Aberrant DNA methylation of imprinted loci in sperm from infertile men and the causal mechanism

• Project/Area Number: 23390385
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Tohoku University
• Principal Investigator: ARIMA Takahiro 東北大学, 医学(系)研究科(研究院), 教授 (80253532)
• Co-Investigator(Kenkyū-buntansha): OKAE Hiroaki 東北大学, 大学院・医学系研究科, 助教 (10582695) ; HIURA Hitoshi 東北大学, 大学院・医学系研究科, 助教 (70451523) ; MIYAUCHI Naoko 東北大学, 大学院・医学系研究科, 技術補佐員 (60596162)
• Co-Investigator(Renkei-kenkyūsha): YAEGASHI Nobuo 東北大学, 大学院・医学系研究科, 教授 (00241597) ; NAKAI Kunihiko 東北大学, 大学院・医学系研究科, 教授 (00291336)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2013: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2012: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2011: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 生殖医学 / ゲノムインプリンティング / 生殖補助医療 / メチル化インプリント / 精子

Research Abstract

Recent studies indicate the possibility of excess imprinting disease occurrence in babies by assisted reproductive technologies (ART). Genomic imprinting is regulated with epigenetic DNA methylation and the allele-specific expression of certain genes. In this study, we examined the DNA methylation status of 22 imprinted genes by bisulphite-based methylation analyses in sperm DNA from male ART patients. We found 43 patients (25.4%) whose sperm had abnormal DNA methylation among the sperm samples of men from 197 infertile couples. In addition, we found that abnormal spermatogenesis (leading to low sperm counts) is associated with defective methylation. These results would be of value in determining the safest and most ethical approach to use in ART.

Research Products

• [Journal Article] RNA sequencing-based identification of aberrant imprinting in cloned mice. (2014)
  • Author(s): Okae H, Matoba S, Nagashima T, Mizutani E, Inoue K, Ogonuki N, Chiba H, Funayama R, Tanaka S, Yaegashi N, Nakayama K, Sasaki H, Ogura A, Arima T.
  • Journal Title: Hum Mol Genet. Volume: 23 Issue: 4 Pages: 992-1001
  • DOI: 10.1093/hmg/ddt495
  • Peer Reviewed
• [Journal Article] Stability of the abnormal imprinting of human induced pluripotent stem cells (2013)
  • Author(s): Hiura H, Toyoda M, Okae H, Sakurai M, Miyauchi N, Sato A, Kiyokawa N, Okita H, Miyagawa Y, Akutsu H, Nishino K, Umezawa A, Arima T
  • Journal Title: BMC Genetics Volume: 14 Issue: 1 Pages: 32-32
  • DOI: 10.1186/1471-2156-14-32
  • Peer Reviewed
• [Journal Article] ヒト生殖補助医療(ART) とエピジェネティクスの異常 (2013)
  • Author(s): 千葉初音, 岡江寛明, 有馬隆博
  • Journal Title: 遺伝子医学 Volume: MOOK25号 Pages: 178-183
  • URL: http://www.bioweb.ne.jp/content/idensi/idensi_mook0025.html
  • Peer Reviewed
• [Journal Article] 生殖細胞と酸化ストレス (2013)
  • Author(s): 井原基公, 有馬隆博
  • Journal Title: 医学のあゆみ Volume: 247(9) Pages: 851-855
  • URL: http://www.ishiyaku.co.jp/magazines/ayumi/AyumiArticleDetail.aspx?BC=286400&AC=13310
  • Peer Reviewed
• [Journal Article] DNA methylation errors in imprinting disorders and assisted reproductive technologies. (2013)
  • Author(s): Chiba H, Hiura H, Okae H, Miyauchi N, Sato F, Sato A, Arima T.
  • Journal Title: Pediatrics international. Volume: 55 Issue: 5 Pages: 542-549
  • DOI: 10.1111/ped.12185
  • Peer Reviewed
• [Journal Article] Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproductive technologies. (2012)
  • Author(s): Hiura H, Okae H, Miyauchi N, Sato F, Sato A , Van De Pette M, John R M, Kagami M, Nakai K, Soejima H, Ogata T, Arima T.
  • Journal Title: Human Reproduction Volume: 27(8) Issue: 8 Pages: 2541-2548
  • DOI: 10.1093/humrep/des197
  • Peer Reviewed
• [Journal Article] High-throughput detection of aberrant imprint methylation in the ovarian cancer by the bisulphite PCR-Luminex method. (2012)
  • Author(s): Hiura H, Okae H, Kobayashi H, Miyauchi N, Sato F, Sato A, Suzuki F, Nagase S, Sugawara J, Nakai K, Yaegashi N, Arima T.
  • Journal Title: BMC Medical Genomics Volume: 5 Issue: 1 Pages: 8-17
  • DOI: 10.1186/1755-8794-5-8
  • Peer Reviewed
• [Journal Article] Distribution and Y397 phosphorylation of focal adhesion kinase on follicular development in the mouse ovary (2012)
  • Author(s): Sakurai M, Ohtake J, Ishikawa T, Tanemura K, Hoshino Y, Arima I, Sato E
  • Journal Title: Cell and Tissue Volume: 347 Issue: 2 Pages: 457-465
  • DOI: 10.1007/s00441-011-1307-2
  • Peer Reviewed
• [Journal Article] Re-investigation and RNA sequencing-based identification of genes with placenta-specific imprinted expression (2012)
  • Author(s): Hiroaki Okae, et al
  • Journal Title: Human Molecular Genetics Volume: 21 Issue: 3 Pages: 548-558
  • DOI: 10.1093/hmg/ddr488
  • Peer Reviewed
• [Journal Article] 生殖補助医療由来の先天性ゲノムインプリンティング異常症 (2012)
  • Author(s): 有馬隆博、樋浦仁、岡江寛明
  • Journal Title: 日本生殖内分泌学会雑誌 Japanese Journal of Reproductive Endocrinology Volume: 17 Pages: 54-58
  • NAID: 40019434316
• [Journal Article] Aberrant DNA Methylation of Imprinted Loci in Male and Female Germ Cells of Infertile Couples (2012)
  • Author(s): Arima T, Okae H, Hiura H, Miyauchi N, Sato F, Sato A, Hayashi C
  • Journal Title: INTECH Volume: 29 Pages: 183-192
  • Peer Reviewed
• [Journal Article] High-throughput detection of imprint methylation errors in the ovarian cancer by the bisulphite PCR-Luminex method (2012)
  • Author(s): Hiura H, Okae H, Kobayashi H, Miyauchi N, Sato F, Sato A, Suzuki F, Nagase S, Junichi Sugawara J, Nakai K, Yaegashi N, Arima T
  • Journal Title: BMC medical Genomics Volume: (In press)
  • Peer Reviewed
• [Journal Article] The physical ability of Japanese female elderly with cerebrovascular disease correlates to the telomere length and subtelomeric methylation status in their peripheral blood leukocytes (2011)
  • Author(s): Maeda T, Oyama J, Higuchi Y, Nishiyama Y, Kudo Y, Yamori Y, Nakazono T, Arima I, Mimori K, Makino N
  • Journal Title: Gerontology Volume: 57 Issue: 2 Pages: 137-143
  • DOI: 10.1159/000314633
  • Peer Reviewed
• [Journal Article] The correlation between the clinical laboratory data and the telomere length in peripheral blood leukocytes of Japanese female patients with hypertension (2011)
  • Author(s): Maeda T, Oyama J, Sasaki M, Arima T, Makino N
  • Journal Title: The Journal of Nutrition, Health and Aging (JNHA) Volume: 15 Pages: 240-244
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/21369674
  • Peer Reviewed
• [Journal Article] Assessing loss of imprint methylation in sperm from subfertile men using novel methylation PCR-Luminex analysis (2011)
  • Author(s): Sato A, Hiura H, Okae H, Miyauchi N, Abe Y, Utsunomiya T, Yaegashi N, Arima T
  • Journal Title: Fertil and Steril Volume: 95 Issue: 1 Pages: 129-134
  • DOI: 10.1016/j.fertnstert.2010.06.076
  • Peer Reviewed
• [Journal Article] Role for piRNAs and non-coding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus (2011)
  • Author(s): Watanabe, T., Tomizawa, S., Mitsuya, K., Totoki, Y., Yamamoto, Y., Kuramochi-Miyagawa, S., Iida, N., Hoki, Y., Murphy, P.J., Toyoda, A., Gotoh, K., Hiura, H., Arima, T., Fujiyama, A., Sado, T., Shibata, T., Nakano, T., Lin, H., Ichiyanagi, K., Soloway, P.D., Sasaki, H
  • Journal Title: Science Volume: 332 Issue: 6031 Pages: 848-52
  • DOI: 10.1126/science.1203919
  • Peer Reviewed
• [Journal Article] ART におけるエピジェティクス異常産婦人科の実際 (2011)
  • Author(s): 有馬隆博, 樋浦仁, 岡江寛明, 佐藤晶子, 宮内尚子, 阿部千鶴, 林千賀
  • Journal Title: 金原出版株式会社 Pages: 741-750
  • URL: http://search.jamas.or.jp/link/ui/2011191627
• [Presentation] ART と先天異常 (2013)
  • Author(s): 有馬隆博
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 江陽グランドホテル, 仙台
  • Year and Date: 2013-11-22
  • Invited
• [Presentation] ART とゲノムインプリンティング (2013)
  • Author(s): 有馬隆博
  • Organizer: 第58回日本生殖医学会学術講演会・総会
  • Place of Presentation: 神戸ポートピアホテル, 神戸
  • Year and Date: 2013-11-16
• [Presentation] 基礎から臨床へ, ART とエピゲノム (2013)
  • Author(s): 有馬隆博
  • Organizer: 第31回日本受精着床学会総会・学術講演会
  • Place of Presentation: 別府 シンポジウム
  • Year and Date: 2013-08-09
• [Presentation] 生殖領域におけるエピジェネティクス研究の最前線 (2013)
  • Author(s): 有馬隆博
  • Organizer: 第54回日本卵子学会
  • Place of Presentation: 学術総合センター2 階一橋記念講堂, 東京
  • Year and Date: 2013-05-25
  • Invited
• [Presentation] 生殖補助医療と小児科医療の接点 (2013)
  • Author(s): 有馬隆博
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島市文化交流会館, 広島
  • Year and Date: 2013-04-20
  • Invited
• [Presentation] 乏精子症とゲノムインプリンティング (2013)
  • Author(s): 千葉初音, 有馬隆博
  • Organizer: 日本生殖再生医学会・第8回学術集会
  • Place of Presentation: シェーンバッハ・サボー, 東京
  • Year and Date: 2013-03-10
• [Presentation] Single-base resolution DNA methylomes of human germ cells and blastocysts (2013)
  • Author(s): Arima T
  • Organizer: 11. International Human Epigenome Consortium (IHEC) Annual Meeting
  • Place of Presentation: Berlin, Germany.
• [Presentation] 乏精子症とゲノムインプリンティング (2013)
  • Author(s): 有馬 隆博、千葉 初音
  • Organizer: 日本生殖再生医学会・第8回学術集会
  • Place of Presentation: 東京
• [Presentation] 生殖医療とエピジェネティクス (2012)
  • Author(s): 有馬隆博
  • Organizer: 第11回学術集会日本不妊カウンセリング学会
  • Place of Presentation: 東京
  • Year and Date: 2012-06-08
  • Invited
• [Presentation] ART におけるエピジェネティク機構 (2012)
  • Author(s): 有馬隆博
  • Organizer: 日本生殖再生医学会・第7回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2012-03-25
• [Presentation] ARTにおけるエピジェネティク機構 (2012)
  • Author(s): 有馬隆博
  • Organizer: 日本生殖再生医学会・第7回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2012-03-25
• [Presentation] ART and Epigenetic Errors-Abnormal DNA methylation in imprinting disorders after ART (2012)
  • Author(s): 有馬隆博
  • Organizer: 卵巣に関する国際カンファレンス2012
  • Place of Presentation: 東京
  • Year and Date: 2012-03-17
• [Presentation] インプリント遺伝子の分子間相互機構の解明 (2012)
  • Author(s): 有馬隆博
  • Organizer: 熊本大学セミナー
  • Place of Presentation: 熊本大学
  • Year and Date: 2012-02-10
• [Presentation] 胎盤特異的インプリント遺伝子の役割 (2011)
  • Author(s): 有馬隆博
  • Organizer: 第4回生殖系列の世代サイクルとエピゲノムネットワーク
  • Place of Presentation: 大阪
  • Year and Date: 2011-11-18
• [Presentation] 「ARTと先天異常」
  • Author(s): 有馬隆博
  • Organizer: 日本人類遺伝学会 第58回大会
  • Place of Presentation: 仙台
  • Invited
• [Presentation] ARTとゲノムインプリンティング」
  • Author(s): 有馬隆博
  • Organizer: 第58回日本生殖医学会 学術講演会・総会
  • Place of Presentation: 神戸
• [Presentation] 基礎から臨床へ、ARTとエピゲノム
  • Author(s): 有馬隆博
  • Organizer: 第31回日本受精着床学会総会・学術講演会
  • Place of Presentation: 別府
• [Presentation] 生殖領域におけるエピジェネティクス研究の最前線
  • Author(s): 有馬隆博
  • Organizer: 第54回日本卵子学会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 生殖補助医療と小児科医療の接点
  • Author(s): 有馬隆博
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島
  • Invited
• [Book] 臨床婦人科産科 (2014)
  • Author(s): 濱田裕貴、岡江寛明、有馬隆博
  • Publisher: 医学書院
• [Book] 遺伝子医学MOOK25号 (2013)
  • Author(s): 千葉初音、岡江寛明、有馬隆博
  • Publisher: 株式会社メディカルドゥ
• [Book] 医学のあゆみ (2013)
  • Author(s): 井原基公、有馬隆博
  • Publisher: 医歯薬出版株式会社
• [Book] 遺伝子医学MOOK 25号 (2013)
  • Author(s): 千葉初音、岡江寛明、有馬隆博
  • Publisher: 株式会社 メディカルドゥ
• [Book] DNA METHYLATION, Aberrant DNA methylation of imprinted loci in male and female germ cells of infertile couples (2012)
  • Author(s): Arima T, Okae H, Hiura H, Miyauchi N, Sato F, Sato A, Hayashi C
  • Publisher: INTECH
• [Book] DNA METHYLATION (2012)
  • Author(s): Arima T, Okae H, Hiura H, Miyauchi N, Sato F, Sato A, Hayashi C.
  • Publisher: INTECH
• [Book] 日本生殖内分泌学会雑誌 (2012)
  • Author(s): 有馬隆博
  • Publisher: 日本生殖内分泌学会(掲載確定)
• [Book] 卵子学 (2011)
  • Author(s): 有馬隆博, 樋浦仁, 岡江寛明, 佐藤晶子, 宮内尚子
  • Publisher: 京都大学学術出版会
• [Book] 産婦人科の実際 (2011)
  • Author(s): 有馬隆博、樋浦仁、岡江寛明、佐藤晶子、宮内尚子、阿部千鶴、林千賀
  • Publisher: 金原出版株式会社
• [Book] 助産雑誌 (2011)
  • Author(s): 有馬隆博、樋浦仁、岡江寛明、佐藤晶子、宮内尚子
  • Total Pages: 11
  • Publisher: 医学書院
• [Book] 癌と化学療法 (2011)
  • Author(s): 有馬隆博、樋浦仁、岡江寛明、宮内尚子、佐藤芙美
  • Publisher: 癌と化学療法社
• [Book] 卵子学 (2011)
  • Author(s): 有馬隆博、樋浦仁、岡江寛明、佐藤晶子、宮内尚子
  • Publisher: 京都大学学術出版会
• [Patent(Industrial Property Rights)] ヒト精子の質的機能評価システムに応用するDNA メチル化解析システムの開発 (2012)
  • Inventor(s): 有馬 隆博
  • Industrial Property Rights Holder: 東北大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-05-16
  • Overseas
• [Patent(Industrial Property Rights)] ヒト精子の質的機能評価システムに応用するDNAメチル化解析システムの開発 (2012)
  • Inventor(s): 有馬隆博
  • Industrial Property Rights Holder: 東北大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-05-16
  • Overseas