UMMS Affiliation
Department of Psychiatry
Publication Date
2007-08-30
Document Type
Article
Subjects
DNA Methylation; Glutamate Decarboxylase; Prefrontal Cortex; Schizophrenia
Disciplines
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
Abstract
Dysfunction of prefrontal cortex in schizophrenia includes changes in GABAergic mRNAs, including decreased expression of GAD1, encoding the 67 kDa glutamate decarboxylase (GAD67) GABA synthesis enzyme. The underlying molecular mechanisms remain unclear. Alterations in DNA methylation as an epigenetic regulator of gene expression are thought to play a role but this hypothesis is difficult to test because no techniques are available to extract DNA from GAD1 expressing neurons efficiently from human postmortem brain. Here, we present an alternative approach that is based on immunoprecipitation of mononucleosomes with anti-methyl-histone antibodies differentiating between sites of potential gene expression as opposed to repressive or silenced chromatin. Methylation patterns of CpG dinucleotides at the GAD1 proximal promoter and intron 2 were determined for each of the two chromatin fractions separately, using a case-control design for 14 schizophrenia subjects affected by a decrease in prefrontal GAD1 mRNA levels. In controls, the methylation frequencies at CpG dinucleotides, while overall higher in repressive as compared to open chromatin, did not exceed 5% at the proximal GAD1 promoter and 30% within intron 2. Subjects with schizophrenia showed a significant, on average 8-fold deficit in repressive chromatin-associated DNA methylation at the promoter. These results suggest that chromatin remodeling mechanisms are involved in dysregulated GABAergic gene expression in schizophrenia.
DOI of Published Version
10.1371/journal.pone.0000809
Source
PLoS ONE. 2007 Aug 29;2(8):e809. Link to article on publisher's site
Journal/Book/Conference Title
PLoS ONE
Related Resources
PubMed ID
17726539
Repository Citation
Huang H, Akbarian S. (2007). GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. Open Access Articles. https://doi.org/10.1371/journal.pone.0000809. Retrieved from https://escholarship.umassmed.edu/oapubs/1348
Comments
Co-author Hsien-Sung Huang is a student in the Neuroscience program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.