The human reelin gene: transcription factors (+), repressors (-) and the methylation switch (+/-) in schizophrenia.
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.
Department of Psychiatry, The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., 60612, USA. dgrayson@psych.uic.edu
Dennis R
DR
Grayson
Ying
Y
Chen
Erminio
E
Costa
Erbo
E
Dong
Alessandro
A
Guidotti
Marija
M
Kundakovic
Rajiv P
RP
Sharma
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D019175:DNA Methylation; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D000091042:Reelin Protein; D012097:Repressor Proteins / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C000717127:RELN protein, human; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1