Elucidation of molecular mechanism for base excision repair pathway-mediated active demethylation by PRDM14

• Project/Area Number: 24681040
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Genome biology
• Research Institution: Kwansei Gakuin University
• Principal Investigator: Seki Yoshiyuki 関西学院大学, 理工学部, 准教授 (20435655)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥26,780,000 (Direct Cost: ¥20,600,000、Indirect Cost: ¥6,180,000); Fiscal Year 2015: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2014: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2013: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2012: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: 多能性幹細胞 / 初期化 / 生殖細胞 / 再生医学 / エピジェネティクス / メチル化 / DNAのメチル化 / リプログラミング / ES細胞 / DNAメチル化 / DNA脱メチル化 / PRDM14 / 塩基除去修復 / TET

Outline of Final Research Achievements

Germline cells are sole source of next generation in multicellular organism, which is called cellular totipoency. Germ cells erase genome-wide DNA methylation and histone modifications to acquire cellular totipotency during their development.
In this study, we have tried to identify the molecular mechanisms and biological significance of base excision repair-mediated active demethyaltion by PRDM14. We have shown that PRDM14 regulates the activity of TET proteins to promotes active DNA demethylation in embryonic stem cells (ESCs). We have further demonstrated that PRDM14 converts epiblast-like cells (EpiLCs) to ESCs mediated by the enhancement of OCT3/4-binding at target locus through active DNA demethylation.

Research Products

• [Int'l Joint Research] ノッティンガム大学(英国)
• [Journal Article] PRDM14 maintains pluripotency of embryonic stem cells through TET-mediated active DNA demethylation., Okashita, N., Saka (2015)
  • Author(s): Okashita N,Sakashita N , Ito K, Mitsuya A, Suwa Y, Seki Y.
  • Journal Title: Biochem. Biophys.Res. Commun. Volume: 466(1) Issue: 1 Pages: 138-45
  • DOI: 10.1016/j.bbrc.2015.08.122
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] PRDM14 promotes active DNA demethylation through the Ten-eleven translocation (TET)-mediated base excision repair pathway in embryonic stem cells. (2014)
  • Author(s): Okashita, N., Kumaki, Y., Ebi, K., Nishi, M., Okamoto, Y., Nakayama, M., Hashimoto, S., Nakamura, T., Sugasawa, K., Kojima, N., Takada, T., Okano, M. and Seki, Y.
  • Journal Title: Development Volume: 141 Issue: 2 Pages: 269-280
  • DOI: 10.1242/dev.099622
  • Peer Reviewed
• [Journal Article] A replication-dependent passive mechanism modulates DNA demethylation in mouse primordial germ cells (2013)
  • Author(s): Ohno R, Nakayama M, Naruse C, Okashita N, Takano O, Tachibana M, Asano M, Saitou M, Seki Y
  • Journal Title: Development Volume: 140 Issue: 14 Pages: 2892-2903
  • DOI: 10.1242/dev.093229
  • Peer Reviewed
• [Journal Article] Effects of Dppa3 on DNA methylation dynamics during primordial germ cell development (2013)
  • Author(s): Nakashima H, Kimura T, Kaga Y. Nakatani T, Seki Y, Nakamura T, Nakano T
  • Journal Title: Biol Rep Volume: 88 Issue: 5 Pages: 1-9
  • DOI: 10.1095/biolreprod.112.105932
  • Peer Reviewed
• [Journal Article] Effects of Dppa3 0n DNA Methylation Dynamics During Primordial Germ Cell Development in Mice. (2013)
  • Author(s): Seki Y, Nakashima H
  • Journal Title: Biology of Reproduction Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Serum-mediated transgenerational effects on sperm: Evidence for lamarckian inheritance? (2013)
  • Author(s): Seki, Y.
  • Journal Title: Hepatology Volume: 57(4) Pages: 1663-1665
  • Peer Reviewed
• [Presentation] 始原生殖細胞によるエピゲノムリプログラミング (2015)
  • Author(s): 関 由行
  • Organizer: 第108 回日本繁殖生物学会大会
  • Place of Presentation: 宮崎大学（宮崎県・宮崎市）
  • Year and Date: 2015-09-17
  • Invited
• [Presentation] PRDM14 による能動的脱メチル化を介した多能性獲得機構の解 明 (2015)
  • Author(s): 関 由行
  • Organizer: 第９回日本エピジェネティクス研究会年会
  • Place of Presentation: 学術総合センター 一橋講堂（東京都・千代田区）
  • Year and Date: 2015-05-25
  • Invited
• [Presentation] 生殖系列の成立に重要なPRDM14の機能ドメインの同定 (2014)
  • Author(s): 阪下奈穂、岡下修己、関由行
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-11-25
• [Presentation] 生殖系列の成立に必要な因子PRDM14の動作原理解析 (2014)
  • Author(s): 関由行
  • Organizer: 第１回北陸エピジェネティクス研究会
  • Place of Presentation: 金沢大学（石川県・金沢市）
  • Year and Date: 2014-11-19
  • Invited
• [Presentation] PRDM14 promotes active DNA demethylation through the TET-BER-mediated base exision repair pathway (2014)
  • Author(s): Yoshiyuki Seki
  • Organizer: 47th Annual Meeting of the Japanease Society of Developmental biologists
  • Place of Presentation: 愛知県産業労働センター（愛知県・名古屋）
  • Year and Date: 2014-05-29
• [Presentation] PRDM14による塩基除去修復を介した能動的脱メチル化機構の解明 (2014)
  • Author(s): 関 由行
  • Organizer: 第８回日本エピジェネティクス研究会
  • Place of Presentation: 東京大学（東京都）
  • Year and Date: 2014-05-25
• [Presentation] PRDM14 promotes active DNA demethylation through the Ten-eleven translocation (TET)-mediated base excision repair pathway. (2013)
  • Author(s): Seki, Y.
  • Organizer: Gordon Research Conference Germinal Stem Cell Biology
  • Place of Presentation: The Chinese University of Hong Kong in Hong Kong China
• [Presentation] PRDM14 promotes active demethylation through the base excision repair pathway (2012)
  • Author(s): 関由行
  • Organizer: 58^<th>/60^<th> NIBB Conference
  • Place of Presentation: 岡崎コンファレンスセンター(愛知)
  • Year and Date: 2012-07-17
• [Presentation] PRDM14による塩基除去修復を介した能動的脱メチル化機構の解明 (2012)
  • Author(s): 関由行
  • Organizer: 第6回 日本エピジェネティクス研究会
  • Place of Presentation: 学術総合センター(東京)
  • Year and Date: 2012-05-14
• [Remarks] 関研究室ホームページ
  • URL: http://sci-tech.ksc.kwansei.ac.jp/~seki/Seki_Lab..html
• [Remarks] 研究室ホームページ
  • URL: http://sci-tech.ksc.kwansei.ac.jp/~seki/Seki_Lab..html
• [Remarks] 関研究室ホームページ
  • URL: http://sci-tech.ksc.kwansei.ac.jp/~seki/Seki_Lab..html
• [Remarks] HP
  • URL: http://sci-tech.ksc.kwansei.ac.jp/~Seki_Lab..html