Construction of constitutive heterochromatin and facultative heterochromatin

• Project/Area Number: 16H04739
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Molecular biology
• Research Institution: Osaka University (2017-2018); Hokkaido University (2016)
• Principal Investigator: Chikashi OBUSE 大阪大学, 理学研究科, 教授 (00273855)
• Research Collaborator: NAGAO Koji ; Isobe Shin-Ya ; Sado Takashi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: ヘテロクロマチン / エピジェネティクス / ヒストン修飾 / クロマチン高次構造 / エピジェネティク / 転写

Outline of Final Research Achievements

Heterochromatin is defined into two categories; constitutive heterochromatin based on H3K9me3 which is responsible for the formation of stable heterochromatin, such as centromere and telomere, and facultative heterochromatin based on H3K27me3 which is responsible for developmentally formed heterochromatin, such as inactive X chromosome and Hox gene clusters. Aim of this study is to understand common and different points between two heterochromatins. Our results showed that H3K9me3 histone mark was on inactive X chromosome and formed domains as well as H3K27me3, and that the H3K9me3 domains were shrunk and replaced to H3K27me3 by knockdown/out of genes which are responsible for compaction of heterochromatin. These results suggest that there is no definition such as constitutive and facultative, rather H3K9me3 and H3K27me3 domains are constituents for the formation of functional heterochromatin to regulate gene expression properly.

Academic Significance and Societal Importance of the Research Achievements

これまで、セントロメアやテロメアなどの構成的なヘテロクロマチンと、発生・分化依存的な条件的ヘテロクロマチンは、同じ凝縮したクロマチン構造をとりながら、基盤となるヒストン修飾や構成する因子が異なると考えられてきた。本課題により、構成的なヘテロクロマチンの形成に必要と考えられているヒストン修飾や因子が、条件的ヘテロクロマチン形成の一要素であることが示唆された。これらの成果は、今後遺伝子発現制御の要であるヘテロクロマチンを理解する上で重要な仮説であると考えられる。

Research Products

• [Journal Article] Genome-wide stability of the DNA replication program in single mammalian cells. (2019)
  • Author(s): Saori Takahashi, Hisashi Miura, Takahiro Shibata, Koji Nagao, Katsuzumi Okumura, Masato Ogata, Chikashi Obuse, Shin-ichiro Takebayashi and Ichiro Hiratani
  • Journal Title: Nat Genet Volume: 51 Pages: 529-540
  • DOI: 10.1038/s41588-019-0347-5
  • Peer Reviewed / Open Access
• [Journal Article] Role of SmcHD1 in establishment of epigenetic states required for the maintenance of the X-inactivated state in mice. (2018)
  • Author(s): Sakakibara Yuki、Nagao Koji、Blewitt Marnie、Sasaki Hiroyuki、Obuse Chikashi、Sado Takashi
  • Journal Title: Development Volume: 145 Pages: 166462-166462
  • DOI: 10.1242/dev.166462
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nucleosomes around a mismatched base pair are excluded via an Msh2-dependent reaction with the aid of SNF2 family ATPase Smarcad1 (2018)
  • Author(s): Terui R, Nagao K, Kawasoe Y, Taki K, Higashi TL, Tanaka S, Nakagawa T, Obuse C, Masukata H, Takahashi TS
  • Journal Title: Genes & Development Volume: 32(11-12) Pages: 806-821
  • DOI: 10.1101/gad.310995.117
  • Peer Reviewed / Open Access
• [Journal Article] Lem2 is retained at the nuclear envelope through its interaction with Bqt4 in fission yeast (2018)
  • Author(s): Hirano Yasuhiro、Kinugasa Yasuha、Asakawa Haruhiko、Chikashige Yuji、Obuse Chikashi、Haraguchi Tokuko、Hiraoka Yasushi
  • Journal Title: Genes to Cells Volume: 23 Pages: 122-135
  • DOI: 10.1111/gtc.12557
  • Peer Reviewed / Open Access
• [Journal Article] Compositionally distinct nuclear pore complexes of functionally distinct dimorphic nuclei in the ciliate Tetrahymena (2017)
  • Author(s): Iwamoto M., Osakada H., Mori C., Fukuda Y., Nagao K., Obuse C., Hiraoka Y., and Haraguchi T.
  • Journal Title: Journal of cell science Volume: 印刷中 Pages: 1822-1834
  • DOI: 10.1242/jcs.199398
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. (2017)
  • Author(s): Takahashi, A., Okada, R., Nagao, K., Kawamata, Y., Hanyu, A., Yoshimoto, S., Takasugi, M., Watanabe, S., Kanemaki, M.T., Obuse, C. & Hara, E.
  • Journal Title: Nat Commun. Volume: - Pages: 15287-15287
  • DOI: 10.1038/ncomms15287
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of RIF1 by SCAI Allows BRCA1-Mediated Repair (2017)
  • Author(s): Isobe S.Y., Nagao K., Nozaki N., Kimura H., and Obuse C.
  • Journal Title: Cell Reports Volume: 2 Pages: 297-307
  • DOI: 10.1016/j.celrep.2017.06.056
  • Peer Reviewed / Open Access
• [Journal Article] Reconstitution of the oocyte nucleolus in mice through a single nucleolar protein, NPM2. (2017)
  • Author(s): Ogushi Sugako、Yamagata Kazuo、Obuse Chikashi、Furuta Keiko、Wakayama Teruhiko、Matzuk Martin M.、Saitou Mitinori
  • Journal Title: Journal of Cell Science Volume: 130 Pages: 2416-2429
  • DOI: 10.1242/jcs.195875
  • Peer Reviewed / Open Access
• [Journal Article] Defects in dosage compensation impact global gene regulation in the mouse trophoblast. (2017)
  • Author(s): Sakata Yuka、Nagao Koji、Hoki Yuko、Sasaki Hiroyuki、Obuse Chikashi、Sado Takashi
  • Journal Title: Development Volume: 144 Pages: 2784-2797
  • DOI: 10.1242/dev.149138
  • Peer Reviewed / Open Access
• [Journal Article] Ser7 of RNAPII-CTD facilitates heterochromatin formation by linking ncRNA to RNAi (2017)
  • Author(s): Kajitani Takuya、Kato Hiroaki、Chikashige Yuji、Tsutsumi Chihiro、Hiraoka Yasushi、Kimura Hiroshi、Ohkawa Yasuyuki、Obuse Chikashi、Hermand Damien、Murakami Yota
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114
  • DOI: 10.1073/pnas.1714579115
  • NAID: 120006539374
  • Peer Reviewed / Open Access
• [Journal Article] BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation (2017)
  • Author(s): Mayu Isono, Atsuko Niimi, Takahiro Oike, Yoshihiko Hagiwara, Hiro Sato, Ryota Sekine, Yukari Yoshida, Shin-Ya Isobe, Chikashi Obuse, Ryotaro Nishi, Elena Petricci, Shinichiro Nakada, Takashi Nakano, Atsushi Shibata
  • Journal Title: Cell Rep. Volume: 18 Pages: 520-532
  • DOI: 10.1016/j.celrep.2016.12.042
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Human RIF1 and protein phosphatase 1 stimulate DNA replication origin licensing but suppress origin activation (2017)
  • Author(s): Hiraga SI, Ly T, Garzon J, Horejsi Z, Ohkubo YN, Endo A, Obuse C, Boulton SJ, Lamond AI, Donaldson AD.
  • Journal Title: EMBO Rep. Volume: 18 Pages: 401-419
  • DOI: 10.15252/embr.201641983
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Usp7-dependent histone H3 deubiquitylation regulates maintenance of DNA methylation (2017)
  • Author(s): Yamaguchi L, Nishiyama A, Misaki T, Johmura Y, Ueda J, Arita K, Nagao K, Obuse C, Nakanishi M
  • Journal Title: SCIENTIFIC REPORTS Volume: 7 Pages: 1-12
  • DOI: 10.1038/s41598-017-00136-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Histone H3K36 trimethylation is essential for multiple silencing mechanisms in fission yeast (2016)
  • Author(s): Shota Suzuki, Hiroaki Kato, Yutaka Suzuki, Yuji Chikashige, Yasushi Hiraoka, Hiroshi Kimura, Koji Nagao, Chikashi Obuse, Shinya Takahata and Yota Murakami
  • Journal Title: Nucleic Acids Res. Volume: 44 (9) Pages: 4147-4162
  • DOI: 10.1093/nar/gkw008
  • NAID: 120005819302
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 14-3-3-zeta participates in TLR3-mediated TICAM-1 signal-platform formation. (2016)
  • Author(s): Kenji Funami, Misako Matsumoto, Chikashi Obuse, Tsukasa Seya
  • Journal Title: Mol Immunol. Volume: 73 Pages: 60-68
  • DOI: 10.1016/j.molimm.2016.03.010
  • Peer Reviewed
• [Journal Article] Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations. (2016)
  • Author(s): Hamanaka, K., Goto, K., Arai, M., Nagao, K., Obuse, C., Noguchi, S., Hayashi, Y. K., Mitsuhashi, S., and Nishino, I.
  • Journal Title: Neuromuscular Disorders Volume: 26 Pages: 300-308
  • DOI: 10.1016/j.nmd.2016.03.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Histone H4 lysine 20 acetylation is associated with gene repression in human cells (2016)
  • Author(s): Kaimori, J. Y., Maehara, K., Hayashi-Takanaka, Y., Harada, A., Fukuda, M., Yamamoto, S., Ichimaru, N., Umehara, T., Yokoyama, S., Matsuda, R., Ikura, T., Nagao, K., Obuse, C., Nozaki, N., Takahara, S., Takao, T., Ohkawa, Y., Kimura, H., and Isaka, Y.
  • Journal Title: Scientific Reports Volume: 6 Pages: 24318-24318
  • DOI: 10.1038/srep24318
  • NAID: 120005770760
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] X染色体不活性化過程におけるSmchd1-Hbix1の役割 (2018)
  • Author(s): 長尾恒治、榊原祐樹、元田裕佳里、坂口武久、木村宏、佐渡敬、小布施力史
  • Organizer: 第91回日本生化学会大会
  • Invited
• [Presentation] RIF1-PP1複合体のDNA損傷における機能解析 (2018)
  • Author(s): 磯部 真也、長尾 恒治、野崎 直仁、木村 宏、小布施 力史
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 染色体不活性化における非コードXIST RNAとSmchd1-Hbix1Xの役割 (2018)
  • Author(s): 長尾 恒治、榊原 祐樹、坂口 武久、木村 宏、佐渡 敬、小布施 力史
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] Smchd1-Hbix1依存的な不活性化X染色体の区画化 (2018)
  • Author(s): 長尾 恒治、榊原 祐樹、柴田 幸子、野澤 竜介、坂口 武久、木村 宏、佐渡 敬、小布施 力史
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 分裂酵母に特異的な核膜孔複合体の構造と機能 (2018)
  • Author(s): 淺川 東彦、糀谷 知子、楊 恵如、大槻 千鶴、小坂田 裕子、松田 厚志、岩本 政明、近重 裕次、高木 尚充、長尾 恒治、小布施 力史、 平岡 泰、原口 徳子
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Single-cell DNA replication timing profiling and 3D genome organization dynamics during development (2018)
  • Author(s): Hisashi Miura, Saori Takahashi, Takahiro Shibata, Koji Nagao, Chikashi Obuse, Shin-ichiro Takebayashi, Ichiro Hiratani
  • Organizer: Nuclear Organization & Function on Cold Spring Harbor Meeting
• [Presentation] 分化前後のES細胞における複製ドメインは細胞間で極めて均一なプロファイルを示す (2018)
  • Author(s): 高橋沙央里、三浦尚、柴田隆豊、長尾恒治、小布施力史、竹林慎一郎、平谷伊智朗
  • Organizer: 第12回日本エピジェネティクス研究会年会
• [Presentation] 遺伝子の傷をどうやって直すか (2018)
  • Author(s): 小布施 力史
  • Organizer: 遺伝子研究の最前線 一般公開シンポジウム
  • Invited
• [Presentation] HP1 結合因子とクロマチン機能 (2018)
  • Author(s): 小布施 力史
  • Organizer: 染色体研究の最前線2018
  • Invited
• [Presentation] HP1結合因子によるクロマチン制御 (2017)
  • Author(s): 小布施力史
  • Organizer: ワークショップ「染色体研究の最前線」
  • Place of Presentation: 大阪大学生命機能研究科（大阪府吹田市）
  • Year and Date: 2017-01-16
  • Int'l Joint Research
• [Presentation] Conserved repressive chromatin properties on inactive X chromosome in human and mouse (2017)
  • Author(s): 小布施 力史
  • Organizer: SMC proteins; Chromosomal organizers from bacteria to human
  • Int'l Joint Research
• [Presentation] Elucidation of structure and function of heterochromatin through human HP1 binding proteins (2017)
  • Author(s): 小布施 力史
  • Organizer: HMGU-Japan meeting
  • Int'l Joint Research / Invited
• [Presentation] ヒストンメチル化酵素G9aと複製開始複合体ORCとの相互作用とその意義 (2017)
  • Author(s): 小布施 力史
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Invited
• [Presentation] ヘテロクロマチンの機能構造と疾患との関わり (2016)
  • Author(s): 長尾恒治、柴田幸子、野澤竜介、磯部真也、元田裕佳里、三橋里美、濱中耕平、西野一三、木村宏、佐渡敬、小布施力史
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-29
  • Invited
• [Presentation] 新規53BP1結合タンパク質SCAIは、Rif1に阻害的に働くことで相同組換え修復を促進する (2016)
  • Author(s): 磯部真也、大久保義真、長尾恒治、野崎直仁、木村宏、小布施力史
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-29
• [Presentation] アリル特異的ChIP/RNA-seq法によるマウス不活性化X染色体のクロマチン動態の解析 (2016)
  • Author(s): 長尾恒治、榊原祐樹、柴田幸子、野澤竜介、坂口武久、木村宏、佐渡敬、小布施力史
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-29
• [Presentation] DSB repair pathway is controlled by differential phosphorylation of 53BP1 (2016)
  • Author(s): Shinya Isobe, Koji Nagao, Naohito Nozaki, Hiroshi Kimura, Chikashi Obuse
  • Organizer: The 10th International 3R Symposium
  • Place of Presentation: ホテル一畑（島根県松江市）
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Conserved repressive chromatin properties on inactive X chromosome between human and mouse (2016)
  • Author(s): Koji Nagao, Sachiko Shibata, Y Sakakibara, Takehisa Sakaguchi, Ryu-suke Nozawa, Hiroshi Kimura, Takashi Sado, Chikashi Obuse
  • Organizer: Royal Society Meeting; X-chromosome inactivation: a tribute to Mary Lyon
  • Place of Presentation: THE ROYAL SOCIETY in London、MRC in Harwell（イギリス）
  • Year and Date: 2016-10-02
  • Int'l Joint Research
• [Presentation] エピジェネティックコードを基盤としたヘテロクロマチンの形成機構 (2016)
  • Author(s): 小布施 力史
  • Organizer: 日本遺伝学会 第88回大会
  • Place of Presentation: 日本大学（静岡県三島市）
  • Year and Date: 2016-09-07
  • Invited
• [Presentation] HP1結合タンパク質を通したクロマチン機能の解明 (2016)
  • Author(s): 小布施 力史
  • Organizer: RNAフロンティアミーティング
  • Place of Presentation: いこいの湯宿 いろは （北海道虻田郡ニセコ町）
  • Year and Date: 2016-08-31
  • Invited
• [Presentation] DNA Double Strand Breaks Repair Pathway is Controlled by Differential Phosphorylation of 53BP1 (2016)
  • Author(s): Isobe S, Ohkubo Y, Nagao K, Nozaki N, Kimura H, Obuse C.
  • Organizer: 12th International Congress of Cell Biology（ICCB)
  • Place of Presentation: プラハ国際会議センター（チェコ プラハ）
  • Year and Date: 2016-07-21
  • Int'l Joint Research
• [Presentation] HPIの解析から見えてきたヘテロクロマチンの構造と機能 (2016)
  • Author(s): 小布施力史
  • Organizer: 第1回ATR-X症候群シンポジウム
  • Place of Presentation: 国立京都国際会館 （京都府京都市）
  • Year and Date: 2016-04-02
  • Invited
• [Remarks] 染色体構造機能学研究室
  • URL: http://www.bio.sci.osaka-u.ac.jp/bio_web/lab_page/obuse/
• [Remarks] 染色体構造機能学研究室
  • URL: https://www.bio.sci.osaka-u.ac.jp/dbs01/re-paper-temp.php?id=98
• [Remarks] 乳がん、卵巣がんの抑制遺伝子の働きを助けるタンパク質SCAIを新発見
  • URL: https://resou.osaka-u.ac.jp/ja/research/2017/20170712_1
• [Remarks] 女性の"働かない"X染色体の仕組みを解明
  • URL: http://www.bio.sci.osaka-u.ac.jp/bio_web/lab_page/obuse/nsmb2013/