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.
    European Journal of Medical Genetics 12/2014; 58(2). DOI:10.1016/j.ejmg.2014.12.001 · 1.47 Impact Factor
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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.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2014; 165(7). DOI:10.1002/ajmg.b.32258 · 3.42 Impact Factor
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    • "In addition, an increased mRNA expression of DNA methyl-transferases (DNMT1 and DNMT3a) has been observed in schizophrenia (Veldic et al., 2004, 2005; Ruzicka et al., 2007; Zhubi et al., 2009). Furthermore, aberrant DNA methylation in brains of patients with schizophrenia (Abdolmaleky et al., 2005, 2006, 2011; Grayson et al., 2005; Iwamoto et al., 2005; Tamura et al., 2007; Mill et al., 2008; Tolosa et al., 2010; Wockner et al., 2014) and the associations of different DNA methylation patterns with phenotypic discordance of schizophrenia between twins (Petronis et al., 2003; Dempster et al., 2011; Kinoshita et al., 2013) have been reported. However, the sample sizes in these previous epigenetic studies of schizophrenia were relatively small and the number of CpG sites interrogated was limited. "
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    ABSTRACT: Background: Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5–1.0%. The pathophysiology of schizophrenia still remains obscure. Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia. Methods: To gain further insight into the molecular mechanisms underlying schizophrenia, a genome-wide DNA methylation profiling (27,578 CpG dinucleotides spanning 14,495 genes) of the human dorsolateral prefrontal cortex (DLPFC) was conducted in a large cohort (n = 216) of well characterized specimens from individuals with schizophrenia and non-psychiatric controls, combined with an analysis of genetic variance at ~880,000 SNPs. Results: Aberrant DNA methylation in schizophrenia was identified at 107 CpG sites at 5% Bonferroni correction (p < 1.99 × 10−6). Of these significantly altered sites, hyper-DNA methylation was observed at 79 sites (73.8%), mostly in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 31 sites; CGI shore: 35 sites; CGI shelf: 3 sites). Furthermore, a large number of cis-methylation quantitative trait loci (mQTL) were identified, including associations with risk SNPs implicated in schizophrenia. Conclusions: These results suggest that altered DNA methylation might be involved in the pathophysiology and/or treatment of schizophrenia, and that a combination of epigenetic and genetic approaches will be useful to understanding the molecular mechanism of this complex disorder.
    Frontiers in Genetics 08/2014; 5:280. DOI:10.3389/fgene.2014.00280
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