DNA Methylation Status of SOX10 Correlates with Its Downregulation and Oligodendrocyte Dysfunction in Schizophrenia

Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2005; 25(22):5376-81. DOI: 10.1523/JNEUROSCI.0766-05.2005
Source: PubMed


Downregulation of oligodendrocyte-related genes, referred to as oligodendrocyte dysfunction, in schizophrenia has been revealed by DNA microarray studies. Because oligodendrocyte-specific transcription factors regulate the differentiation of oligodendrocytes, genes encoding them are prime candidates for oligodendrocyte dysfunction in schizophrenia. We found that the cytosine-guanine dinucleotide (CpG) island of sex-determining region Y-box containing gene 10 (SOX10), an oligodendrocyte-specific transcription factor, tended to be highly methylated in brains of patients with schizophrenia, correlated with reduced expression of SOX10. We also found that DNA methylation status of SOX10 also was associated with other oligodendrocyte gene expressions in schizophrenia. This may be specific to SOX10, because the CpG island of OLIG2, which encodes another oligodendrocyte-specific transcription factor, was rarely methylated in brains, and the methylation status of myelin-associated oligodendrocytic basic protein, which encodes structural protein in oligodendrocytes, did not account for their expressions or other oligodendrocyte gene expressions. Therefore, DNA methylation status of the SOX10 CpG island could be an epigenetic sign of oligodendrocyte dysfunction in schizophrenia.

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    • "Epigenetic alterations can reflect the interaction between genetic factors and environmental ones in the development of SCZ [Abdolmaleky and Thiagalingam, 2011]. As the major component of epigenetic regulation, DNA methylation of GAD, RELN, COMT, SOX10, BDNF, and CTLA4 genes have been reported to be correlated with the risk of SCZ [Abdolmaleky et al., 2005, 2006; Abdolmaleky and Thiagalingam, 2011; Grayson et al., 2005; Ikegame et al., 2013; Iwamoto et al., 2005; Kordi-Tamandani et al., 2013; Nohesara et al., 2011; Pun et al., 2011; Sharma et al., 2008; Tolosa et al., 2010]. SCZ is a complex mixed disorder with two major subtypes, paranoid and undifferentiated SCZ. "
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    ABSTRACT: Schizophrenia (SCZ) is a complex mental disorder contributed by both genetic and epigenetic factors. Long noncoding RNAs (lncRNAs) was recently found playing an important regulatory role in mental disorders. However, little was known about the DNA methylation of lncRNAs, although numerous SCZ studies have been performed on genetic polymorphisms or epigenetic marks in protein coding genes. We presented a comprehensive genome wide DNA methylation study of both protein coding genes and lncRNAs in female patients with paranoid and undifferentiated SCZ. Using the methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), 8,163 and 764 peaks were identified in paranoid and undifferentiated SCZ, respectively (p < 1×10-5). Gene ontology analysis showed that the hypermethylated regions were enriched in the genes related to neuron system and brain for both paranoid and undifferentiated SCZ (p < 0.05). Among these peaks, 121 peaks were located in gene promoter regions that might affect gene expression and influence the SCZ related pathways. Interestingly, DNA methylation of 136 and 23 known lncRNAs in Refseq database were identified in paranoid and undifferentiated SCZ, respectively. In addition, ∼20% of intergenic peaks annotated based on Refseq genes were overlapped with lncRNAs in UCSC and gencode databases. In order to show the results well for most biological researchers, we created an online database to display and visualize the information of DNA methyation peaks in both types of SCZ ( Our results showed that the aberrant DNA methylation of lncRNAs might be another important epigenetic factor for SCZ. Copyright © 2014. Published by Elsevier Masson SAS.
    Full-text · Article · Dec 2014 · European Journal of Medical Genetics
    • "OLIG2, which encodes the transcription factor central to oligodendrocyte development (Ross et al., 2006), is yet another prime candidate for susceptibility variants with wide-ranging secondary effects on OMR gene expression (Lyudmila et al., 2006). Several studies have reported reduced OLIG2 mRNA in postmortem schizophrenia brains (Tkachev et al., 2003;Iwamoto et al., 2005;Kastel et al., 2005). Postmortem studies performed byMitkus et al. (2008)revealed that two OLIG2 SNPS, rs1059004 and rs9653711, both previously associated with schizophrenia (Georgieva et al., 2006), predicted lower OLIG2 mRNA expression levels in the DLPFC white matter of patients with schizophrenia. "
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    ABSTRACT: The neuropathological basis of schizophrenia and related psychoses remains elusive despite intensive scientific investigation. Symptoms of psychosis have been reported in a number of conditions where normal myelin development is interrupted. The nature, location, and timing of white matter pathology seem to be key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes that could affect neuronal connectivity, which has been implicated as a central abnormality in schizophrenia. Phenocopies of schizophrenia with a known pathological basis involving demyelination or dysmyelination may offer insights into the biology of schizophrenia itself. This article reviews the pathological changes in white matter of patients with schizophrenia, as well as demyelinating diseases associated with psychosis. In an attempt to understand the potential role of dysmyelination in schizophrenia, we outline the evidence from a number of both clinically-based and post-mortem studies that provide evidence that OMR genes are genetically associated with increased risk for schizophrenia. To further understand the implication of white matter dysfunction and dysmyelination in schizophrenia, we examine diffusion tensor imaging (DTI), which has shown volumetric and microstructural white matter differences in patients with schizophrenia. While classical clinical–neuropathological correlations have established that disruption in myelination can produce a high fidelity phenocopy of psychosis similar to schizophrenia, the role of dysmyelination in schizophrenia remains controversial.
    No preview · Article · Oct 2014 · Schizophrenia Research
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    • "Microarray-based studies, measuring the methylation profiles of thousands of CpG sites across the genome in diverse tissues, have identified various additional candidate genes whose methylation may be associated with schizophrenia [Kinoshita et al., 2013; Wockner et al., 2014]. Other studies using varying methodologies, and targeting a variety of tissues, have found partly consistent evidence for epigenetic alterations associated with schizophrenia at genes including RELN [Abdolmaleky et al., 2005; Grayson et al., 2005], COMT [Abdolmaleky et al., 2006], SOX10 [Iwamoto et al., 2005], HTR2A [Abdolmaleky et al., 2011], BDNF, and ST6GALNAC1 [Nishioka et al., 2012]. Among the genes previously implicated in schizophrenia by genetic linkage or association, LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) is of particular interest from an epigenetic perspective [Francks et al., 2007; Francks et al., 2003]. "
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    ABSTRACT: Epigenetic effects on psychiatric traits remain relatively under-studied, and it remains unclear what the sizes of individual epigenetic effects may be, or how they vary between different clinical populations. The gene LRRTM1 (chromosome 2p12) has previously been linked and associated with schizophrenia in a parent-of-origin manner in a set of affected siblings (LOD = 4.72), indirectly suggesting a disruption of paternal imprinting at this locus in these families. From the same set of siblings that originally showed strong linkage at this locus, we analyzed 99 individuals using 454-bisulfite sequencing, from whole blood DNA, to measure the level of DNA methylation in the promoter region of LRRTM1. We also assessed seven additional loci that would be informative to compare. Paternal identity-by-descent sharing at LRRTM1, within sibling pairs, was linked to their similarity of methylation at the gene's promoter. Reduced methylation at the promoter showed a significant association with schizophrenia. Sibling pairs concordant for schizophrenia showed more similar methylation levels at the LRRTM1 promoter than diagnostically discordant pairs. The alleles of common SNPs spanning the locus did not explain this epigenetic linkage, which can therefore be considered as largely independent of DNA sequence variation and would not be detected in standard genetic association analysis. Our data suggest that hypomethylation at the LRRTM1 promoter, particularly of the paternally inherited allele, was a risk factor for the development of schizophrenia in this set of siblings affected with familial schizophrenia, and that had previously showed linkage at this locus in an affected-sib-pair context. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2014 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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