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Molecular Pharmacology

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Research ArticleArticle

DNA Methyltransferase Inhibitors Coordinately Induce Expression of the Human Reelin and Glutamic Acid Decarboxylase 67 Genes

Marija Kundakovic, Ying Chen, Erminio Costa and Dennis R. Grayson
Molecular Pharmacology March 2007, 71 (3) 644-653; DOI: https://doi.org/10.1124/mol.106.030635
Marija Kundakovic
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Ying Chen
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Erminio Costa
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Dennis R. Grayson
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Abstract

Reelin and glutamic acid decarboxylase 67 (GAD67) mRNAs and protein levels are substantially reduced in postmortem brains of patients with schizophrenia. Increasing evidence suggests that the observed down-regulation of reelin and GAD67 gene expression may be caused by dysfunction of the epigenetic regulatory mechanisms operative in cortical GABAergic interneurons. To explore whether human reelin and GAD67 mRNAs are coordinately regulated through DNA methylation-dependent mechanisms, we studied the effects of DNA methyltransferase inhibitors on reelin and GAD67 expression in NT-2 neuronal precursor cells. Competitive reverse transcription-polymerase chain reaction with internal standards was used to quantitate mRNA levels. The data showed that reelin and GAD67 mRNAs are induced in the same dose- and time-dependent manners. We further demonstrated that the activation of these two genes correlated with a reduction in DNA methyl-transferase activity and DNA methyltransferase 1 (DNMT1) protein levels. Time course Western blot analysis showed that DNMT1 protein down-regulation occurs temporally before the reelin and GAD67 mRNA increase. In addition, chromatin immunoprecipitation assays demonstrated that the activation of the reelin gene correlates with the dissociation of DNMT1 and methyl-CpG binding protein 2 (MeCP2) from the promoter, and an increased acetylation of histones H3 in the region. Together, our data strongly imply that human reelin and GAD67 genes are coordinately regulated through epigenetic mechanisms that include the action of DNMT1. Our study also suggests that negative regulation of the reelin gene involves methylation-dependent recruitment of DNMT1, MeCP2, and certain histone deacetylases, which most likely reduce the activity of the promoter by shifting the surrounding chromatin into a more compact state.

Footnotes

  • This work was supported by grant MH62682-05 from the National Institutes of Mental Health (to D.R.G.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.030635.

  • ABBREVIATIONS: DNMT, DNA methyltransferase; AZA, 5-aza-2′-deoxycytidine; ChIP, chromatin immunoprecipitation; DOXO, doxorubicin; G3PDH, glyceraldehyde 3-phosphate dehydrogenase; GAD67, glutamic acid decarboxylase 67; HDAC, histone deacetylase; MeCP2, methyl-CpG binding protein 2; NT-2, N-tera 2 neuronal progenitor cells; ZEB, zebularine; ANOVA, analysis of variance; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; bp, base pair(s); PBS, phosphate-buffered saline.

    • Received September 6, 2006.
    • Accepted October 24, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (3)
Molecular Pharmacology
Vol. 71, Issue 3
1 Mar 2007
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Research ArticleArticle

DNA Methyltransferase Inhibitors Coordinately Induce Expression of the Human Reelin and Glutamic Acid Decarboxylase 67 Genes

Marija Kundakovic, Ying Chen, Erminio Costa and Dennis R. Grayson
Molecular Pharmacology March 1, 2007, 71 (3) 644-653; DOI: https://doi.org/10.1124/mol.106.030635

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Research ArticleArticle

DNA Methyltransferase Inhibitors Coordinately Induce Expression of the Human Reelin and Glutamic Acid Decarboxylase 67 Genes

Marija Kundakovic, Ying Chen, Erminio Costa and Dennis R. Grayson
Molecular Pharmacology March 1, 2007, 71 (3) 644-653; DOI: https://doi.org/10.1124/mol.106.030635
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