応用酵素・疾患代謝研究部門

応用酵素・疾患代謝研究部門オリジナルサイトはこちら

 

 

主要研究テーマ研究内容メンバー発表論文

 

主要研究テーマ

 

ヒストンメチル化酵素および脱メチル化酵素によるエピゲノム制御の分子基盤の解明

 

 

遺伝子改変マウスを用いた、エピゲノム制御因子の生理機能解析

 

 

哺乳類の初期発生におけるヒストンメチル化修飾のダイナミズムと機能の解析

 

 

研究内容

 

 細胞には、発生・分化といった時間軸に沿ったプログラムや、外界からのシグナルに対応して適切な遺伝子発現制御を行うメカニズムが備わっています。ゲノムの1次情報(機能配列)からクロマチンの高次構造、更には核内の様々な構造体がこの遺伝子発現制御に深く関わっています。 

 

 近年、ゲノム情報とクロマチン構造をつなぐ最も基本的な蛋白質であるヒストンの持つ転写制御機能の解明が進みました。中でも、ヒストン機能の調節にアセチル化、メチル化、リン酸化などの化学修飾が重要な役割を持つことが示されてきました。特にこの数年、ヒストンメチル化修飾が遺伝子発現制御を始めとした様々な生命機能に深く関わっていることが明らかになりつつあります。エピジェネティックな遺伝子発現制御、特にヒストンの化学修飾を介したクロマチンの構造・ 機能制御、及びその破綻が、我々ヒトを含めたほ乳類の生命活動(健康と疾患)にどのように関わっているのかについて明らかにしていこうと考えています。

 

エピジェネティックな遺伝子発現制御

 

 

メンバー

教授 立花誠教授
立花 誠
Makoto Tachibana
TEL : 088-634-6421
E-mail : mtachiba@tokushima-u.ac.jp
助教 黒木俊介助教
黒木 俊介
Shunsuke Kuroki
TEL : 088-633-9253
E-mail : skuroki@tokushima-u.ac.jp
助教 岡下修己助教
岡下 修己
Naoki Okashita
TEL : 088-633-9253
E-mail : okashita.naoki@tokushima-u.ac.jp
 

 

発表論文

1. Kuroki S, Matoba S, Akiyoshi M, Matsumura Y, Miyachi H, Mise N, Abe K, Ogura A, Wilhelm D, Koopman P, Nozaki M, Kanai Y, Shinkai Y, Tachibana M.
Epigenetic Regulation of Mouse Sex Determination by the Histone Demethylase Jmjd1a.
Science. 2013 Sep 6;341(6150):1106-1109

 

 2. Kuroki S, Akiyoshi M, Tokura M, Miyachi H, Nakai Y, Kimura H, Shinkai Y, Tachibana M.
JMJD1C, a JmjC Domain-Containing Protein, Is Required for Long-Term Maintenance of Male Germ Cells in Mice.
Biol Reprod. 2013 Sep 4.

 

 3. Fujimoto Y, Tanaka SS, Yamaguchi YL, Kobayashi H, Kuroki S, Tachibana M,Shinomura M, Kanai Y, Morohashi K, Kawakami K, Nishinakamura R.
Homeoproteins six1 and six4 regulate male sex determination and mouse gonadal development.
Dev Cell. 2013 Aug 26;26(4):416-30.

 

 4. Inagawa M, Nakajima K, Makino T, Ogawa S, Kojima M, Ito S, Ikenishi A, Hayashi T, Schwartz RJ, Nakamura K, Obayashi T, Tachibana M, Shinkai Y, Maeda K, Miyagawa-Tomita S, Takeuchi T.
Histone H3 lysine 9 methyltransferases,G9a and GLP are essential for cardiac morphogenesis.
Mech Dev. 2013 Jul 24.

 

 5. Muramatsu D, Singh PB, Kimura H, Tachibana M, Shinkai Y.
Pericentric Heterochromatin Generated by HP1 Protein Interaction-defective Histone Methyltransferase Suv39h1.
J Biol Chem. 2013 Aug 30;288(35):25285-96.

 

 6. Ohno R, Nakayama M, Naruse C, Okashita N, Takano O, Tachibana M, Asano M, Saitou M, Seki Y.
A replication-dependent passive mechanism modulates DNA demethylation in mouse primordial germ cells.
Development. 2013 Jul;140(14):2892-903.

 

 7. Deguchi K, Nagamatsu G, Miyachi H, Kato Y, Morita S, Kimura H, Kitano S, Hatada I, Saga Y, Tachibana M, Shinkai Y.
Posttranscriptional Regulation ofHistone Lysine Methyltransferase GLP in Embryonic Male Mouse Germ Cells
.
Biol Reprod. 2013 Feb 14;88(2):36.

 

 8. Balemans MC, Nadif Kasri N, Kopanitsa MV, Afinowi NO, Ramakers G, Peters TA, Beynon AJ, Janssen SM, van Summeren RC, Eeftens JM, Eikelenboom N, Benevento M, Tachibana M, Shinkai Y, Kleefstra T, van Bokhoven H, Van der Zee CE.
Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome
.
Hum Mol Genet. 2013 Mar 1;22(5):852-66.

 

 9. Nakamura T, Liu YJ, Nakashima H, Umehara H, Inoue K, Matoba S, Tachibana M, Ogura A, Shinkai Y, Nakano T.
PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos.
Nature. 2012 Jun 3;486(7403):415-9.

 

10. Yamamizu K, Fujihara M, Tachibana M, Katayama S, Takahashi A, Hara E, Imai H, Shinkai Y, Yamashita JK.
Protein kinase A determines timing of early differentiation through epigenetic regulation with G9a.
Cell Stem Cell. 2012 Jun 14;10(6):759-70.

 

11. Takahashi M, Takemoto Y, Shimazu T, Kawasaki H, Tachibana M, Shinkai Y, Takagi M, Shin-ya K, Igarashi Y, Ito A, Yoshida M.
Inhibition of histone H3K9 methyltransferases by gliotoxin and related epipolythiodioxopiperazines.
J Antibiot (Tokyo). 2012 May;65(5):263-5.

 

12. 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.
DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells.
Mol Cell. 2012 Jan 13;45(1):123-31.

 

13. Takada Y, Naruse C, Costa Y, Shirakawa T, Tachibana M, Sharif J, Kezuka-Shiotani F, Kakiuchi D, Masumoto H, Shinkai Y, Ohbo K, Peters AH, Turner JM, Asano M, Koseki H.
HP1γ links histone methylation marks to meiotic synapsis in mice.
Development. 2011 Oct;138(19):4207-17.

 

14. Hayashi-Takanaka Y, Yamagata K, Wakayama T, Stasevich TJ, Kainuma T, Tsurimoto T, Tachibana M, Shinkai Y, Kurumizaka H, Nozaki N, Kimura H.
Tracking epigenetic histone modifications in single cells using Fab-based live endogenous modification labeling.
Nucleic Acids Res. 2011 Aug;39(15):6475-88.

 

15. Shinkai Y, Tachibana M.
H3K9 methyltransferase G9a and the related molecule GLP
Genes Dev. 2011 Apr 15;25(8):781-8.

 

16. Leung, D. Dong, K. Maksakova, I. Goyal, P. Appanah, R. Lee, S. Tachibana, M. Shinkai, Y. Lehnertz, B. Mager, D. Rossi, F. and Lorincz, M.C.*.
Lysine methyltransferase G9a is required for de novo DNA methylation and establishment but not maintenance of proviral silencing.
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5718-23.

 

17. Hashimoto H, Takami Y, Sonoda E, Iwasaki T, Iwano H, Tachibana M, Takeda S, Nakayama T, Kimura H, Shinkai Y*.
Histone H1 null vertebrate cells exhibit altered nucleosome architecture.
Nucleic Acids Res. 2010 Jun;38(11):3533-45.

 

18. Matsui T#, Leung D#, Miyashita H, Maksakova IA, Miyachi H, Kimura H, Tachibana M, Lorincz MC*, Shinkai Y*.
Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET.
Nature. 2010 Apr 8;464(7290):927-31.

 

19. Balemans, M*. Huibers, M. Eikelenboom, N. Kuipers, A. van Summeren, R. Pijpers, M. Tachibana, M. Shinkai, Y. van Bokhoven, H. and van der Zee, C.E..
Reduced exploration, increased anxiety, and altered social behavior: autistic-like features in Ehmt1+/- mice.
Behav Brain Res. 2010 Mar 17;208(1):47-55.

 

20. Yokochi T. Poduch K. Ryba T. Lu J. Hiratani T. Tachibana M. Shinkai Y.and Gilbert D.M*.
G9a selectively represses a class of late-replicating genes at the nuclear periphery.
Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19363-8.

 

21. Inagaki, T#. Tachibana, M#. Magoori, K. Kudo, H. Tanaka, T. Okamura, M. Naito, M. Kodama, T. Shinkai, Y*. and Sakai , Y*.
Obesity and metabolic syndrome in histone demethylase JHDM2a deficient mice.
Genes to Cells, 2009 Aug;14(8):991-1001. (#equal contribution)

 

22. Link, P. Gangisetty, O.James, S. Woloszynska-Read, A. Tachibana, M. Shinkai, Y. Karpf, A*.
Distinct Roles for Histone Methyltransferases G9a and GLP in Cancer Germ-Line Antigen Gene Regulation in Human Cancer Cells and Murine Embryonic Stem Cells.
Mol Cancer Res. 2009 Jun;7(6):851-62.

 

23. Shirato, H. Ogawa, S. Nakajima , K. Inagawa, M. Kojima, M. Tachibana, M. Shinkai, Y. and Takeuchi, T*.
A Jumonji (Jarid2) protein complex represses cyclin D1 expression by methylation of histone H3-K9.
J Biol Chem.2009 Jan 9;284(2):733-9.

 

24. Tachibana M*. Matsumura Y. Fukuda M. Kimura H. and Shinkai Y*.
G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription.
EMBO J. 2008 Oct 22;27(20):2681-90.

 

25. Dong KB, Maksakova IA, Mohn F, Leung D, Appanah R, Lee S, Yang HW, Lam LL, Mager DL, Schubeler D, Tachibana M, Shinkai Y, Lorincz MC.*
DNA methylation in ES cells requires the lysine methyltransferase G9a but not its catalytic activity.
EMBO J. 2008 Oct 22;27(20):2691-701.

 

26. Okamoto K. Iwano T. Tachibana M. and Shinkai Y*.
Distinct roles of TRF1 in the regulation of telomere structure and lengthening.
J. Biol. Chem., 2008 Aug 29;283(35):23981-8.

 

27. Thomas, L.R. Miyashita, H. Cobb, R.M. Pierce S. Tachibana, M. Hobeika, E. Reth, M. Shinkai, Y. and Oltz, E.M*.
Functional Analysis of Histone Methyltransferase G9a in B and T Lymphocytes.
J.Immunol. 2008 Jul 1;181(1):485-93.

 

28. Kato, Y. Kato, M. Tachibana, M. Shinkai, Y. and Yamaguchi, M*.
Characterization of Drosophila G9a in vivo and identification of genetic interactions.
Genes to Cells. 2008 Jul;13(7):703-22.

 

29. Hashimoto, H. Sonoda, E. Takami, Y. Kimura, H. Nakayama, T. Tachibana, M. Takeda, S. and Shinkai, Y*.
Histone H1 variant, H1R is involved in DNA damage response.
DNA repair, 2007 Nov;6(11):1584-95.

 

30. Tachibana, M*. Nozaki, M. Takeda, N. and Shinkai, Y*.
Functional Dynamics of H3K9 Methylation During Meiotic Prophase Progression.
EMBO J. 2007 Jul 25;26(14):3346-59.

 

31. Nishida, M. Kato, M. Kato, Y. Sasai, N. Ueda, J. Tachibana, M. Shinkai, Y. and Yamaguchi M*.
Identification of ZNF200 as a novel binding partner of histone H3 methyltransferase G9a.
Genes to Cells, 2007 Jul;12(7):877-88.

 

32. Seki, Y. Yamaji, M. Yabuta, Y. Sano, M. Shigeta, M. Tachibana, M. Matsui, Y. Saga, Y. Shinkai, Y. and Saitou, M*.
A cellular dynamics associated with the genome-wide epigenetic reprogramming in primordial germ cells in mice.
Development, 2007 Jul;134(14):2627-38.

 

33. Ikegami, K. Iwatani, M. Suzuki, M. Tachibana, M. Shinkai, Y. Tanaka, S. Greally, J.M. Yagi, S. Hattori, N. and Shiota, K*.
Genome-wide and locus-specific DNA hypomethylation in G9a deficient mouse embryonic stem cells.
Genes to Cells, 2007 Jan;12(1):1-11.

 

34. Akiyama, K. Yusa, K. Hashimoto, H. Poonepalli, A. Hande, M.P. Kakazu, N. Takeda, J. Tachibana, M. and Shinkai, Y*.
Rad54 is dispensable for the ALT pathway.
Genes to Cells, 2006 Nov;11(11):1305-15.

 

35. Ueda J.Tachibana, M. Ikura, T. and Shinkai, Y.
Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor molecule CtBP.
J Biol Chem. 2006 Jul 21;281(29):20120-8.

 

36. Tachibana, M. Ueda, J. Fukuda, M. Takeda, N. Ohta, T. Iwanari, H. Sakihama, T. Kodama, T. Hamakubo, T. and Shinkai, Y.
Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9.
Genes Dev. 2005 Apr 1;19(7):815-26.

 

37. Collins, R.E. Tachibana, M. Tamaru, H. Smith, K.M. Jia, D. Zhang, X. Selker, E.U. Shinkai, Y. and Cheng, X.
In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases.
J Biol Chem. 2005 Feb 18;280(7):5563-70.

 

38. Ohhata, T. Tachibana, M. Tada, M. Tada, T. Sasaki, H. Shinkai, Y. and Sado, T.
X-inactivation is stably maintained in mouse embryos deficient for G9a.
Genesis. 2004 Nov;40(3):151-6.

 

39. Osipovitch, O. Meade, A. Milley, R. Oestreich, K. Tachibana, M. Shinkai, Y. Krangel, M.S. and Oltz, E.M.
Targeted inhibition of V(D)J recombination by a histone methyltransferase.
Nat Immunol. 2004 Mar;5(3):309-16.

 

40. Iwano T, Tachibana M, Reth M, Shinkai Y.
Importance of TRF1 for functional telomere structure.
J Biol Chem. 2004 Jan 9; 279(2): 1442-8.

 

41. Peters, A. Kubicek, S. Mechtler, K. O’ Sullivan, R.J. Derijck, A.A. Perez-Burgos, L. Kohlmaier, A. Opravil, S. Tachibana, M. Shinkai, Y. Martens, J.H. and Jenuwein, T*.
Partitioning and plasticity of repressive histone methylation states in mammalian chromatin.
Mol Cell. 2003 Dec;12(6):1577-89.

 

42. Fujita N, Watanabe S, Ichimura T, Tsuruzoe S, Shinkai Y, Tachibana M, Chiba T, Nakao M.
Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression.
J Biol Chem. 2003 Jun 27;278(26):24132-8.

 

43. Xin, Z. Tachibana, M. Guggiari, M. Heard, E. Shinkai, Y. and Wagstaff, J.
Role of histone methyltransferase G9a in CpG methylation of the Prader-Willi syndrome imprinting center.
J Biol Chem. 2003 Apr 25;278(17):14996-5000.

 

44. Tachibana, M. Sugimoto, K. Nozaki, M. Ueda, J. Ohta, T. Ohki, M. Fukuda, M. Takeda, N. Niida, H. Kato, H. and Shinkai, Y.
G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis.
Genes Dev. 2002 Jul 15;16(14):1779-91.

 

45. Tachibana, M. Narumi, O. Muguruma, K. Yamamoto, I. Shinkai, Y. and Yokota, Y.
Genomic organization and chromosomal mapping of the basic helix-loop-helix factor OUT (Tcf23/TCF23).
Cytogenet Cell Genet. 2001;94(1-2):23-5.

 

46. Ono, Y. Shimozawa, N. Kimoto, S. Tachibana, M. Shinkai, Y. Ito, M. and Kono, T.
Production of cloned mice from embryonic stem cells arrested at metaphase.
Reproduction. 2001 Nov;122(5):731-6.

 

47. Tachibana, M. Sugimoto, K. Fukushima, T. and Shinkai, Y.
SET-domain containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3.
J Biol Chem. 2001 Jul 6;276(27):25309-17.

 

47. Wakayama, T. Shinkai, Y. Tamashiro, K.L.K. Niida, H. Blanchard, C.D. Blanchard, R.J. Ogura, A. Tanemura, K. Tachibana, M. Perry, A.C.F. Monbaerts, P. and Yanagimachi, R.
Cloning of mice to six generations.
Nature. 2000 Sep 21;407(6802):318-9.

 

48. Tachibana M, Siddiqi MA, Ikegami Y, Eshima K, Shirota-Someya Y, Tahara-Hanaoka S, Koito A, Iizuka M, Shinohara N.
Related Articles Coreceptor function of mutant human CD4 molecules without affinity to gp120 of human immunodeficiency virus.
J Biol Chem. 2000 Jul 7;275(27):20288-94.

 

49. Niida, H. Shinkai, Y*. Hande, M.P. Matsumoto, T. Takehara, S. Tachibana, M. Oshimura, M. Lansdorp, P.M. and Furuichi, Y.
Telomere maintenance in telomerase-deficient mouse embryonic stem cells: characterization of an amplified telomeric DNA.
Mol Cell Biol. 2000 Jun;20(11):4115-27.

 

49. Senoo, M. Seki, N. Ohira, M. Sugano, S. Watanabe, M. Tachibana, M. Tanaka, T. Shinkai, Y* . and Kato, H*.
A second p53-related protein, p73L, with high homology to p73.
Biochem Biophys Res Commun. 1998 Jul 30;248(3):603-7.