ポリコム群抑制クロマチン形成におけるＣｐＧ配列認識の意義の解明

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23249015
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 古関 明彦 独立行政法人理化学研究所, 統合生命医科学研究センター, グループディレクター (40225446)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: CpGアイランド / CXXCモチーフ / SRAドメイン / Cxxc5 / Np95/UHRF1

Research Abstract

CpGアイランド（CGI）は、哺乳類では，転写開始点付近に集中的に局在している。ES細胞を用いたゲノムワイド解析から、１kb以上の長いCGIはDNAメチル化を受けづらく、エピジェネティック制御因子のひとつであるポリコム群による制御を受け易い一方、短いCGI（特に0.5kb以下）は軽度のDNAメチル化を受け、メチル化依存的な制御を受ける。これらの観察は，CGIがエピジェネティック制御のためのプラットフォームとなっていること、そして、その長さやDNAメチル化状態がエピジェネティック制御の選択性を決定する因子となっている可能性を示している。本研究では，CGIがどのように認識されてポリコム群による抑制クロマチンを樹立するのか、CpG配列のメチル化状態を読み取りうる構造であるCXXCモチーフとSRAドメインに焦点を絞った解析を開始した。CXXCモチーフタンパクをコードするCxxc1遺伝子について、ノックアウトマウス、コンディショナルノックアウトES細胞、タンパク複合体の解析を行った。Cxxc1ノックアウトマウスでは、胎生初期に致死となる。それに呼応して、コンディショナルノックアウトES細胞においても、Cxxc1をノックアウトすると細胞増殖が障害された。Cxxc1は発現している遺伝子のプロモーター付近に強く結合する他、発現の有無にかかわらず、エンハンサーとして記載されている領域に結合があることが見出された。また、Cxxc1を強制的に、遺伝子砂漠領域に結合させるとその領域で転写が誘導されることが示された。Cxxc1は、エンハンサー機能と密接にリンクすることが示されてきている。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

いずれのプロジェクトについても、当初の予定に従って粛々と進んでいる。

Strategy for Future Research Activity

Cxxc1が、ポリコム群によって抑制されている遺伝子群の活性化に寄与するのかを明らかにする。

Research Products

• [Journal Article] The Polycomb Potentiates Meis2 Activation in Midbrain by Mediating Interaction of the Promoter with a Tissue-Specific Enhancer. (2014)
  • Author(s): Kondo T., Isono K, Kondo K, Endo TA, Itohara S, Vidal M, and Koseki H.
  • Journal Title: Dev Cell. Volume: 28 Pages: 94-101
  • DOI: 10.1016/j.devcel.2013.11.021
  • Peer Reviewed
• [Journal Article] Is there a role for endogenous retroviruses to mediate long-term adaptive phenotypic response upon environmental inputs? (2013)
  • Author(s): Sharif J, Shinkai Y, Koseki H.
  • Journal Title: Philos Trans R Soc Lond B Biol Sci. Volume: 368 Pages: ―
  • DOI: 10.1098/rstb.2011.0340
  • Peer Reviewed
• [Journal Article] Role of SOX17 in hematopoietic development from human embryonic stem cells. (2013)
  • Author(s): Nakajima-Takagi Y, Osawa M, Oshima M, Takagi H, Miyagi S, Endoh M, Endo TA, Takayama N, Eto K, Toyoda T, Koseki H, Nakauchi H, Iwama A.
  • Journal Title: Blood. Volume: 121 Pages: 447-58
  • DOI: 10.1182/blood-2012-05-431403.
  • Peer Reviewed
• [Journal Article] KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands. (2013)
  • Author(s): Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose NR, Lee S, Sims D, Cerase A, Sheahan TW, Koseki H, Brockdorff N, Ponting CP, Kessler BM, Klose RJ.
  • Journal Title: elife. Volume: 1 Pages: ―
  • DOI: 10.7554/eLife.00205
  • Peer Reviewed
• [Journal Article] Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8(+) T Cells. (2013)
  • Author(s): Vizcardo R, Masuda K, Yamada D, Ikawa T, Shimizu K, Fujii S, Koseki H, Kawamoto H.
  • Journal Title: Cell Stem Cell. Volume: 12 Pages: 31-6
  • DOI: 10.1016/j.stem.2012.12.006
  • Peer Reviewed
• [Journal Article] Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. (2013)
  • Author(s): Nishimura T, Koseki H, Nakauchi H. 他
  • Journal Title: Cell Stem Cell. Volume: 12 Pages: 114-26
  • DOI: 10.1016/j.stem.2012.11.002
  • Peer Reviewed
• [Journal Article] UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9. (2013)
  • Author(s): Liu X, Gao Q, Li P, Zhao Q, Zhang J, Li J, Koseki H, Wong J.
  • Journal Title: Nat Commun. Volume: 4 Pages: 1563
  • DOI: 10.1038/ncomms2562
  • Peer Reviewed
• [Journal Article] Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression. (2013)
  • Author(s): Zhu Y, Li Y, Haraguchi S, Yu M, Ohira M, Ozaki T, Nakagawa A, Ushijima T, Isogai E, Koseki H, Nakamura Y, Kong C, Mehlen P, Arakawa H, Nakagawara A.
  • Journal Title: J Clin Invest. Volume: 123 Pages: 2935-47
  • DOI: 10.1172/JCI65988
  • Peer Reviewed
• [Journal Article] CCN3 protein participates in bone regeneration as an inhibitory factor. (2013)
  • Author(s): Matsushita Y, Sakamoto K, Tamamura Y, Shibata Y, Minamizato T, Kihara T, Ito M, Katsube K, Hiraoka S, Koseki H, Harada K, Yamaguchi A.
  • Journal Title: J Biol Chem. Volume: 288 Pages: 19973-85
  • DOI: 10.1074/jbc.M113.454652
  • Peer Reviewed
• [Journal Article] Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation. (2013)
  • Author(s): Kometani K, Nakagawa R, Shinnakasu R, Kaji T, Rybouchkin A, Moriyama S, Furukawa K, Koseki H, Takemori T, Kurosaki T.
  • Journal Title: Immunity. Volume: 39 Pages: 136-47
  • DOI: 10.1016/j.immuni.2013.06.011
  • Peer Reviewed
• [Journal Article] WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation. (2013)
  • Author(s): Choi DW, Na W, Kabir MH, Yi E, Kwon S, Yeom J, Ahn JW, Choi HH, Lee Y, Seo KW, Shin MK, Park SH, Yoo HY, Isono K, Koseki H, Kim ST, Lee C, Kwon YK, Choi CY.
  • Journal Title: Mol Cell. Volume: 51 Pages: 374-85
  • DOI: 10.1016/j.molcel.2013.06.010
  • Peer Reviewed
• [Journal Article] An epigenetic switch is crucial for spermatogonia to exit the undifferentiated state toward a Kit-positive identity. (2013)
  • Author(s): Shirakawa T, Yaman-Deveci R, Tomizawa S, Kamizato Y, Nakajima K, Sone H, Sato Y, Sharif J, Yamashita A, Takada-Horisawa Y, Yoshida S, Ura K, Muto M, Koseki H, Suda T, Ohbo K.
  • Journal Title: Development. Volume: 140 Pages: 3565-76
  • DOI: 10.1242/dev.094045
  • Peer Reviewed
• [Journal Article] SAM Domain Polymerization Links Subnuclear Clustering of PRC1 to Gene Silencing. (2013)
  • Author(s): Isono K, Endo TA, Ku M, Yamada D, Suzuki R, Sharif J, Ishikura T, Toyoda T, Bernstein BE, Koseki H.
  • Journal Title: Dev Cell. Volume: 26 Pages: 565-577
  • DOI: 10.1016/j.devcel.2013.08.016
  • Peer Reviewed
• [Journal Article] Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. (2013)
  • Author(s): Nishiyama A, Yamaguchi L, Sharif J, Johmura Y, Kawamura T, Nakanishi K, Shimamura S, Arita K, Kodama T, Ishikawa F, Koseki H, Nakanishi M.
  • Journal Title: Nature. Volume: 502 Pages: 249-253
  • DOI: 10.1038/nature12488
  • Peer Reviewed
• [Journal Article] A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient. (2013)
  • Author(s): Higashimoto K, Jozaki K, Kosho T, Matsubara K, Fuke T, Yamada D, Yatsuki H, Maeda T, Ohtsuka Y, Nishioka K, Joh K, Koseki H, Ogata T, Soejima H.
  • Journal Title: Clin Genet. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/cge.12318
  • Peer Reviewed
• [Presentation] Activation of polycomb-repressed genes (2014)
  • Author(s): Koseki H.
  • Organizer: Seminar at Ecole polytechnique federale de Lausanne
  • Place of Presentation: Lausanne, Switzerland
  • Year and Date: 20140127-20140127
  • Invited
• [Presentation] Activation of polycomb-repressed genes (2014)
  • Author(s): Koseki H.
  • Organizer: Trinity College Seminar Series
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 20140124-20140124
  • Invited
• [Presentation] Activation of polycomb-repressed genes (2013)
  • Author(s): Koseki H.
  • Organizer: 第42回日本免疫学会総会・学術集会
  • Place of Presentation: Chiba, Japan
  • Year and Date: 20131211-20131211
  • Invited
• [Presentation] Activation of polycomb-repressed genes (2013)
  • Author(s): Koseki H.
  • Organizer: Mouse Molecular Genetics Conference
  • Place of Presentation: Cambridge, UK
  • Year and Date: 20130920-20130920
  • Invited
• [Presentation] Epigetic regulation of spermiogenesis (2013)
  • Author(s): Koseki H.
  • Organizer: The 10th Annual Meeting of Asian Reproductive Biotechnology Society
  • Place of Presentation: Phan Thiet, Vietnam
  • Year and Date: 20130821-20130821
  • Invited
• [Presentation] DNA methylation in T cells and gut immune homeostasis (2013)
  • Author(s): Koseki H.
  • Organizer: 3rd McGill-RIKEN Workshop
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20130621-20130621
  • Invited