Title

Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia

PubMed ID

16061760

UMMS Affiliation

Brudnick Neuropsychiatric Research Institute; Department of Psychiatry; Graduate School of Biomedical Sciences

Date

8-3-2005

Document Type

Article

Subjects

Chromatin; Down Syndrome; Epigenesis, Genetic; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Histones; Humans; Immunoblotting; Immunohistochemistry; Oligonucleotide Array Sequence Analysis; Prefrontal Cortex; Reverse Transcriptase Polymerase Chain Reaction; Schizophrenia

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

BACKGROUND: Schizophrenia is frequently accompanied by hypometabolism and altered gene expression in the prefrontal cortex. Cellular metabolism regulates chromatin structure, including covalent histone modifications, which are epigenetic regulators of gene expression. OBJECTIVE: To test the hypothesis that down-regulated metabolic gene expression is associated with histone modification changes in the prefrontal cortex of subjects with schizophrenia. DESIGN AND SUBJECTS: Histones and gene transcripts were profiled in the postmortem prefrontal cortex of 41 subjects with schizophrenia and 41 matched controls. The phosphorylation, acetylation, and methylation of 6 lysine, serine, and arginine residues of histones H3 and H4 were examined together with 16 metabolic gene transcripts using serial immunoblotting, immunohistochemical analysis, custom-made complementary DNA arrays, and quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Subjects with schizophrenia, as a group, showed no significant alterations in histone profiles or gene expression. In a subgroup of 8 patients with schizophrenia, levels of H3-(methyl)arginine 17, H3meR17, exceeded control values by 30%, and this was associated with the decreased expression of 4 metabolic transcripts. CONCLUSIONS: High levels of H3-(methyl)arginine 17 are associated with down-regulated metabolic gene expression in the prefrontal cortex of a subset of subjects with schizophrenia. Histone modifications may contribute to the pathogenesis of prefrontal dysfunction in schizophrenia.

Rights and Permissions

Citation: Arch Gen Psychiatry. 2005 Aug;62(8):829-40. Link to article on publisher's site

Related Resources

Link to article in PubMed