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)

Alterations in RNA levels are frequently reported in brain of subjects diagnosed with autism, schizophrenia, depression, and other psychiatric diseases, but it remains unclear whether the underlying molecular pathology involves changes in gene expression, as opposed to alterations in messenger RNA processing. Pre-clinical studies have revealed that stress, drugs, and a variety of other environmental factors lead to changes in RNA levels in brain via epigenetic mechanisms, including modification of histone proteins. A number of site-specific modifications of the nucleosome core histones-including the trimethylated forms of histone H3 lysines K4, K9, and K27-are of particular interest for postmortem research, because these marks differentiate between active and inactive chromatin and seem to remain relatively stable during tissue autolysis. Therefore, histone methylation profiling at promoter regions could provide important clues about mechanisms of gene expression in human brain during development and in disease. Intriguingly, mutations within the genes encoding the H3K9-specific methyltransferase, EHMT1, and the H3K4-specific histone demethylase, JARID1C/SMCX, have been linked to mental retardation and autism, respectively. In addition, the H3K4-specific methyltransferase, MLL1, is essential for hippocampal synaptic plasticity and might be involved in cortical dysfunction of some cases of schizophrenia. Together, these findings emphasize the potential significance of histone lysine methylation for orderly brain development and also as a molecular toolbox to study chromatin function in postmortem tissue.
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PMID:Epigenetic regulation in human brain-focus on histone lysine methylation. 1881 64

The epigenetic down-regulation of genes is emerging as a possible underlying mechanism of the GABAergic neuron dysfunction in schizophrenia. For example, evidence has been presented to show that the promoters associated with reelin and GAD67 are down-regulated as a consequence of DNA methyltransferase (DNMT)-mediated hypermethylation. Using neuronal progenitor cells to study this regulation, we have previously demonstrated that DNMT inhibitors coordinately increase reelin and GAD67 mRNAs. Here, we report that another group of epigenetic drugs, histone deacetylase (HDAC) inhibitors, activate these two genes with dose and time dependence comparable with that of DNMT inhibitors. In parallel, both groups of drugs decrease DNMT1, DNMT3A, and DNMT3B protein levels and reduce DNMT enzyme activity. Furthermore, induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. Our data imply that drug-induced promoter demethylation is relevant for maximal activation of reelin and GAD67 transcription. The results suggest that HDAC and DNMT inhibitors activate reelin and GAD67 expression through similar mechanisms. Both classes of drugs attenuate, directly or indirectly, the enzymatic and transcriptional repressor activities of DNMTs and HDACs. These data provide a mechanistic rationale for the use of epigenetic drugs, individually or in combination, as a potential novel therapeutic strategy to alleviate deficits associated with schizophrenia.
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PMID:The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. 1902 85

Chronic neuropsychiatric illnesses such as schizophrenia, bipolar disease and autism are thought to result from a combination of genetic and environmental factors that might result in epigenetic alterations of gene expression and other molecular pathology. Traditionally, however, expression studies in postmortem brain were confined to quantification of mRNA or protein. The limitations encountered in postmortem brain research such as variabilities in autolysis time and tissue integrities are also likely to impact any studies of higher order chromatin structures. However, the nucleosomal organization of genomic DNA including DNA:core histone binding - appears to be largely preserved in representative samples provided by various brain banks. Therefore, it is possible to study the methylation pattern and other covalent modifications of the core histones at defined genomic loci in postmortem brain. Here, we present a simplified native chromatin immunoprecipitation (NChIP) protocol for frozen (never-fixed) human brain specimens. Starting with micrococcal nuclease digestion of brain homogenates, NChIP followed by qPCR can be completed within three days. The methodology presented here should be useful to elucidate epigenetic mechanisms of gene expression in normal and diseased human brain.
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PMID:A chromatin assay for human brain tissue. 1906 69

The neuronal GABAergic mechanisms that mediate the symptomatic beneficial effects elicited by a combination of antipsychotics with valproate (a histone deacetylase inhibitor) in the treatment of psychosis (expressed by schizophrenia or bipolar disorder patients) are unknown. This prompted us to investigate whether the beneficial action of this combination results from a modification of histone tail covalent esterification or is secondary to specific chromatin remodeling. The results suggest that clozapine, or sulpiride associated with valproate, by increasing DNA demethylation with an unknown mechanism, causes a chromatin remodeling that brings about a beneficial change in the epigenetic GABAergic dysfunction typical of schizophrenia and bipolar disorder patients.
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PMID:GABAergic promoter hypermethylation as a model to study the neurochemistry of schizophrenia vulnerability. 1910 71

The approval of suberoylanilide hydroxamic acid by the FDA for the treatment of cutaneous T-cell lymphoma in October, 2006 sparked a dramatic increase in the development of inhibitors for the class of enzymes known as the histone deacetylases (HDACs). In recent years, a large number of combination therapies involving histone deacetylase inhibitors (HDACIs) have been developed for the treatment of a variety of malignancies and neurodegenerative disorders. Promising evidence has been reported for the treatment of pancreatic cancer, prostate cancer, and leukemia as well as a number of other previously difficult to treat cancers. Drug combination approaches have also shown promise for the treatment of mood disorders including bipolar disorder and depression. In addition to these drug combination approaches, HDACIs alone have demonstrated effectiveness in the treatment of Parkinson's disease, Alzheimer's disease, Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease, multiple sclerosis, anxiety, and schizophrenia. Adverse inflammatory affects observed with traumatic brain injury and arthritis have also been alleviated by treatment with certain HDACIs. Based on the diverse utility and wide range of mechanistic actions observed with this class of drugs, the future development of better drug combination therapies and more selective HDACIs is warranted.
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PMID:Creating zinc monkey wrenches in the treatment of epigenetic disorders. 1954 31

Epidemiological research suggests that both an individual's genes and the environment underlie the pathophysiology of schizophrenia. Molecular mechanisms mediating the interplay between genes and the environment are likely to have a significant role in the onset of the disorder. Recent work indicates that epigenetic mechanisms, or the chemical markings of the DNA and the surrounding histone proteins, remain labile through the lifespan and can be altered by environmental factors. Thus, epigenetic mechanisms are an attractive molecular hypothesis for environmental contributions to schizophrenia. In this review, we first present an overview of schizophrenia and discuss the role of nature versus nurture in its pathology, where 'nature' is considered to be inherited or genetic vulnerability to schizophrenia, and 'nurture' is proposed to exert its effects through epigenetic mechanisms. Second, we define DNA methylation and discuss the evidence for its role in schizophrenia. Third, we define posttranslational histone modifications and discuss their place in schizophrenia. This research is likely to lead to the development of epigenetic therapy, which holds the promise of alleviating cognitive deficits associated with schizophrenia.
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PMID:Epigenetic mechanisms in schizophrenia. 1955 55

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.
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PMID:Common variants on chromosome 6p22.1 are associated with schizophrenia. 1957 9

Dysfunction of cerebral cortex and other brain regions in schizophrenia is often accompanied by dysregulated expression of numerous genes. However, the underlying genetic risk architecture remains unclear for a large majority of cases. Therefore, the study of epigenetic regulators of gene expression, including covalent modifications of DNA and nucleosome core histones, offers an attractive alternative to further explore the molecular pathology of schizophrenia beyond the level of RNA quantification. Several studies reported alterations in DNA cytosine methylation and histone methylation at specific genes and promoters in postmortem brain of subjects with schizophrenia, often in conjunction with changes in levels of the corresponding RNAs. While evidence for such "epigenetic dysregulation" is increasing, many of the reported alterations await independent replication. Interestingly, studies across the lifespan indicate that DNA and histone methylation markings are developmentally regulated in human cerebral cortex, suggesting that at least some of the epigenetic changes in the brain of adult subjects with schizophrenia reflect disordered neurodevelopment.
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PMID:The molecular pathology of schizophrenia--focus on histone and DNA modifications. 1972 53

Studies have demonstrated that several schizophrenia candidate genes are especially susceptible to changes in transcriptional activity as a result of histone modifications and DNA methylation. Increased expression of epigenetic enzymes which generally reduce transcription have been reported in schizophrenia postmortem brain samples. An abnormal chromatin state leading to reduced candidate gene expression can be explained by aberrant coordination of epigenetic mechanisms in schizophrenia. Dynamic epigenetic processes are difficult to study using static measures such as postmortem brain samples. Therefore, we have developed a model using cultured peripheral blood mononuclear cells (PBMCs) capable of pharmacologically probing these processes in human subjects. This approach has revealed several promising findings indicating that schizophrenia subject PBMC chromatin may be less capable of responding to agents which normally 'open' chromatin. We suggest that the ability to appropriately modify chromatin structure may be a factor in treatment response. Several pharmacological approaches for targeting epigenetic processes are reviewed.
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PMID:Histone modifications, DNA methylation, and schizophrenia. 1987 93

In recent years, it has become widely recognized that a comprehensive understanding of chromatin biology is necessary to better appreciate its role in a wide range of diseases. The histone code has developed as a new layer of our appreciation of transcription factor-based mechanisms of gene expression. Although epigenetic regulation refers to a host of chromatin modifications that occur at the level of DNA, histones, and histone-associated proteins, how this regulation is orchestrated is still incompletely understood. Of those processes that comprise the epigenetic regulatory machinery, DNA methylation and histone acetylation/deacetylation have been the most thoroughly studied. Compounds that act as inhibitors of DNA methyltransferases or histone deacetylases (HDACs) activate a variety of intracellular signaling pathways that ultimately affect the coordinated expression of multiple genes. The altered patterns of mRNA and protein expression collectively converge on pathways linked to apoptosis and cell cycle arrest, among others. This has prompted a widespread search for epigenetic inhibitors that could be used as chemotherapeutic agents, and several are undergoing clinical evaluation. More recently, there has been interest in the use of HDAC inhibitors to activate the expression of mRNAs that are down-regulated in various neurological and psychiatric conditions. Considerably less is known regarding the effect these drugs have on postmitotic cells such as neurons. Before we consider the clinical use of additional HDAC inhibitors to treat schizophrenia or unipolar depression, there are a number of key issues that need to be resolved.
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PMID:Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders? 1991 78


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