PubMed  CAS  Google Scholar 

  • 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 276:36734–36741

    Article  PubMed  CAS  Google Scholar 

  • Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610

    Article  PubMed  CAS  Google Scholar 

  • Sng JC, Taniura H, Yoneda Y (2006) Histone modifications in kainate-induced status epilepticus. Eur J Neurosci 23:1269–1282

    Article  PubMed  Google Scholar 

  • Tsankova NM, Kumar A, Nestler EJ (2004) Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J Neurosci 24:5603–5610

    Article  PubMed  CAS  Google Scholar 

  • 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 111:115–122

    Article  PubMed  CAS  Google Scholar 

  • Zucker RS (2005) Minis: whence and wherefore? Neuron 45:482–484

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xue-feng Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, Q., Wang, L., Zhang, Y. et al. Increased Expression of DNA methyltransferase 1 and 3a in Human Temporal Lobe Epilepsy. J Mol Neurosci 46, 420–426 (2012). https://doi.org/10.1007/s12031-011-9602-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-011-9602-7

Keywords

Navigation