Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters

Abstract

Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5Ј end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D 2 and D 3 receptors, suggesting that blockade of D 2 -like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia.

Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

“…The promoter of reelin contains several sites for DNA methylation and HDAC and DNA methyltransferase inhibitors increase expression of reelin, indicating that epigenetic mechanisms govern the expression of this protein [37]. In subsequent studies, increases in the number of GABAergic mRNA transcripts including glutamic acid decarboxylase 1 (GAD1), a key enzyme for GABA synthesis, were observed in the prefrontal cortex of humans diagnosed with schizophrenia [38,39]. These increases were associated with chromatin remodeling in that an increase in methylation of lysine 4 of histone 3 (H3K4) was observed at GABAergic gene loci over this period of time [38,39].…”

“…In subsequent studies, increases in the number of GABAergic mRNA transcripts including glutamic acid decarboxylase 1 (GAD1), a key enzyme for GABA synthesis, were observed in the prefrontal cortex of humans diagnosed with schizophrenia [38,39]. These increases were associated with chromatin remodeling in that an increase in methylation of lysine 4 of histone 3 (H3K4) was observed at GABAergic gene loci over this period of time [38,39]. Although it is as yet too early to know, these observations are consistent with the notion that drugs that target the epigenome are viable therapies for treating this serious mental disorder.…”

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.…”

“…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. Strikingly, however, it is the genetic variants surrounding the GAD1 promoter that recently emerged as a major driver for the disease-related decline in GAD67 transcript and the epigenetic decoration of the proximal GAD1 promoter in subjects with schizoprenia, including the balance between 'open' and 'repressive' histone methylation markings histone H3 trimethyl-lysines, K4me3 and K27me3 (Huang et al, 2007b). Notably, the same halplotype and polymorphisms, positioned within few Kb from the GAD1 transcription start site, confer genetic risk for accelerated loss of frontal lobe gray matter (Addington et al, 2005;Straub et al, 2007b) and, via epistatic interaction with COMT alleles regulating synaptic dopamine, modulate overall GABA tissue levels in the prefrontal cortex (Marenco et al, 2010).…”

“…Additional differences may exist between chromatin of specific neuronal subtypes. For example, some of reported changes, such as the hypermethylation of the REELIN promoter DNA in cortical layer I of subjects with schizophrenia Veldic et al, 2004;Veldic et al, 2005), or the aforementioned shift from open chromatin-associated (H3-trimethyl-K4) to repressive histone methylation (H3-trimethylK27) at the GAD1 gene promoter could indicate an epigenetic defect in the population of inhibitory interneurons in psychosis (Huang et al, 2007b). This is a very attractive working hypothesis that could potentially explain the observed deficits in the corresponding REELIN and GAD1 (GAD67) RNAs (Guidotti et al, 2009).…”