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Chromatin Alterations Associated with Down-Regulated Metabolic Gene Expression in the Prefrontal Cortex of Subjects with Schizophrenia

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Chromatin Alterations Associated with Down-Regulated Metabolic Gene Expression in the Prefrontal Cortex of Subjects with Schizophrenia ORIGINAL ARTICLE 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 Background: Schizophrenia is frequently accompanied cal analysis, custom-made complementary DNA arrays, by hypometabolism and altered gene expression in the pre- and quantitative real-time reverse transcriptase– frontal cortex. Cellular metabolism regulates chromatin polymerase chain reaction. structure, including covalent histone modifications, which are epigenetic regulators of gene expression. Results: Subjects with schizophrenia, as a group, showed no significant alterations in histone profiles or gene ex- Objective: To test the hypothesis that down-regulated pression. In a subgroup of 8 patients with schizophrenia, metabolic gene expression is associated with histone modi- levels of H3-(methyl)arginine 17, H3meR17, exceeded con- fication changes in the prefrontal cortex of subjects with trol values by 30%, and this was associated with the de- schizophrenia. creased expression of 4 metabolic transcripts. Design and Subjects: Histones and gene transcripts Conclusions: High levels of H3-(methyl)arginine 17 are were profiled in the postmortem prefrontal cortex of 41 associated with down-regulated metabolic gene expres- subjects with schizophrenia and 41 matched controls. The sion in the prefrontal cortex of a subset of subjects with phosphorylation, acetylation, and methylation of 6 schizophrenia. Histone modifications may contribute to the lysine, serine, and arginine residues of histones H3 and pathogenesis of prefrontal dysfunction in schizophrenia. H4 were examined together with 16 metabolic gene tran- scripts using serial immunoblotting, immunohistochemi- Arch Gen Psychiatry. 2005;62:829-840 YSFUNCTION, HYPOACTIV- core histones, H2A, H2B, H3, and H4, ity, and hypometabolism together with 147 base pairs of genomic Author Affiliations: Brudnick Neuropsychiatric Research of the prefrontal DNA wrapped around them, compose Institute, Department of cortex (PFC) may con- the nucleosomes, the basic units of chro- Psychiatry (Drs Akbarian and tribute to the negative matin. Chromatin fibers are composed of Guo, Mr Ruehl, and Mss Bliven, symptoms and cognitive deficits of schizo- arrays of nucleosomes connected by D1-6 26,27 Luiz, and Peranelli) and phrenia. The molecular pathogenesis of linker histones and DNA. Dynamic Bioinformatics Unit, prefrontal dysfunction in schizophrenia is changes in chromatin conformation and Information Services still not clear, but the down-regulated ex- accessibility of transcription factors are (Mr Baker), University of pression of a subset of metabolic genes is highly regulated by the N-terminal his- Massachusetts Medical School, thought to be involved.7-9 Alterations in cel- tone tails.28,29 Covalent modifications at Worcester; Maryland Psychiatric Research Center, lular metabolism may then further histone N-terminal tails are differentially University of Maryland, compromise orderly gene expression, af- regulated in chromatin at sites of active 10-20 Baltimore (Drs Roberts and fecting neurotransmission, myelina- gene expression compared with inactive Conley); Department of tion,10,21,22 and other functions.23,24 There is and silenced chromatin.28,29 For example, Psychiatry and Human evidence that in individual schizophrenic the methylation of histone H3 at the Behavior, University of patients, PFC hypometabolism persists for arginine 17 position (H3meR17), or the California at Irvine decades,25 suggesting that the underlying phosphoacetylation of H3 at the serine (Dr Bunney); Center for molecular mechanisms, including dysregu- 10/lysine 14 position (H3pS10-acK14), Neuroscience, Department of lated metabolic gene expression, remain defines the open chromatin state and Psychiatry, University of 28-34 California at Davis (Dr Jones); stable for extended periods. actual or potential transcription. and Department of Psychiatry, In eukaryotes, the rate-limiting bio- Studies in rodents showed that treatment University of Texas chemical response that leads to the acti- with (1) antipsychotic drugs that block 35 Southwestern Medical Center, vation of gene expression involves alter- dopamine D2 -like receptors, (2) 26 36 Dallas (Dr Tamminga). ations in chromatin structure. The 4 D1-agonists, or (3) the anticonvulsant (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, AUG 2005 WWW.ARCHGENPSYCHIATRY.COM 829 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 and mood-stabilizing drug valproate sodium37-39 edge, this is the first evidence that histone modifica- induces histone modification changes not only at tions as epigenetic regulators of gene expression may defined genomic sequences but also on a global and contribute to prefrontal dysfunction in schizophrenia. genome-wide level in selected areas of the forebrain. The drug-induced, coordinated regulation of histone METHODS chemistry in whole or “bulk” chromatin is thought to have profound effects on nuclear signaling and chroma- RATIONALE AND STUDY DESIGN tin function, including transcription and cellular differ- 28,29,40 entiation. The D2-like antagonist drugs and valpro- According to a recent study by Middleton and colleagues,7 a ate sodium are frequently prescribed for the treatment subset of 10 metabolic genes are expressed at decreased levels of schizophrenia and other major psychiatric in the PFC of subjects with schizophrenia. This set of 10 tran- diseases,41-43 which raises the question of whether chro- scripts includes malate dehydrogenase I (MDH), for which 4 matin modifications are involved in the molecular studies reported either a significant decrease7-9 or increase10 in mechanism of action of these drugs. Furthermore, in the PFC of subjects with schizophrenia. Therefore, we sought eukaryotes, cellular metabolism is tightly coupled to (1) to examine the expression of these metabolic genes in a larger chromatin structure because many chromatin- cohort of schizophrenic subjects and controls and (2) to de- remodeling complexes require adenosine triphos- termine whether altered metabolic gene expression is linked phatase activity.44,45 In addition, caloric restriction to an abnormal histone modification profile. This study was conducted in 2 parts (Figure 1). First, 6 different histone modi- up-regulates histone deacetylase activity, which in turn 46,47 fications and 16 metabolic gene transcripts were profiled in 21 leads to transcriptional silencing of chromatin. matched pairs of schizophrenic subjects and controls. For the Given this background, we hypothesized that hypome- overall cohort of 21 subjects with schizophrenia, we did not find tabolism and decreased metabolic gene expression in significant changes in histone or transcript levels. Therefore, as the PFC of subjects with schizophrenia is accompanied the next step, we defined subgroups of subjects with schizophre- by abnormal levels of 1 or several covalent histone nia based on histone modification levels. Then, the association modifications. These changes may reflect an adaptive between modifications and down-regulated metabolic gene ex- response to prefrontal hypoactivity, may play a caus- pression was further tested by conducting additional studies on ative role in prefrontal dysfunction, or both. In any another 20 pairs of subjects with schizophrenia and controls col- case, chromatin-related abnormalities are likely to have lected independently of the 21 matched pairs in part 1. profound and lasting implications for cellular function and PFC circuitry. Furthermore, molecular studies on POSTMORTEM TISSUE chromatin from diseased brain is pivotal to gain further insight into epigenetic factors that are thought to be The present study used the brains of 82 subjects, or 41 matched involved in the etiology of the schizophrenia.48-52 pairs of subjects with schizophrenia and controls (Table 1). All subjects were matched for age and autolysis time (±15%), Herein, we identify a subgroup of subjects with schizo- and 38 of 41 pairs were also matched for sex, as described pre- phrenia affected by down-regulated expression of 4 of viously.53 The entire matching process was finished before any 16 metabolic genes in conjunction with high levels of experimental procedures were performed. Of the 41 pairs, 21 histone H3 methylation (H3meR17). To our knowl- were obtained from a brain collection at the University of Cali- fornia and were used in previous studies12,53 of GAD67 gene ex- pression and white matter neuron distribution. Key findings reported for this postmortem collection were independently rep- 21 Patients With Schizophrenia and I. Histone Profiling 15-17,54-58 21 Matched Controls (California II. Gene Expression Profiling licated. Therefore, this postmortem cohort seems to be Brain Collection) III. Subgrouping of Subjects With representative of the disease. Another 20 pairs were obtained Schizophrenia by Histone Profile from a brain bank at the University of Maryland that includes + a tissue collection from subjects diagnosed as having schizo- phrenia.55,59,60 For both brain banks, procedures for tissue col- 20 Subjects With Schizophrenia and IV. Confirm Histone–Gene Expression lection, neuropathologic examination
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