Methylation of a HTR3A promoter variant alters the binding of transcription factor CTCF (original) (raw)
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DNA methylation in schizophrenia: progress and challenges
Science Bulletin, 2015
Schizophrenia is a heterogeneous psychiatric disorder broadly accepted being caused by genetic and environmental factors. Although conventional genetic studies have identified some candidate genes for schizophrenia, low odds ratios and penetrance, and a lack of reproducibility have limited their explanatory power. Despite the major efforts made toward identifying environmental factors in schizophrenia, methodological limitations and inconsistent findings of epidemiological reports have obstructed attempts to identify exogenous causal factors. Epigenetic mechanisms, mediating between environment and genes, have recently been proposed to play an important role in the pathogenesis of schizophrenia. DNA methylation is the most stable and well-characterized epi-genetic modification. In this paper, we briefly introduce DNA methylation mechanisms, genome-wide DNA methylation studies, and identify specific genomic methylation sites in individuals diagnosed with schizophrenia. The outline candidate genes such as Reelin and COMT, are also outlined before paying attention to the conundrum of recent researches.
DNA Methylation and Schizophrenia: Current Literature and Future Perspective
Cells
Schizophrenia is a neuropsychiatric disorder characterized by dissociation of thoughts, idea, identity, and emotions. It has no central pathophysiological mechanism and precise diagnostic markers. Despite its high heritability, there are also environmental factors implicated in the development of schizophrenia. Epigenetic factors are thought to mediate the effects of environmental factors in the development of the disorder. Epigenetic modifications like DNA methylation are a risk factor for schizophrenia. Targeted gene approach studies attempted to find candidate gene methylation, but the results are contradictory. Genome-wide methylation studies are insufficient in literature and the available data do not cover different populations like the African populations. The current genome-wide studies have limitations related to the sample and methods used. Studies are required to control for these limitations. Integration of DNA methylation, gene expression, and their effects are importan...
Sains Malaysiana, 2020
Dysfunction of cognitive performance in schizophrenia has been associated with aberrant alteration of DNA methylation of several schizophrenia-risk genes. AKT1 and HTR2A are among the candidate genes for schizophrenia. Their expressions were found reduced in schizophrenia patients. Thus, we aimed to study the methylation status of AKT1 promoter and HTR2A exon-I in Malaysian schizophrenia patients and their affected family members. In this study, each participant was required to perform Trail Making Test (TMT) part A and B to measure their cognitive performance. Genomic DNA extracted from the peripheral blood of 12 Malaysian schizophrenia families and 12 controls families, was subjected to bisulfite conversion. The methylation status of CpG sites of AKT1 promoter at Chr14: 104796054 and HTR2A exon-I at Chr13: 46896918 were identified using methylation-specific polymerase chain reaction (MSP). Our results showed that schizophrenia patients performed worse in both TMT-A and B (p<0.0001) than healthy controls. The patients also displayed significantly (p=0.023) high level of methylation in AKT1 promoter compared to controls. Meanwhile, no significant difference (p=0.248) in methylation status was observed in HTR2A exon-I between schizophrenia and control groups. Therefore, methylation of AKT1 promoter in peripheral bloods of patients may involve in cognitive impairment and schizophrenia pathology. In addition, we were able to demonstrate the heritability of DNA methylation status across family members.
The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders
Neuropsychopharmacology, 2013
Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+ ) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures, including multiple mRNAs that are downregulated in both inhibitory GABAergic and excitatory pyramidal neurons compared with non-psychiatric subjects (NPS). Several reports show increased expression of DNA methyltransferases in telencephalic GABAergic neurons. Accumulating evidence suggests a critical role for altered DNA methylation processes in the pathogenesis of SZ and related psychiatric disorders. The establishment and maintenance of CpG site methylation is essential during central nervous system differentiation and this methylation has been implicated in synaptic plasticity, learning, and memory. Atypical hypermethylation of candidate gene promoters expressed in GABAergic neurons is associated with transcriptional downregulation of the corresponding mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent reports indicate that the methylation status of promoter proximal CpG dinucleotides is in a dynamic balance between DNA methylation and DNA hydroxymethylation. Hydroxymethylation and subsequent DNA demethylation is more complex and involves additional proteins downstream of 5-hydroxymethylcytosine, including members of the base excision repair (BER) pathway. Recent advances in our understanding of altered CpG methylation, hydroxymethylation, and active DNA demethylation provide a framework for the identification of new targets, which may be exploited for the pharmacological intervention of the psychosis associated with SZ and possibly BP+ .
Psychiatry Research, 2014
In this study we assessed the BDNF promoter IV methylation state of a large genomic region surrounding promoter IV and evaluated BDNF transcript IV expression from prefrontal cortex and striatum of 15 schizophrenic and 15 control subjects. In prefrontal cortex, a single CpG site at À 93, appeared to be undermethylated in patients'group. BDNF mRNA levels in frontal cortex and striatum were variable among individuals but did not associate with disease.
Genome-Wide Methylation Profiling of Schizophrenia
Balkan Journal of Medical Genetics, 2014
Schizophrenia is one of the major psychiatric disorders. It is a disorder of complex inheritance, involving both heritable and environmental factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution. We have performed 26 high-resolution genomewide methylation array analyses to determine the methylation status of 27,627 CpG islands and compared the data between patients and healthy controls. Methylation profiles of DNAs were analyzed in six pools: 220 schizophrenia patients; 220 age-matched healthy controls; 110 female schizophrenia patients; 110 age-matched healthy females; 110 male schizophrenia patients; 110 age-matched healthy males. We also investigated the methylation status of 20 individual patient DNA samples (eight females and 12 males. We found significant differences in the methylation profile between schizophrenia an...
PLOS ONE, 2016
The number of patients with schizophrenia has increased over the past decade. Previously, many studies have been performed to establish its diagnostic criteria, prophylactic methods, and effective therapies. In this study, we analyzed whether the ratios of DNA methylation in CpG islands of the Shati/Nat8l is decreased in model mice of schizophrenia-like phenotype using genomic DNA collected from brain regions and peripheral blood, since the mouse model of schizophrenia-like phenotype, mice treated repeatedly with methamphetamine showed increase of Shati/Nat8l mRNA expression in our previous experiment. The ratios of Shati/ Nat8l CpG island methylation were significantly decreased in both the nucleus accumbens and the peripheral blood of model mice compared with those of control mice. We also investigated Shati/Nat8l methylation in the blood of patients with schizophrenia. We found that Shati/ Nat8l CpG island methylation ratios were lower in the patients with schizophrenia than in the healthy controls, which is consistent with our findings in the mice model. To our knowledge, this is the first study to show similar alterations in methylation status of a particular genomic DNA site in both the brain and peripheral blood of mice. Furthermore, the same phenomenon was observed in corresponding human genomic sequences of the DNA extracted from the peripheral blood of patients with schizophrenia. Based on our findings, DNA methylation profiles of the CpG island of Shati/Nat8l might be a diagnostic biomarker of schizophrenia.