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.
Highlights
Epigenetic mechanisms of gene regulation involve both DNA methylation and posttranslational modifications of histone proteins.[1]
We selected eight diverse ‘‘schizophrenia-related’’ genes (Table 1) for this study based on the following criteria: (1) genes showing differential expression in schizophrenia and/or bipolar disorder from published microarray studies;[30,31] (2) genes showing CNS cell type-specific expression patterns based on comparison with previous transcriptome studies performed on isolated astrocytes, neurons and oligodendrocytes;[32] (3) genes representing different functions/pathways related to schizophrenia based on review of the literature.[20,33,34,35]
We first tested for expression differences for five neuronally expressed genes, GABAergic neurotransmission: glutamic acid decarboxylase 1 (GAD1); mitochondrial function/import: TOMM70A; neurotransmitter receptor signaling: serotonin 5-hydroxytryptamine receptor 2C (HTR2C) and regulator of G protein signaling 4 (RGS4); signal transduction: protein phosphatase, Mg2 þ /Mn2 þ dependent, 1E (PPM1E) in the postmortem prefrontal cortex (Brodmann area 10) from a cohort of subjects with schizophrenia and bipolar disorder from the Harvard Tissue Resource Center
Summary
Epigenetic mechanisms of gene regulation involve both DNA methylation and posttranslational modifications of histone proteins.[1] it is known that DNA methylation of cytosine residues at CpG dinucleotide sites results in gene silencing, the effects of posttranslational modifications on histone proteins are more complex.[2] Histone tails are subjected to many kinds of chemical modifications, such as methylation, acetylation, phosphorylation, ubiquitination and ribosylation,[3] which can lead to diverse effects on chromatin structure and gene activity. Acetylation of lysine residues usually correlates with chromatin accessibility and transcriptional activation, whereby lysine methylation has either activating or repressive effects on gene regulation.[3]. During the last several years, there has been an increased interest in the epigenetic origins of psychiatric diseases.[4,5,6,7] Of the diverse epigenetic machinery associated with gene regulation, DNA methylation has been the most widely studied in the context of psychiatric disorders. Altered methylation status of CpG sites has been found within the regulatory regions of several candidate genes in subjects with schizophrenia, including HTR1A,8 HTR2A,9 glutamic acid decarboxylase 1 (GAD1),[10,11] REELIN,[12,13] COMT,[14] DRD215 and SOX10.16 More recently, epigenome-wide profiling has revealed large scale changes in DNA-methylation associated with major psychosis, some of which involve genes associated with neuronal development as well as genes involved with glutamatergic and GABAergic neurotransmission.[17]
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