DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia
ABSTRACT 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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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 (http://www.bioinfo.org/scz/scz.htm). 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 · 1.49 Impact Factor
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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 · 3.27 Impact Factor
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ABSTRACT: Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10−12), while Dnmt3a KO signature does not (P = 0.017).Molecular Systems Biology 07/2014; 10(7). DOI:10.15252/msb.20145304 · 14.10 Impact Factor