Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levels of acetylated Histone 3 and 4 proteins are strongly predictive of a chromatin structure that is conducive to gene expression. In cell and animal studies, valproic acid is a potent inhibitor of histone deactylating enzymes, and consequently results in increased levels of acetylated Histone 3 (acH3) and acetylated Histone 4 proteins (acH4). To examine this effect in a clinical setting, 14 schizophrenic and bipolar patients were treated with valproic acid (Depakote ER), either as monotherapy or in combination with antipsychotics, over a period of 4 weeks. AcH3 and acH4 levels from lymphocyte nuclear protein extracts were measured by Western Blot. Treatment with Depakote ER resulted in a significant increase of acH3 and a trend-level increase of acH4. Levels of valproic acid were positively and significantly correlated with percent increase in acH3 but not acH4. Schizophrenia patients were significantly less likely to increase their acH3 and acH4 levels after 4 weeks on Depakote ER. The authors consider these results in the context of future application of HDAC inhibitors to the treatment of psychiatric disorders.
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PMID:Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: preliminary results from a clinical population. 1699 18

Histone deactylase enzymes are responsible for the deacetylation of histone tails, and consequently influence gene regulation through their ability to modify chromatin structure surrounding promoter regions. We analyzed the microarray collection of the National Brain Databank to investigate differential expression of these enzymes in the prefrontal cortices of control, schizophrenia and bipolar subjects. HDAC1 expression levels were significantly higher in schizophrenia versus normal subjects. The mRNA expression level of an epigenetically regulated schizophrenia candidate gene GAD67 was strongly and negatively correlated with the mRNA expression levels of HDAC1, HDAC3 and HDAC4 levels. These findings provide additional support for the proposal that epigenetic factors are operative in the brain pathology of patients with schizophrenia.
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PMID:Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: analysis of the National Brain Databank microarray collection. 1796 87

Histone deacetylases (HDACs) are pivotal enzymes in the epigenetic modification or regulatory mechanisms of gene transcription. Based on previous assertions that the pathophysiology of schizophrenia is associated with epigenetics, we hypothesized that polymorphisms of HDAC genes might be related to schizophrenia. We recruited 278 patients with schizophrenia and 234 normal controls from a Korean population. Clinical information of the group with schizophrenia was obtained from medical records, the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Operational Criteria Checklist (OPCRIT). Three single-nucleotide polymorphisms (SNPs) in HDAC genes were selected, including rs2530223 of HDAC3, rs1063639 of HDAC4, and rs1555048 of HDAC10. For the analysis of genetic data, SNPStats, SNPAnalyzer, and Helixtree programs were used. In the present study, rs1063639 of the HDAC4 gene showed associations with schizophrenia in the codominant and dominant models. In the analysis of clinical phenotypes, smoking status was associated with rs2530223 of HDAC3 in the codominant and recessive models. The results suggest that HDAC3 and HDAC4 genes might play a role in the pathophysiology of schizophrenia in a Korean population.
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PMID:Association of histone deacetylase genes with schizophrenia in Korean population. 2047 94

Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT(2A) receptor-dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment.
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PMID:HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. 2292 11

Schizophrenia is a common psychiatric disorder and caused by a combination of environmental, social and genetic factors. Histone deacetylases (HDACs) can translate epigenetic effects to the genome by modifying chromatin structure and gene expression. Inappropriate activity of HDACs is associated with cancer, cardiovascular and neurological diseases, and HDAC inhibitors are shown to improve the derivation of induced pluripotent stem (iPS) cells and to modulate cell lineage differentiation during brain development. We demonstrate that one of the HDAC genes, HDAC9, is hemizygously deleted in a small proportion of schizophrenia patients, and is widely expressed in mouse brain including areas where the neuropathology of schizophrenia is found. High levels of expression are observed in the hippocampus, layers II/III and V of the cerebral cortex, prefrontal and medial prefrontal cortex, piriform and cingulum cortex, basolateral amygdaloid nuclei and choroid plexus. HDAC9 protein is found in the cell body as well as in nerve fibers. Importantly, HDAC9 is not expressed in adult neural stem cells, glia, astrocytes, or oligodendrocytes, but expressed exclusively in post-mitotic and mature neurons. Our data suggest that HDAC9 may play a crucial role in neuronal function of adult brain.
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PMID:HDAC9 is implicated in schizophrenia and expressed specifically in post-mitotic neurons but not in adult neural stem cells. 2367 95

Histone lysine methylation is a well-established transcriptional mechanism for the regulation of gene expression changes in eukaryotic cells and is now believed to function in neurons of the central nervous system to mediate the process of memory formation and behavior. In mature neurons, methylation of histone proteins can serve to both activate and repress gene transcription. This is in stark contrast to other epigenetic modifications, including histone acetylation and DNA methylation, which have largely been associated with one transcriptional state in the brain. In this review, we discuss the evidence for histone methylation mechanisms in the coordination of complex cognitive processes such as long-term memory formation and storage. In addition, we address the current literature highlighting the role of histone methylation in intellectual disability, addiction, schizophrenia, autism, depression, and neurodegeneration. Further, we discuss histone methylation within the context of other epigenetic modifications and the potential advantages of exploring this newly identified mechanism of cognition, emphasizing the possibility that this molecular process may provide an alternative locus for intervention in long-term psychopathologies that cannot be clearly linked to genes or environment alone.
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PMID:Histone lysine methylation: critical regulator of memory and behavior. 2372 18

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
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PMID:Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. 2660 85

Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression.
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PMID:Epigenetic Mechanisms of Serotonin Signaling. 2573 78

Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Psychiatric disorders such as schizophrenia and depression are complex and heterogeneous diseases with multiple and independent factors that may contribute to their pathophysiology, making challenging to find a link between specific elements and the underlying mechanisms responsible for the disorder and its treatment. Growing evidences suggest that epigenetic modifications in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychiatric conditions throughout life. This review focuses on recent advances that directly implicate epigenetic modifications in schizophrenia and antipsychotic drug action.
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PMID:Epigenetic signaling in schizophrenia. 2612 9

We investigated the blood levels of mixed-lineage leukemia 1 (MLL1) mRNA and BDNF (brain derived neurotrophic factor) exon IV promoter on histone Histone 3 lysine 4 trimethylation (H3K4me3) in peripheral blood of patients with schizophrenia and controls. Over one year, 36 patients with schizophrenia and 32 controls were recruited. Psychiatric diagnoses were made based on DSM-IV criteria. Higher blood MLL1 mRNA and BDNF exon IV promoter on H3K4me3 levels were noted in patients with schizophrenia than in controls. The results showed that blood MLL1 mRNA and BDNF exon IV on H3K4me3 levels might be involved in the psychopathology of schizophrenia.
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PMID:Higher blood MLL1 mRNA and BDNF promoter IV on histone H3K4me3 levels in patients with schizophrenia. 2741 50


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