Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins
Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins
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DOI：
10.1038/sj.mp.4002001
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发表时间：
2008-04-01
影响因子：
11
通讯作者：
Kato, T.
中科院分区：
文献类型：
--
作者：
Kuratomi, G.;Iwamoto, K.;Kato, T.
为了寻找双相情感障碍不一致的单卵双胞胎之间的DNA甲基化差异，我们应用了一种全面的基因组扫描方法，甲基化敏感的代表性差异分析（MS-RDA），从双胞胎来源的淋巴母细胞。MS-RDA从50个已知基因/EST区域中分离出10个DNA片段。在这10个区域中，通过亚硫酸氢盐测序证实了四个区域在双极双胎和对照共胎之间显示DNA甲基化差异。我们通过焦磷酸测序对这四个区域的DNA甲基化状态进行了病例对照研究。在双相情感障碍患者中，精胺合酶（SMS）和肽基脯氨酰异构酶E样（PPIEL）（CN 265253）的两个上游区域显示出异常的DNA甲基化状态。SMS是X染色体上的一个基因，与对照组女性相比，双相情感障碍女性患者的DNA甲基化水平显著升高。但mRNA表达无差异。在PPIEL中，双相II型障碍患者的DNA甲基化水平显著低于对照组。PPIEL的表达水平在双相II型障碍中显著高于对照组。我们发现PPIEL的基因表达和DNA甲基化水平之间存在很强的负相关性。这些结果表明PPIEL DNA甲基化状态的改变可能在双相情感障碍的病理生理学中具有一定意义。
To search DNA methylation difference between monozygotic twins discordant for bipolar disorder, we applied a comprehensive genome scan method, methylation-sensitive representational difference analysis (MS-RDA) to lymphoblastoid cells derived from the twins. MS-RDA isolated 10 DNA fragments derived from 50 region of known genes/ESTs. Among these 10 regions, four regions showed DNA methylation differences between bipolar twin and control co-twin confirmed by bisulfite sequencing. We performed a case-control study of DNA methylation status of these four regions by pyrosequencing. Two regions, upstream regions of spermine synthase (SMS) and peptidylprolyl isomerase E-like (PPIEL) (CN265253), showed aberrant DNA methylation status in bipolar disorder. SMS, a gene on X chromosome, showed significantly higher DNA methylation level in female patients with bipolar disorder compared with control females. However, there was no difference of mRNA expression. In PPIEL, DNA methylation level was significantly lower in patients with bipolar II disorder than in controls. The expression level of PPIEL was significantly higher in bipolar II disorder than in controls. We found strong inverse correlation between gene expression and DNA methylation levels of PPIEL. These results suggest that altered DNA methylation statuses of PPIEL might have some significance in pathophysiology of bipolar disorder.