Cell Adhesion Molecules, Neuronal

Publication Title: 
Nucleic Acids Research

Reln mRNA and protein levels are reduced by approximately 50% in various cortical structures of post-mortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. To study mechanisms responsible for this down-regulation, we have analyzed the promoter of the human reelin gene. We show that the reelin promoter directs expression of a reporter construct in multiple human cell types: neuroblastoma cells (SHSY5Y), neuronal precursor cells (NT2), differentiated neurons (hNT) and hepatoma cells (HepG2).

Author(s): 
Chen, Ying
Sharma, Rajiv P.
Costa, Robert H.
Costa, Erminio
Grayson, Dennis R.
Publication Title: 
Schizophrenia Research

Covalent modifications of DNA and its surrounding chromatin constitute an essential and powerful regulatory mechanism for gene transcription. Epigenetics is the study of this regulatory system. There is now strong albeit indirect evidence that epigenetic mechanisms contribute to the pathophysiology of schizophrenia. Furthermore, the discovery that valproic acid, a widely used psychotropic, has powerful epigenetic effects in clinically relevant concentrations suggests new therapeutic possibilities, i.e., drugs that act on chromatin structure.

Author(s): 
Sharma, Rajiv P.
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

The polygenic nature of complex psychiatric disorders suggests a common pathway that may be involved in the down-regulation of multiple genes through an epigenetic mechanism. To investigate the role of methylation in down-regulating the expression of mRNAs that may be associated with the schizophrenia phenotype, we have adopted a cell-culture model amenable to this line of investigation.

Author(s): 
Noh, Jai Sung
Sharma, Rajiv P.
Veldic, Marin
Salvacion, Alain A.
Jia, Xiaomei
Chen, Ying
Costa, Erminio
Guidotti, Alessandro
Grayson, Dennis R.
Publication Title: 
American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics

DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns.

Author(s): 
Abdolmaleky, Hamid Mostafavi
Cheng, Kuang-hung
Russo, Andrea
Smith, Cassandra L.
Faraone, Stephen V.
Wilcox, Marsha
Shafa, Rahim
Glatt, Stephen J.
Nguyen, Giang
Ponte, Joe F.
Thiagalingam, Sam
Tsuang, Ming T.
Publication Title: 
American Journal of Pharmacogenomics: Genomics-Related Research in Drug Development and Clinical Practice

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms.

Author(s): 
Abdolmaleky, Hamid M.
Thiagalingam, Sam
Wilcox, Marsha
Publication Title: 
Pharmacology & Therapeutics

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.

Author(s): 
Grayson, Dennis R.
Chen, Ying
Costa, Erminio
Dong, Erbo
Guidotti, Alessandro
Kundakovic, Marija
Sharma, Rajiv P.
Publication Title: 
Molecular Pharmacology

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.

Author(s): 
Kundakovic, Marija
Chen, Ying
Costa, Erminio
Grayson, Dennis R.
Publication Title: 
Schizophrenia Research

In the cerebral prefrontal cortex (PFC), DNA-methyltransferase 1 (DNMT1), the enzyme that catalyzes the methylation of cytosine at carbon atoms in position 5 in CpG dinucleotides, is expressed selectively in GABAergic neurons and is upregulated in layers I and II of schizophrenia (SZ) and bipolar disorder patients with psychosis (BDP).

Author(s): 
Veldic, Marin
Kadriu, Bashkim
Maloku, Ekrem
Agis-Balboa, Roberto C.
Guidotti, Alessandro
Davis, John M.
Costa, Erminio
Publication Title: 
Molecular Psychiatry

Epigenetic genome modifications such as DNA methylation appear to be involved in various diseases. Here, we suggest that the levels of DNA methylation at the BssHII methylation-sensitive restriction enzyme sites in the human REELIN (RELN) gene in the forebrain vary among individuals. Interestingly, although a statistically significant correlation between the levels of DNA methylation in RELN and age was detected in healthy individuals, no such correlations were seen in either schizophrenic or bipolar patients.

Author(s): 
Tamura, Y.
Kunugi, H.
Ohashi, J.
Hohjoh, H.
Publication Title: 
Molecular Pharmacology

The epigenetic down-regulation of genes is emerging as a possible underlying mechanism of the GABAergic neuron dysfunction in schizophrenia. For example, evidence has been presented to show that the promoters associated with reelin and GAD67 are down-regulated as a consequence of DNA methyltransferase (DNMT)-mediated hypermethylation. Using neuronal progenitor cells to study this regulation, we have previously demonstrated that DNMT inhibitors coordinately increase reelin and GAD67 mRNAs.

Author(s): 
Kundakovic, Marija
Chen, Ying
Guidotti, Alessandro
Grayson, Dennis R.

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