The human reelin gene: transcription factors (+), repressors (-) and the methylation switch (+/-) in schizophrenia

• Published in: Pharmacology & therapeutics (Oxford) 2006-07, Vol.111 (1), p.272-286
• Main Authors: Grayson, Dennis R, Chen, Ying, Costa, Erminio, Dong, Erbo, Guidotti, Alessandro, Kundakovic, Marija, Sharma, Rajiv P
• Format: Article
• Language: English
• Subjects: Animals; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Central Nervous System - metabolism; DNA Methylation; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Gene Expression Regulation; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - metabolism; Humans; Isoenzymes - genetics; Isoenzymes - metabolism; Jia; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - metabolism; Promoter Regions, Genetic; Repressor Proteins - metabolism; RNA, Messenger - metabolism; Schizophrenia - genetics; Schizophrenia - metabolism; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Transcription Factors - metabolism
• ISSN: 0163-7258
• DOI: 10.1016/j.pharmthera.2005.01.007

A recent report suggests that the down-regulation of reelin and glutamic acid decarboxylase (GAD(67)) mRNAs represents 2 of the more consistent findings thus far described in post-mortem material from schizophrenia (SZ) patients [reviewed in. Neurochemical markers for schizophrenia, bipolar disorder amd major depression in postmortem brains. Biol Psychiatry 57, 252-260]. To study mechanisms responsible for this down-regulation, we have analyzed the promoter of the human reelin gene. Collectively, our studies suggest that SZ is characterized by a gamma-amino butyric acid (GABA)-ergic neuron pathology presumably mediated by promoter hypermethylation facilitated by the over-expression of the methylating enzyme DNA methyltransferase (Dnmt) 1. Using transient expression assays, promoter deletions and co-transfection assays with various transcription factors, we have shown a clear synergistic action that is a critical component of the mechanism of the trans-activation process. Equally important is the observation that the reelin promoter is more heavily methylated in brain regions in patients diagnosed with SZ as compared to non-psychiatric control subjects [Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., & Guidotti, A., et al. (2005). Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A 102, 9341-9346]. The combination of studies in cell lines and in animal models of SZ, coupled with data obtained from post-mortem human material provides compelling evidence that aberrant methylation may be part of a core dysfunction in this psychiatric disease. More interestingly, the hypermethylation concept provides a coherent mechanism that establishes a plausible link between the epigenetic misregulation of multiple genes that are affected in SZ and that collectively contribute to the associated symptomatology.