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Chromatin (Epigenetic) regulation of neuronal development

開催日 2014/9/12
時間 9:00 - 11:00
会場 Room A(Main Hall)
Chairperson(s) 後藤 由季子 / Yukiko Gotoh (東京大学大学院薬学系研究科 / Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan)
内匠 透 / Toru Takumi (理化学研究所 脳科学総合研究センター / RIKEN Brain Science Institute, Japan)

Neural genome analysis of bipolar disoder and schizophrenia

  • S2-A-1-3
  • 加藤 忠史 / Tadafumi Kato:1 岩本 和也 / Kazuya Iwamoto:2 
  • 1:理化学研究所脳科学研究センター / RIKEN Brain Science Institute, Japan 2:東京大学医学部分子精神医学講座 / Department of Molecular Psychiatry, Faculty of Medicine, University of Tokyo, Japan 

Twin studies showed the role of genetic factors in bipolar disorder and schizophrenia. Recent genome wide association studies showed the roles of single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and rare single nucleotide variations. In addition, de novo CNVs and point mutations were also reported to contribute to schizophrenia.
The concordance rate of these disorders between monozygotic twins is not 100%, suggesting the role of other non-heritable factors.
Among the genomic factors contributing to these mental disorders, somatic mutations in the brain and epigenetic regulation of gene expression are still unexplored area of research.
To identify the DNA methylation signature associated with these mental disorders, we performed promoter-wide epigenomic analysis of the neuronal nuclei derived from the frozen postmortem brains of patients with bipolar disorder, schizophrenia as well as controls. Frozen brain samples were separated into neuronal- and non-neuronal nuclei using fluorescent activated cell sorter after staining by NeuN antibody. Methylated DNA was selected by methylated CpG binding domain-conjugated beads and the obtained DNA was analyzed by promoter tiling array. We detected characteristic differential methylation in neuronal nuclei in patients with bipolar disorder and schizophrenia.
We also examined the possible role of somatic mutations in the brain. We quantified the levels of retrotransposon LINE-1 (Long Interspersed Nuclear Element 1), and found that it was increased in the postmortem neuronal nuclei of patients with schizophrenia.
To elucidate the role of posttranscriptional modification of RNA in mental disorders, we quantified the levels of ADAR2 (adenosine deaminase acting on RNA2) mRNA in the postmortem brains, and it was decreased in bipolar disorder. Decreased ADAR2 mRNA was correlated with decreased RNA editing of the R/G site of AMPA receptors.
These studies altogether suggest the roles of somatic mutations, epigenetic DNA modification, and posttranscriptional gene regulation in the pathophysiology of bipolar disorder and schizophrenia.

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