Regulation and roles of histone methylation dynamics in germ-lineage cells

• Project Area: The germline: its developmental cycle and epigenome network
• Project/Area Number: 20062005
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The Institute of Physical and Chemical Research (2011-2012); Kyoto University (2008-2010)
• Principal Investigator: SHINKAI Yoichi 独立行政法人理化学研究所, 眞貝細胞記憶研究室, 主任研究員 (20211972)
• Co-Investigator(Kenkyū-buntansha): TACHIBANA Makoto 国立大学法人京都大学, ウイルス研究所・感染症モデル研究センター・ゲノム改変マウス研究領域, 准教授 (80303915)
• Project Period (FY): 2008 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥93,300,000 (Direct Cost: ¥93,300,000); Fiscal Year 2012: ¥21,200,000 (Direct Cost: ¥21,200,000); Fiscal Year 2011: ¥21,200,000 (Direct Cost: ¥21,200,000); Fiscal Year 2010: ¥21,200,000 (Direct Cost: ¥21,200,000); Fiscal Year 2009: ¥21,200,000 (Direct Cost: ¥21,200,000); Fiscal Year 2008: ¥8,500,000 (Direct Cost: ¥8,500,000)
• Keywords: 生殖細胞 / ヒストン / メチル化 / エピジェネティクス / 内在性転移因子 / 転写制御 / 脱メチル化

Research Abstract

1. We discovered that GLP protein expression is posttranscriptionally regulated in murine embryonic male germ cells after sex determination and that low H3K9me2 level results from the absence of GLP (severe reduction of the G9a-GLP heteromeric complex).
2. We demonstrated that that H3K9 methyltransferase G9a/GLP complex suppresses transcription by independently inducing both H3K9 and DNA methylation.
3. We discovered that H3K9 methyltransferase ESET and ESET.mediated H3K9me3 play a crucial role in proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.

Research Products

• [Journal Article] Posttranscriptional regulation of histone lysine methyltransferase GLP in embryonic male germ cells. (2013)
  • Author(s): Deguchi, K. Nagamatsu, G. Miyachi, H. Kato, Y. Morita, S. Kimura, H. Kitano, S. Hatada, I. Saga, Y. Tachibana. M. and Shinkai.Y
  • Journal Title: Biol. Reprod. Volume: 88 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development. (2012)
  • Author(s): Tan, S. Nishi, M. Ohtsuka, T. Matsui, T. Takemoto, K. Kamio-Miura, A. Aburatani, H. Shinkai, Y. and Kageyama, R
  • Journal Title: Development Volume: 139 Pages: 3806-3816
  • Peer Reviewed
• [Journal Article] PGC7 binds histone H3K9me2 to protect against conversion of 5MeC to 5HmC in early embryos (2012)
  • Author(s): Nakamura, T., Liu, Y.U., Nakashima, H., Umehara, H., Inoue, K., Matoba, S., Tachibana, M., Ogura, A., Shinkai, Y., Nakano, T
  • Journal Title: Nature Volume: 486 Issue: 7403 Pages: 415-419
  • DOI: 10.1038/nature11093
  • Peer Reviewed
• [Journal Article] DNA damage signalling triggers degradation of histone methyltransferases through APC/C^<Cdh1> in senescent cells (2012)
  • Author(s): Takahashi, A.Imai, Y.Yamakoshi, K.Kuninaka, S.Ohtani, N.Yoshimoto, S.Hori, S.Tachibana, M.Anderton, E.Takeuchi, T.Shinkai, Y.Peters, G.Saya, H., Hara, E.
  • Journal Title: Mol Cell Volume: 45 Pages: 123-131
  • Peer Reviewed
• [Journal Article] H3K9 methyltransferase G9a and the related molecule GLP. (2011)
  • Author(s): Shinkai, Y. and Tachibana, M
  • Journal Title: Genes Dev. Volume: 25 Pages: 781-788
  • Peer Reviewed
• [Journal Article] DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements and chimaeric transcripts in mouse ES cells. (2011)
  • Author(s): Karimi, M.M. Goyal, P. Maksakova, I.A. Bilenky, M. Leung, D. Tang, J.X. Shinkai, Y. Mager, D.L. Jones, S. Hirst M. and Lorincz, M.C
  • Journal Title: Cell Stem Cell Volume: 8 Pages: 676-687
  • Peer Reviewed
• [Journal Article] DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements and chimaeric transcripts in mouse ES cells (2011)
  • Author(s): Karimi, M.M.Goyal, P.Maksakova, I.A.Bilenky, M.Leung, D.Tang, J.X.Shinkai, Y.Mager, D.L.Jones, S.Hirst M., Lorincz, M.C.
  • Journal Title: Cell Stem Cell Volume: 8 Pages: 676-687
  • Peer Reviewed
• [Journal Article] Tracking epigenetic histone modifications in single cells using Fab-based live endogenous modification labeling (2011)
  • Author(s): Hayashi-Takanaka, Y.Yamagata, K.Wakayama, T.Stasevich, T.J.Kainuma, T.Tsurimoto, T.Tachibana, M.Shinkai, Y.Kurumizaka, H.Nozaki, N., Kimura, H.
  • Journal Title: Nucleic Acids Res Volume: 39 Pages: 6475-6488
  • Peer Reviewed
• [Journal Article] HP1γ links histone methylation marks to meiotic synapsis in mice (2011)
  • Author(s): Takada, Y.Naruse, C.Costa, Y.Shirakawa, T.Tachibana, M.Sharif, J.Kezuka-Shiotani, F.Kakiuchi, D.Masumoto, H.Shinkai, Y.Ohbo, K.Peters, A.H.F.M.Turner, J.M.A.Asano, M., Koseki, H.
  • Journal Title: Development Volume: 138 Pages: 4207-4217
  • Peer Reviewed
• [Journal Article] MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a (2011)
  • Author(s): Chang, Y.Sun, L.Kokura, K.Horton, J.R.Fukuda, M.Espejo, A.Izumi, V.Koomen, J.M.Bedford, M.T.Zhang, X.Shinkai, Y.Fang, J., Cheng, X.
  • Journal Title: Nature Commun Volume: 2 Pages: 533-533
  • Peer Reviewed
• [Journal Article] DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements andchimaeric transcripts in mouse ES cells. (2011)
  • Author(s): Karimi, M.M.Goyal, P.Maksakova, I.A.Bilenky, M.Leung, D.Tang, J.X.Shinkai, Y.Mager, D.L.Jones, S.Hirst M., Lorincz, M.C.
  • Journal Title: Cell Stem Cell. in press
• [Journal Article] H3K9 methyltransferase G9a and the related molecule GLP. (2011)
  • Author(s): Shinkai Y., Tachibana M.
  • Journal Title: Genes Dev. 25 Pages: 781-788
• [Journal Article] Lysine methyltransferase G9a is required for de novo DNA methylation and establishment but not maintenance of proviral silencing (2011)
  • Author(s): Leung T, et al
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Pages: 5718-5723
  • Peer Reviewed
• [Journal Article] H3K9 methyltransferase G9a and the related molecule GLP (2011)
  • Author(s): Shinkai Y, Tachibana M
  • Journal Title: Gene Dev. Volume: 25(未定)
  • Peer Reviewed
• [Journal Article] Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. (2010)
  • Author(s): Matsui, T^#. Leung, D^#. Miyashita, H. Maksakova, I.A. Miyachi, H. Kimura, H. Tachibana, M. Lorincz, M.C. and Shinkai, Y
  • Journal Title: Nature. Volume: 464 Pages: 927-931
  • NAID: 120002140757
  • Peer Reviewed
• [Journal Article] Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. (2010)
  • Author(s): Matsui, T.Leung, D.Miyashita, H.Maksakova, I.A.Miyachi, H.Kimura, H.Tachibana, M.Lorincz, M.C., Shinkai, Y.
  • Journal Title: Nature. 464 Pages: 927-931
  • NAID: 120002140757
• [Journal Article] Histone H1 null vertebrate cells exhibit altered nucleosome architecture. (2010)
  • Author(s): Hashimoto, H.Takami, Y.Sonoda, E.Iwasaki, T.Iwano, H.Tachibana, M.Takeda, S.Nakayama, T.Kimura, H., Shinkai, Y.
  • Journal Title: Nucleic Acids Res. 38 Pages: 3533-3545
• [Journal Article] Proviral silencing in embryonic stem cells requires. the histone methyltransferase ESET (2010)
  • Author(s): Matsui T, et al
  • Journal Title: Nature 464 Pages: 927-931
  • Peer Reviewed
• [Journal Article] Histone H1 null vertebrate cells exhibit altered nucleosome architecture (2010)
  • Author(s): Hashimoto H, et al
  • Journal Title: Nucleic Acids Research (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Obesity and metabolic syndrome in histone demethylase JHDM2a deficient mice. (2009)
  • Author(s): Inagaki, T^#. Tachibana, M^#. Magoori, K. Kudo, H. Tanaka, T. Okamura, M. Naito, M. Kodama, T. Shinkai, Y. and Sakai, Y
  • Journal Title: Genes to Cells Volume: 14 Pages: 991-1001
  • Peer Reviewed
• [Journal Article] G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. (2008)
  • Author(s): Tachibana M. Matsumura Y. Fukuda M. Kimura H. and Shinkai Y
  • Journal Title: EMBO J. Volume: 27 Pages: 2681-2690
  • Peer Reviewed
• [Journal Article] G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. (2008)
  • Author(s): Tachibana M.Matsumura Y.Fukuda M.Kimura H., Shinkai Y.
  • Journal Title: EMBO J. 27 Pages: 2681-2690
• [Journal Article] Identification of new non-histone targets of human G9a protein lysine methyltransferase using peptide arrays (2008)
  • Author(s): Rathert R. Dhayalan A. Murakami H. Zhang X. Tamas R. Jurkowska R. Komatsu Y. Shinkai Y. Cheng X. and Jeltsch A
  • Journal Title: Nat Chem Biol 4 Pages: 344-346
  • Peer Reviewed
• [Journal Article] DNA methylation of retrotransposons in stem cells requires the histone-methyltransferase G9a but not its catalytic activity (2008)
  • Author(s): Dong K.D. Maksakova L.A. Mohn F. Leung D. Appanah R. Lee S. Yang H.W. Hager D. Schttheler D. Tachibana M. Shinkai Y. and Lorincz M. C
  • Journal Title: IEMBO J 27 Pages: 2691-2701
  • Peer Reviewed
• [Journal Article] G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription (2008)
  • Author(s): Tachibana M. Matsumura Y. Fukuda M. Kimura H. and Shinkai Y
  • Journal Title: IEMBO J 27 Pages: 2681-2690
  • Peer Reviewed
• [Presentation] ESET-mediated endogenous retrovirus silencing (2012)
  • Author(s): Yoichi Shinkai
  • Organizer: 第35回日本分子生物学会大会
  • Place of Presentation: 福岡国際会議場(福岡)(招待講演)
  • Year and Date: 2012-12-13
• [Presentation] SUV39H-mediated heterochromatin formation without accumulation of HP1 (2012)
  • Author(s): Daisuke Muramatsu, Yoichi Shinkai
  • Organizer: CSH meeting Epigenetics & Chromatin
  • Place of Presentation: Cold Spring Harbor (USA)
  • Year and Date: 2012-09-14
• [Presentation] Roles of the histone methyltransferase ESET in brain development : transcriptional regulation of neural developmental genes, endogenous retroviruses (ERVs) and ERV-linked genes (2012)
  • Author(s): SiokLay Tan, Keio Takemoto, Ryoichiro Kageyama, Yoichi Shinkai
  • Organizer: 藤原セミナー
  • Place of Presentation: 芝蘭会館(京都)(招待講演)
  • Year and Date: 2012-08-02
• [Presentation] ESET-mediated endogenous retrovirus silencing. (2012)
  • Author(s): Shinkai Y
  • Organizer: CSH-Asia meeting on "Epigenetics, Chromatin, and Transcription"
  • Place of Presentation: Suzhou, China
  • Year and Date: 2012-04-25
• [Presentation] ESET-mediated endogenous retrovirus silencing (2012)
  • Author(s): Yoichi Shinkai
  • Organizer: CSH-Asia meeting on "Epigenetics, Chromatin, and Transcription"
  • Place of Presentation: Suzhou (China)(招待講演)
  • Year and Date: 2012-04-25
• [Presentation] ESET-mediated endogenous retrovirus silencing (2011)
  • Author(s): 眞貝洋一
  • Organizer: 第34回日本分子生物学会年会シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-16
• [Presentation] ヒストンメチル化酵素ESETによる生命機能制御 (2011)
  • Author(s): 眞貝洋一
  • Organizer: 第34回日本分子生物学会年会シンポジウム
  • Place of Presentation: パシフィコ横浜(横浜市)(招待講演)
  • Year and Date: 2011-12-16
• [Presentation] The role of H3K9 methyltranferase in genome integrity (2011)
  • Author(s): 眞貝洋一
  • Organizer: 27th RBC-NIRS International Symposium
  • Place of Presentation: コープ.イン.京都(京都市)(招待講演)
  • Year and Date: 2011-12-09
• [Presentation] ヒストンメチル化ダイナミクスの制御と生殖系列での機能 (2011)
  • Author(s): 眞貝洋一
  • Organizer: 第4回特定領域研究「生殖系列」班会議
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府豊中市)
  • Year and Date: 2011-11-17
• [Presentation] ヒストンメチル化酵素ESETによる生命機能制御 (2011)
  • Author(s): 眞貝洋一
  • Organizer: 第11回日本分子生物学会春季シンポジウム
  • Place of Presentation: 石川県立音楽堂(石川県金沢市)(招待講演)
  • Year and Date: 2011-05-26
• [Presentation] ヒストンメチル化酵素ESETによるES細胞の機能・分化制御機構 (2011)
  • Author(s): 眞貝洋一
  • Organizer: 第10回日本再生医療学会総会
  • Place of Presentation: 東京都
  • Year and Date: 2011-03-02
• [Presentation] ヒストンリジンメチル化酵素ESETによる内在性レトロウイルス抑制機構 (2010)
  • Author(s): 眞貝洋一、松井稔幸
  • Organizer: 日本遺伝学会第82回大会
  • Place of Presentation: 札幌
  • Year and Date: 2010-09-20
• [Presentation] ヒストンリジンメチル化酵素ESETによる内在性レトロウイルス抑制機構 (2010)
  • Author(s): 眞貝洋一
  • Organizer: 日本遺伝学会第82回大会
  • Place of Presentation: 札幌市
  • Year and Date: 2010-09-20
• [Presentation] ヒストンリジンメチル化酵素ESET による内在性レトロウイルス抑制機構 (2010)
  • Author(s): 眞貝洋一、松井稔幸
  • Organizer: 日本遺伝学会第82回大会
  • Place of Presentation: 札幌
  • Year and Date: 2010-09-02
• [Presentation] Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. (2010)
  • Author(s): Matsui, T., Leung, D., Miyashita, H., Maksakova, I.A., Miyachi, H., Kimura, H., Tachibana, M., Lorincz, M.C., Shinkai, Y.
  • Organizer: Gordon Research Conference "Chromatn Structure and Function"
  • Place of Presentation: Bryant University, Smithfield, RI, USA
• [Presentation] Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET (2010)
  • Author(s): Shinkai Y
  • Organizer: Gordon Research Conference "Chromatin Structure and Function"
  • Place of Presentation: Bryant University, Smithfield, RI, USA
• [Presentation] Histone methyltransferase ESET constrains endogenous retrovirus (ERV) transcription (2010)
  • Author(s): Shinkai Y
  • Organizer: International Symposium on "Epigenome Network, Development and Reprogramming of Germ Cells'
  • Place of Presentation: 福岡市
• [Presentation] ヒストンリジンメチル化コードと生命機能制御 (2009)
  • Author(s): 眞貝洋一
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-21
• [Presentation] ESET/SETDB1 is essential for LTR-retroelement silencing in mouse ES Cells (2009)
  • Author(s): Shinkai Y
  • Organizer: FASEB Summer Research Conferences "Epigenetics, Chromatin and Transcription"
  • Place of Presentation: Snowmass Village, Colorado, USA
  • Year and Date: 2009-07-13
• [Presentation] ESET/SETDB1 is essential for LTR-retroelement silencing in mouse embryonic stem cells. (2009)
  • Author(s): Shinkai Y
  • Organizer: FASEB Summer Research Conferences, "Epigenetics, Chromatin & Transcription"
  • Place of Presentation: Snowmass Village, Colorado, USA
• [Presentation] ESET/SETDB1 is essential for LTR-retroelement silencing in mouse embryonic stem cells. (2009)
  • Author(s): Shinkai Y.
  • Organizer: FASEB Summer Research Conferences, "Epigenetics, Chromatin & Transcription".
  • Place of Presentation: Snowmass Village, Colorado, USA
• [Presentation] Function and regulation of histone lysine methylation (2008)
  • Author(s): 眞貝洋一
  • Organizer: 第31回日本分子生物学会大会、第81回日本生化学会大会合同大会シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Function and regulation of histone lysine methylation (2008)
  • Author(s): 眞貝洋一
  • Organizer: 第31回日本分子生物学会大会、第81回日本生化学会会合同大会シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Epigenetic Gene Silencing Mechanisms of the G9a/GLP Histone Methyltransferase Complex. (2008)
  • Author(s): Shinkai, Y
  • Organizer: 6th NIBB-EMBL joint Meeting
  • Place of Presentation: EMBL Heidelberg, Germany
• [Book] Mammalian epigenetics in biology and medicine (2013)
  • Author(s): Ishino F. Shinkai Y. and Whitelaw E
  • Total Pages: 368
  • Publisher: Philos Trans R Soc Lond B Biol Sci.
• [Book] 実験医学別冊 エピジェネティクス実験プロトコール編 (2008)
  • Author(s): 牛島俊和、眞貝洋一
  • Publisher: 羊土社
• [Remarks]
  • URL: http://www.riken.jp/research/labs/chief/cell_mem/
• [Remarks]
  • URL: http://www.kyoto-u.ac.jp/ja/news_data/h/h1/news6/2009/100218_1.htm