QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.030635v1 71/3/644    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Related articles in MolPharm Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kundakovic, M. Articles by Grayson, D. R. Search for Related Content PubMed PubMed Citation Articles by Kundakovic, M. Articles by Grayson, D. R.

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

The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

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.

Received for publication September 6, 2006.

Accepted for publication October 24, 2006.

Address correspondence to: Dr. Dennis R. Grayson, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago IL, 60612. E-mail: dgrayson{at}psych.uic.edu

Related articles in MolPharm:

DNA (Cytosine-5) Methyltransferase Inhibitors: A Potential Therapeutic Agent for Schizophrenia

Jonathan M. Levenson
MolPharm 2007 71: 635-637. [Abstract] [Full Text]  

This article has been cited by other articles:

				Q. Li, D. L. Bartlett, M. C. Gorry, M. E. O'Malley, and Z. S. Guo Three Epigenetic Drugs Up-Regulate Homeobox Gene Rhox5 in Cancer Cells through Overlapping and Distinct Molecular Mechanisms Mol. Pharmacol., November 1, 2009; 76(5): 1072 - 1081. [Abstract] [Full Text] [PDF]

				M. Kundakovic, Y. Chen, A. Guidotti, and D. R. Grayson The Reelin and GAD67 Promoters Are Activated by Epigenetic Drugs That Facilitate the Disruption of Local Repressor Complexes Mol. Pharmacol., February 1, 2009; 75(2): 342 - 354. [Abstract] [Full Text] [PDF]

				J. M. Levenson DNA (Cytosine-5) Methyltransferase Inhibitors: A Potential Therapeutic Agent for Schizophrenia Mol. Pharmacol., March 1, 2007; 71(3): 635 - 637. [Abstract] [Full Text] [PDF]