Genome mapping of 5-hydroxymethylcytosine using human postmortem brains

• Project/Area Number: 24591676
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: The University of Tokyo
• Principal Investigator: BUNDO Miki 東京大学, 医学部附属病院, 特任助教 (00597221)
• Co-Investigator(Renkei-kenkyūsha): IWAMOTO Kazuya 東京大学, 大学院医学系研究科, 特任准教授 (40342753)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ハイドロキシメチルシトシン / DNAメチル化 / ヒト死後脳 / 精神疾患 / 死後脳 / エピジェネティクス / 死後脳研究

Outline of Final Research Achievements

Despite a huge number of studies, the etiology of psychiatric disorders has not been clarified. Recently, 5-hydroxymethylcytosine (5-hmc) was identified as a novel form of modified cytosine, and it is considered as an intermediate form in demethylation step of 5-methylcytosine (5-mc). As the content of 5-hmc in the brain tissues is higher than in any other tissues, it is expected to have the novel roles in the brains.
We have reported that the copy number of Long Interspersed Elements-1 (LINE-1), which has autonomous retrotransposition activity in human genome, increases genomic DNA derived from postmortem brains of patients with major mental disorders, but its mechanism remains unknown. In this study, we have studied the 5-hmc and 5-mc status at LINE-1 regions of genomic DNA from neurons and non-neuronal cells in a healthy human postmortem brain. We found that the content of 5-hmc is especially concentrated at evolutionarily young (active) LINE-1 region in neuronal cells.

Research Products

• [Journal Article] Effects of quetiapine on DNA methylation in neuroblastoma cells. (2014)
  • Author(s): Sugawara H, Bundo M, Asai T, Sunaga F, Ueda J, Ishigooka J, Kasai K, Kato T, Iwamoto K.
  • Journal Title: Progress in Neuro-Psychopharmacology and Biological Psychiatry Volume: 56C Pages: 117-121
  • DOI: 10.1016/j.pnpbp.2014.08.010
  • Peer Reviewed
• [Journal Article] 統合失調症の患者死後脳ではLINE-1配列が増加している (2014)
  • Author(s): 文東美紀、加藤忠史、岩本和也
  • Journal Title: 科学 Volume: 84 Pages: 808-810
• [Journal Article] 統合失調症の神経細胞ゲノムではLINE-1のコピー数が増加している (2014)
  • Author(s): 文東美紀、加藤忠史、岩本和也
  • Journal Title: 実験医学 Volume: 32 Pages: 1257-1260
• [Journal Article] DNA methylation analysis of BDNF gene promoters in peripheral blood cells of schizophrenia patients. (2013)
  • Author(s): Ikegame T, Bundo M et al. (equal contribution)
  • Journal Title: Neuroscience Research Volume: 77 Issue: 4 Pages: 208-214
  • DOI: 10.1016/j.neures.2013.08.004
  • Peer Reviewed
• [Journal Article] Effect of mood stabilizers on DNA methylation in human neuroblastoma cells. (2013)
  • Author(s): Asai T, Bundo M et al. (equal contribution)
  • Journal Title: International Journal of Neuropsychopharmacology Volume: 16 Issue: 10 Pages: 2285-2294
  • DOI: 10.1017/s1461145713000710
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal cell-type specific DNA methylation patterns of the Cacna1c gene. (2013)
  • Author(s): Nishioka M et al.
  • Journal Title: International Journal of Developmental Neuroscience Volume: 31 Pages: 89-95
  • Peer Reviewed
• [Journal Article] Comprehensive DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia. (2013)
  • Author(s): Nishioka M, Bundo M, Koike S, Takizawa R, Kakiuchi C, Araki T, Kasai K, Iwamoto K
  • Journal Title: J Hum Genet Volume: 58(2) Issue: 2 Pages: 91-7
  • DOI: 10.1038/jhg.2012.140
  • NAID: 10031156430
  • Peer Reviewed
• [Journal Article] A systematic evaluation of whole genome amplification of bisulfite-modified DNA. (2012)
  • Author(s): Bundo Miki, Sunaga Fumiko, Ueda Junko, Kasai Kiyoto, Kato Tadafumi, Iwamoto Kazuya.
  • Journal Title: Clinical Epigenetics Volume: 4 Issue: 1 Pages: 22-22
  • DOI: 10.1186/1868-7083-4-22
  • Peer Reviewed
• [Journal Article] DNA methylation in schizophrenia: progress and challenges of epigenetic studies. (2012)
  • Author(s): Nishioka Masaki, Bundo Miki, Kasai Kiyoto, Iwamoto Kazuya.
  • Journal Title: Genome Medicine Volume: 4 Issue: 12 Pages: 96-96
  • DOI: 10.1186/gm397
  • Peer Reviewed
• [Presentation] ヒト死後脳神経細胞・非神経細胞ゲノムにおけるLINE-1のハイドロキシメチル化状態の検証 (2015)
  • Author(s): 澤井大和、西岡将基、文東美紀、上田順子、石井貴男、鵜飼渉、橋本恵理、笠井清登、加藤忠史、岩本和也
  • Organizer: 第10回統合失調症学会
  • Place of Presentation: 都市センターホテル・東京
  • Year and Date: 2015-03-27 – 2015-03-28
• [Presentation] 脳ゲノム解析と精神疾患 (2014)
  • Author(s): 岩本和也、文東美紀、加藤忠史
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: パシフィコ横浜・神奈川
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] 双極性障害のエピジェネティクス～セロトニントランスポーターにおける候補遺伝子解析 (2014)
  • Author(s): 岩本和也、文東美紀、池亀天平、菅原裕子、石郷岡純、笠井清登、加藤忠史
  • Organizer: 第36回日本生物学的精神医学会・第57回日本神経化学会大会シンポジウム
  • Place of Presentation: 奈良県文化会館・奈良
  • Year and Date: 2014-09-29 – 2014-10-01
  • Invited
• [Presentation] 統合失調症患者死後脳ではLINE-1コピー数が増大している (2014)
  • Author(s): 文東美紀、加藤忠史、岩本和也
  • Organizer: 第8回日本エピジェネティクス研究会年会
  • Place of Presentation: 伊藤国際学術研究センター・東京
  • Year and Date: 2014-05-25 – 2014-05-27
  • Invited
• [Presentation] ヒト死後脳ゲノムDNAにおけるレトロトランスポゾンのコピー数定量 (2012)
  • Author(s): 文東美紀
  • Organizer: 日本エピジェネティクス研究会第6回年回
  • Place of Presentation: 東京一ツ橋学術総合センター
• [Presentation] Increasing of LINE-1 copy number in postmortem brains of psychiatric disorder patients (2012)
  • Author(s): Bundo Miki
  • Organizer: 28th CINP Congress
  • Place of Presentation: Stockholm, Sweden
• [Remarks] 東京大学大学院医学系研究科・分子精神医学講座
  • URL: http://www.molpsy.com/
• [Remarks] 東京大学大学院 医学系研究科 分子精神医学講座
  • URL: http://www.molpsy.com/