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Chromatin Alterations Associated With Down-regulated Metabolic Gene Expression in the Prefrontal Cortex of Subjects With Schizophrenia
Schahram Akbarian, MD, PhD;
Martin G. Ruehl, Dipl Ing;
Erin Bliven, BS;
Lori A. Luiz, BS;
Amy C. Peranelli, BS;
Stephen P. Baker, MScPH;
Rosalinda C. Roberts, PhD;
William E. Bunney, Jr, MD;
Robert C. Conley, MD;
Edward G. Jones, MD, PhD;
Carol A. Tamminga, MD;
Yin Guo, MD
Arch Gen Psychiatry. 2005;62:829-840.
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.
Author Affiliations: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry (Drs Akbarian and Guo, Mr Ruehl, and Mss Bliven, Luiz, and Peranelli) and Bioinformatics Unit, Information Services (Mr Baker), University of Massachusetts Medical School, Worcester; Maryland Psychiatric Research Center, University of Maryland, Baltimore (Drs Roberts and Conley); Department of Psychiatry and Human Behavior, University of California at Irvine (Dr Bunney); Center for Neuroscience, Department of Psychiatry, University of California at Davis (Dr Jones); and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas (Dr Tamminga).
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