An investigation of the involvement of methylation in the parhogenesis of mental diseases by differential genomic analyses of monozygotic twins discordant for the diseases.

通过对疾病不一致的同卵双胞胎进行差异基因组分析，研究甲基化在精神疾病单发中的作用。

• 批准号: 13307027
• 负责人: OKAZAKI Yuji
• 金额: $ 33.28万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13307027/
• 关键词: Mental Diseases; Methylation; Monozygotic twin discordant for a disease; Scizophrenia; Bipolar disorder; XBP1; Autism; Methylated cytosine; メチル化; 組織特異性; FRGP; ゲノム差異; 遺伝子発現; 一卵性双生児; 成因; エピジェネティックス; メチレーション; ゲノム解析

(1) Methylation and schizophreniaTotal me ethylated cytosine volumes in leucocytes were measured using HPLC and compared between patients with schizophrenia and age and sex matched normal controls. Leucocytes from male patients with schizophrenia contained significantly less total me ethylated cytosine than those from normal controls. The difference was observed especially in the young patients (<35 years old). There was no significant difference for female patients. Two Human endogenous retrovirus (HERV) that retain the transcriptional activity which is inhibited by methylation were located on chromosome 1q21-q22 and 22q12 which were susceptible loci repeatedly observed in the linkage study of schizophrenia. These suggest the involvement of methylation in the pathogenesis of schizophrenia(2) Differential genomic scans of discordant monozygotic twinsFluorescent representational genomic profiling (FRGP) was applied to DNAs from monozygotic twins discordant for schizophrenia, bipolar disorder, autism and narcolepsy. Discordant spots containing discordant DNA fragments between affected and non-affected twins from the monozygotic twins from autism, schizophrenia and bipolar disorder. Two candidate genes (4p14, 12q24.11) for autism, 1gnee (6q13) and 1 gene (7q31) were implicated by the direct cloning of the spots. Furthermore, the difference of an autism gene was revealed due to its different methylation status in the promoter region.(3) The discovery of bipolar disorder susceptibility gene, XBP1DNA Microarray analysis of lymphoblasted cells from two monozygotic twins discordant for bipolar disorder revealed lower expression of XBP1 and GRP78 genes that involved in the lowered endoplasmic reticulum (ER) stress. A polymorphism (-116 G/C) in the promoter region of XBP1 was responsible for lowered expression. The involvement of methylation in the expression of XBP1 is a next focus

(1)甲基化和精神分裂症使用HPLC测量白细胞中总甲基化胞嘧啶体积，并在精神分裂症患者与年龄和性别匹配的正常对照之间进行比较。男性精神分裂症患者的白细胞中甲基化胞嘧啶总量明显少于正常对照者。这种差异在年轻患者（<35 岁）中尤其明显。女性患者无显着差异。两个保留被甲基化抑制的转录活性的人内源性逆转录病毒（HERV）位于染色体1q21-q22和22q12上，这两个位点是精神分裂症连锁研究中反复观察到的易感位点。这些表明甲基化参与了精神分裂症的发病机制(2) 不一致的同卵双胞胎的差异基因组扫描荧光代表性基因组分析 (FRGP) 应用于精神分裂症、双相情感障碍、自闭症和发作性睡病不一致的同卵双胞胎的 DNA。患有自闭症、精神分裂症和双相情感障碍的同卵双胞胎中受影响和未受影响的双胞胎之间含有不一致的 DNA 片段的不一致点。斑点的直接克隆涉及自闭症的两个候选基因（4p14、12q24.11）、1gnee（6q13）和1个基因（7q31）。此外，由于其启动子区域的甲基化状态不同，揭示了自闭症基因的差异。（3）双相情感障碍易感基因XBP1DNA的发现对两个双相情感障碍不一致的同卵双胞胎的淋巴母细胞进行微阵列分析，发现双相情感障碍的低表达XBP1 和 GRP78 基因参与降低内质网 (ER) 应激。 XBP1 启动子区域的多态性 (-116 G/C) 是导致表达降低的原因。 XBP1 表达中甲基化的参与是下一个焦点

项目成果

Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, Miyazaki T, Ogura C, Okazaki Y, Jinno Y: "Age related changes of the 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study."Annals of Human Genetics. (in p

Fuke C、Shimabukuro M、Petronis A、Sugimoto J、Oda T、Miura K、Miyazaki T、Ogura C、Okazaki Y、Jinno Y：“人外周血白细胞和胎盘中 5-甲基胞嘧啶含量的年龄相关变化：HPLC-

C.Fuke, M.Shimabukuro, A.Petronis, J.Sugimoto, T.Oda, K.Miura, T.Miyazaki, C.Ogura, Y.Okazaki, Y.Jinno: "Age related changes of the 5-methylcytosine content in human peripheral leukocytes and placentas : an HPLC-based study."Annals of Human Genetics. (in

C.Fuke、M.Shimabukuro、A.Petronis、J.Sugimoto、T.Oda、K.Miura、T.Miyazaki、C.Ogura、Y.Okazaki、Y.Jinno：“5-甲基胞嘧啶含量的年龄相关变化

Imamura A: "Lack of association between the hKCa3 gene and Japanese schizophrenia patients"Psychiatric Genetics. 11・4. 227-229 (2001)

今村 A：“hKCa3 基因与日本精神分裂症患者之间缺乏关联”《精神病遗传学》11・4（2001 年）。

Tochigi M, Okazaki Y, Kato N, Sasaki T: "What causes seasonality of birth in schizophrenia?"Neuroscience Research. 48. 1571-1575 (2004)

Tochigi M、Okazaki Y、Kato N、Sasaki T：“精神分裂症出生季节性的原因是什么？”神经科学研究。

岡崎祐士: "精神分裂病の発達的脆弱性形成とエピジェネティックス"脳と精神の医学. 12・4. 293-302 (2001)

冈崎裕二：“精神分裂症的发育脆弱性形成和表观遗传学”《脑与精神医学》12・4（2001）。