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

Comparative Study

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

B Tang et al. Transl Psychiatry. .

Abstract

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.

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Figures

Figure 1
Figure 1

Real-time PCR analysis for the indicated genes in subjects with schizophrenia, bipolar disorder and non-psychiatric controls. Real-time qPCR assays were performed as described in the materials and methods on postmortem Brodmann area (BA) 10 from subjects with schizophrenia, bipolar disorder and matched controls (group 1; n=50 total). Data shown are gene expression values normalized by the housekeeping gene, B2M. Asterisks denote significant differences in expression as determined by one-way ANOVA followed by Student's t-test: *P<0.05; +P<0.08; **P<0.01; ***P<0.001.

Figure 2
Figure 2

Correlation between gene expression levels and acetylation of histone H3 at K9 and K14. ChIP-qPCR assays were performed on postmortem BA10 from the same subjects as in Figure 1, measuring ac-H3K9K14 levels at the promoter regions of the indicated genes (as designated by UniGene IDs). Rabbit IgG was used as a negative control for the pull-down. Histone acetylation is presented as percentage input DNA. Gene expression levels were determined by real-time qPCR, from Figure 1. Each point represents one subject. Pink, control subjects; blue, subjects with schizophrenia; black, subjects with bipolar disorder. Pearson's correlation (r) values are indicated within each graph.

Figure 3
Figure 3

Ac-H3K9K14 levels as a function of age in control subjects and those with schizophrenia. ChIP-qPCR assays were performed on postmortem BA46 from control subjects (closed circles, solid line) and those with schizophrenia (open circles, dashed line) representing a wide age range (group 2; n=32 subjects in total). Pearson's (r) values are shown in Table 2.

Figure 4
Figure 4

Histone H3K9K14 is hypoacetylated at the promoter regions of genes in young subjects with schizophrenia and associated with decreased gene expression levels. (a) ChIP-qPCR assays were performed on young and old subjects with schizophrenia and age-matched controls (group 2; n=32 subjects in total), measuring ac-H3K9K14 levels at the promoter regions of the indicated genes (UniGene IDs). Asterisks denote significant differences in ac-H3K9K14 levels, as determined by Student's t-test: *, P<0.05, +, P<0.08. (b) Significant differences in microarray expression values were determined by ANOVA as described in Materials and methods; *, P<0.05, **, P<0.01.

Figure 5
Figure 5

Heatmap depiction of the 17 schizophrenia candidate genes found to be significantly regulated by HDACi 4b treatment in the mouse brain. Official UniGene symbols are shown for each gene. Each colored pixel represents an individual gene expression value. Relative decreases in gene expression are indicated by green and increases in expression by red. Two-dimensional hierarchical clustering of the samples is shown along the top.

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