Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders

被引:94
作者
Tang, B. [1 ]
Dean, B. [2 ,3 ]
Thomas, E. A. [1 ]
机构
[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[2] Mental Hlth Res Inst, Rebecca L Cooper Res Labs, Parkville, Vic, Australia
[3] Univ Melbourne, Dept Psychiat, Melbourne, Vic, Australia
基金
美国国家卫生研究院;
关键词
bipolar disorder; chromatin; epigenetic; HDAC inhibitor; schizophrenia; DNA METHYLATION STATUS; PREFRONTAL CORTEX; DEACETYLASE INHIBITORS; ACUTE EXACERBATIONS; DIVALPROEX SODIUM; SCHIZOPHRENIA; EXPRESSION; BRAIN; HYPERMETHYLATION; ABNORMALITIES;
D O I
10.1038/tp.2011.61
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities. Here, we have used chromatin immunoprecipitation-qPCR to measure levels of acetylated histone H3 at lysines 9/14 (ac-H3K9K14), two epigenetic marks associated with transcriptionally active chromatin, at the promoter regions of eight schizophrenia-related genes in n = 82 postmortem prefrontal cortical samples from normal subjects and those with schizophrenia and bipolar disorder. We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E). Ac-H3K9K14 levels of several of the genes tested were significantly negatively associated with age in normal subjects and those with bipolar disorder, but not in subjects with schizophrenia, whereby low levels of histone acetylation were observed in early age and throughout aging. Consistent with this observation, significant hypoacetylation of H3K9K14 was detected in young subjects with schizophrenia when compared with age-matched controls. Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation. We further find that treatment with a histone deacetylase (HDAC) inhibitor alters the expression of several candidate genes for schizophrenia in mouse brain. These findings may have therapeutic implications for the clinical use of HDAC inhibitors in psychiatric disorders. Translational Psychiatry (2011) 1, e64; doi:10.1038/tp.2011.61; published online 20 December 2011
引用
收藏
页码:e64 / e64
页数:9
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