Epigenetic changes of male germ line cells affecting behavior of offspring in mice

• Project/Area Number: 15K12764
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Basic / Social brain science
• Research Institution: Tohoku University
• Principal Investigator: OSUMI Noriko 東北大学, 医学系研究科, 教授 (00220343)
• Co-Investigator(Kenkyū-buntansha): 吉崎 嘉一 東北大学, 医学系研究科, 助教 (50393161) ; 稲田 仁 東北大学, 医学系研究科, 講師 (60419893)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 加齢精子 / エピゲノム変化 / DNAメチル化 / ターゲットメチローム / 父加齢 / 精子エピゲノム / ヒストン化学修飾

Outline of Final Research Achievements

Young or aged sperm cells of Pax6 mutant heterozygous (Sey) mice were fertilized in vitro with young wild type (WT) female eggs to obtain offspring. Comprehensive behavior analyses showed different phenotypes in Sey offspring derived from young or aged sperm compared with WT littermates. DNA methylome analyses on the whole genome of sperm obtained from young or aged WT revealed differentially methylated regions (DMRs) in the aged sperm. These DMRs were enriched with GO terms involved in neuronal functions and neurons, suggesting that paternal aging may cause neurodevelopmental disorders via establishing the DMRs.

Research Products

• [Int'l Joint Research] Italian Institute of Technology(イタリア)
• [Journal Article] Paternal Aging Affects Behavior in Pax6 Mutant Mice: A Gene/Environment Interaction in Understanding Neurodevelopmental Disorders. (2016)
  • Author(s): Yoshizaki K, Furuse, T, Kimura R, Tucci V, Kaneda H, Wakana S and Osumi N
  • Journal Title: PLoS One Volume: 11 Issue: 11 Pages: e0166665-e0166665
  • DOI: 10.1371/journal.pone.0166665
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maternal dietary imbalance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development via epoxy metabolites. (2016)
  • Author(s): Sakayori N, Kikkawa T, Tokuda H, Kiryu E, Yoshizaki K, Kawashima H, Yamada T, Arai H, Kang JX, Katagiri H, Shibata H, Innis SM, Arita M, Osumi N.
  • Journal Title: Stem Cells. Volume: 34(2) Issue: 2 Pages: 470-482
  • DOI: 10.1002/stem.2246
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic expression patterns of Pax6 during spermatogenesis in the mouse. (2015)
  • Author(s): Kimura R., Yoshizaki K., Osumi N.
  • Journal Title: J Anatomy Volume: 227(1) Issue: 1 Pages: 1-9
  • DOI: 10.1111/joa.12318
  • Peer Reviewed
• [Journal Article] Fatty acid binding proteins and the nervous system: Their impact on mental conditions. (2014)
  • Author(s): Matsumata M, Inada H, Osumi N.
  • Journal Title: Neurosci Res. Volume: Epub ahead of print Pages: 47-55
  • DOI: 10.1016/j.neures.2014.08.012
  • Peer Reviewed
• [Presentation] Targeted methylome analysis of aged mouse sperm: significance in transgenerational epigenetics (2016)
  • Author(s): Koike T., Jincho Y., Kobayashi H., Yoshizaki K., Kikkawa T., Matsui Y., Osumi N., Kono T.
  • Organizer: CREST班会議【エピゲノム】
  • Place of Presentation: 熊本（メルパルク熊本）
  • Year and Date: 2016-01-06
• [Presentation] Combinatorial effects of paternal aging and Pax6 mutation on behavior of offspring : possible involvement of transgenerational epigenetics (2016)
  • Author(s): Kimura R., Yoshizaki K., Koike K., Inada H., Kikkawa T., Yaegashi A., Matui Y., Osumi N.
  • Organizer: CREST班会議【エピゲノム】
  • Place of Presentation: 熊本（メルパルク熊本）
  • Year and Date: 2016-01-06
• [Presentation] 雄性生殖細胞系列におけるPax6の発現－Pax6の新規機能－ (2015)
  • Author(s): 木村龍一, 吉崎嘉一, 小池航平, 稲田仁, 大隅典子
  • Organizer: 第38回日本分子生物学会
  • Place of Presentation: 神戸（神戸コンベンションセンター）
  • Year and Date: 2015-12-01
• [Presentation] Advanced paternal age affect maternal separation-induced vocal communication deficits in the offspring. (2015)
  • Author(s): Yoshizaki K., Kimura R., Koike K., Inada H., Osumi N.
  • Organizer: NTNU-Tohoku Univ. Brain Science Exchange Meeting
  • Place of Presentation: 仙台（東北大学）
  • Year and Date: 2015-11-26
• [Presentation] Paternal Pax6 haploinsufficiency precociously accelerated vocal communication deficits by advanced paternal aging. (2015)
  • Author(s): Yoshizaki K., Kimura R., Koike K., Inada H., Osumi N.
  • Organizer: 第37回日本生物学的精神医学会
  • Place of Presentation: 東京（タワーホール船堀）
  • Year and Date: 2015-09-25
• [Presentation] Autistic symptoms induced due to paternal aging are accompanied other medical condition and challenges such like PPI deficits. (2015)
  • Author(s): Koike K., Yoshizaki K., Kimura R., Inada H., Osumi N.
  • Organizer: 第38回日本神経科学会
  • Place of Presentation: 神戸（神戸コンベンションセンター）
  • Year and Date: 2015-07-28
• [Presentation] Crosstalk between Pax6 haploinsufficiency and paternal aging in modulating offspring behavior: a possible biomarker for sperm aging. (2015)
  • Author(s): Yoshizaki K., Kimura R., Koike K., Inada H., Osumi N.
  • Organizer: 第38回日本神経科学会
  • Place of Presentation: 神戸（神戸コンベンションセンター）
  • Year and Date: 2015-07-28
• [Presentation] Dynamic expression pattern of Pax6 during spermatogenesis in the mouse (2015)
  • Author(s): Kimura R., Yoshizaki K., Osumi N.
  • Organizer: 第13回幹細胞シンポジウム
  • Place of Presentation: 東京(東京大学）
  • Year and Date: 2015-05-30
• [Book] 脳からみた自閉症 「障害」と「個性」のあいだ (2016)
  • Author(s): 大隅 典子
  • Total Pages: 256
  • Publisher: 講談社
• [Remarks] 世界初：遺伝子変異の遺伝的リスクと父の加齢との関係性を説明
  • URL: http://www.med.tohoku.ac.jp/news/3310.html