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

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.

Epigenetic Dysregulation in the Schizophrenic Brain

“…For example, the GAD1(GAD67) GABA synthesis enzyme gene promoter shows in the SCZ cortex a shift from facilitative histone acetylation and H3K4 methylation toward repressive histone methylation markings [68,69]. Interestingly, such histone PTM changes have been reported in animals exposed to suboptimal postnatal care and parenting [70] or antimitotic drugs during prenatal development [71], which would be consistent with the neurodevelopmental hypothesis of schizophrenia.…”

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

“…HDAC inhibitors have been used to increase acetylated levels of genes, thus restoring the expression of genes that are compromised during aging (Peleg et al, 2010;Tang et al, 2011). In addition, preclinical and clinical studies have found that VPA, a class I HDAC inhibitor, can augment the therapeutic effects of antipsychotics (Guidotti et al, 2009;Suzuki et al, 2009).…”

Epigenetics in the Human Brain

“…The GAD67 transcript is downregulated in cerebral and cerebellar cortex of a significant portion of subjects diagnosed with schizophrenia, depression or autism and this type of alteration may contribute to desynchronization of cortical networks and cognitive dysfunction because of defective GABAergic inhibition Benes et al, 2007;Blatt and Fatemi, 2011;Curley and Lewis, 2012;Guidotti et al, 2000;Volman et al, 2011). Importantly, both in human and rodent cerebral cortex, Gad1/GAD1 promoter-associated DNA methylation, and multiple histone acetylation and methylation markings are highly regulated during the course of normal development and aging (Huang and Akbarian, 2007a;Huang et al, 2007b;Siegmund et al, 2007;Tang et al, 2011;Zhang et al, 2010b), and are sensitive to exposure of histone deacetylase inhibitor drugs and even to the atypical antipsychotic, clozapine (Chen et al, 2011;Huang et al, 2007b). These findings, taken together, would imply that epigenetic decoration and activity of the Gad1/ GAD1 promoter in the prefrontal cortex is highly sensitive to the impact of multiple non-genetic factors such as drug exposure, disturbed neurodevelopment and so on.…”

“…Still, hundreds of promoters are subject to epigenetic changes that seemingly continue into old age, and these data, taken together, leave little doubt that chromatin structures undergo remodeling throughout the lifespan of the human brain (Hernandez et al, 2011;Numata et al, 2012;Siegmund et al, 2007), including neurons and other terminally differentiated cells (Cheung et al, 2010). Based on postmortem brain work, epigenetic risk architectures are beginning to emerge for a number of common psychiatric conditions and disorders, including autism (Shulha et al, 2011), schizophrenia (Akbarian, 2010), depression and bipolar disorder (Gamazon et al, 2012;Tang et al, 2011) and alcoholism (Taqi et al, 2011) Table 1). We predict that only very few, if any, loci will show group-based differences when assayed in genome-wide epigenetic screens.…”