Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia
Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia
复制标题
DOI：
10.1001/archpsyc.62.8.829
复制
发表时间：
2005-08-01
影响因子：
--
通讯作者：
Guo, Y
中科院分区：
文献类型：
--
作者：
Akbarian, S;Ruehl, MG;Guo, Y
背景：精神分裂症常伴有代谢减退和前额叶皮质基因表达改变。细胞代谢调节染色质结构，包括共价组蛋白修饰，这是基因表达的表观遗传调节因子。目的：为了检验以下假设，即下调代谢基因表达与精神分裂症受试者前额皮质中组蛋白修饰变化相关。设计和受试者：对41名精神分裂症受试者和41名对照者的死后前额叶皮层进行了组蛋白和基因转录谱分析。磷酸化，乙酰化和甲基化的6赖氨酸，丝氨酸，和精氨酸残基的历史H3和H4一起检查16代谢基因转录使用系列免疫印迹，免疫组化分析，定制的互补DNA阵列，和定量实时逆转录酶-聚合酶链反应。精神分裂症受试者作为一个群体，在组蛋白谱或基因表达方面没有显着改变。在一个亚组的8例精神分裂症患者中，H3-（甲基）精氨酸17，H3 meR 17的水平，超过控制值的30%，这是与4代谢transcript.Conclusions的表达降低：高水平的H3-（甲基）精氨酸17与下调代谢基因表达在前额叶皮层的一个子集的受试者与精神分裂症。组蛋白修饰可能与精神分裂症患者前额叶功能障碍的发病机制有关。
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 histories 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.