ポリコム群による抑制ドメインの複製機構の解明

• Project Area: Mechanisms underlying replication of non-genomic codes that mediate plasticity and robustness for cellular inheritance
• Project/Area Number: 19H05745
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 古関 明彦 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (40225446)
• Co-Investigator(Kenkyū-buntansha): 遠藤 高帆 国立研究開発法人理化学研究所, 生命医科学研究センター, 技師 (40384862)
• Project Period (FY): 2019-06-28 – 2024-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥137,280,000 (Direct Cost: ¥105,600,000、Indirect Cost: ¥31,680,000); Fiscal Year 2023: ¥23,400,000 (Direct Cost: ¥18,000,000、Indirect Cost: ¥5,400,000); Fiscal Year 2022: ¥25,220,000 (Direct Cost: ¥19,400,000、Indirect Cost: ¥5,820,000); Fiscal Year 2021: ¥27,170,000 (Direct Cost: ¥20,900,000、Indirect Cost: ¥6,270,000); Fiscal Year 2020: ¥23,400,000 (Direct Cost: ¥18,000,000、Indirect Cost: ¥5,400,000); Fiscal Year 2019: ¥38,090,000 (Direct Cost: ¥29,300,000、Indirect Cost: ¥8,790,000)
• Keywords: ポリコム群 / クロマチン複製 / DNA複製 / DNAメチル化

Outline of Research at the Start

ポリコム群による抑制が、分裂後の細胞へ伝達されるメカニズムは今も未知である。ポリコム群のひとつEPCが、DNA複製メカニズムとカップルし、DNA メチル化維持、複製後ヌクレオソーム再構築メカニズムとリンクすることを見出し、この問題解決へのひとつの入り口を与えた。一方、DNA複製とカップルするDNAメチル化維持メカニズムとポリコム群による抑制がリンクすることも明らかにしてきた。本研究では、DNA メチル化維持メカニズムとポリコム群の再構築過程はどのように機能的にリンクするのか？、及び、ヌクレオソーム再構築メカニズムとポリコム群再構築過程の間の機能的にリンクするのか？という問いに挑戦する。

Outline of Annual Research Achievements

ヌクレオソーム再構築メカニズム、ヴァリアントヒストン、及び、ポリコム群再構築過程の間の機能的にリンクするのかという点について、Enhancer of Polycomb複合体とPCGF1-PRC1複合体に焦点を絞った研究を行った。Enhancer of Polycomb複合体は、複製フォークにPCNAと結合しながらそんざいし、複製にカップルして起こる親染色体からのヒストンのリサイクルと、新規合成されたヒストンの取り込みの２つの経路を介して、複製に伴うヌクレオソーム再構築に寄与すると結論付けられた。Enhancer of Polycomb複合体は、バリアントヒストンH2A.ZとそのトンシャペロンであるANP32E、娘DNA鎖のメチル化に関わるDNMT1とNP95(UHRF1)、ヒストンメチル化の関連因子であるポリコム群タンパク質（SUZ12, EZH2など）などを新生ヌクレオソームにロードし、複製後の非ゲノム情報の維持に寄与することを示した。また、PCGF1-PRC1についても、複製フォーク近傍に局在して作用していることを見出した。特に血球系前駆細胞において、PCGF1-PRC1はDNA複製期に、複製フォーク近傍へのクロマチンリモデリング因子SWI/SNF複合体の接近を阻害することで、複製フォーク通過直後のクロマチン複製を最適化し、ミエロイド分化の亢進を制御することを示した。

Current Status of Research Progress

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

Reason

論文受理にまで至らなかった。

Strategy for Future Research Activity

Enhancer of Polycomb複合体が、クロマチン複製に必須の因子であることは明らかになったが、これらがどのようにポリコム群機能の制御に寄与するのかは未知である。この埋められていないギャップに当てはまる候補として、DNMT1/NP95 (UHRF1)を見出してきた。これらは、複製フォークに結合し、DNAメチル化の維持に寄与するタンパク複合体として同定してきたものだが、同時にヒストンにリンクする様々なクロマチン制御に寄与することも見出してきた。実際、Enhancer of Polycomb複合体の欠損により、DNMT1/UHRF1の複製フォークへのリクルートメントは大きく損なわれる。また、DNMT1の欠損により、ポリコム群の標的遺伝子群への結合も大きく損なわれることを見出してきた。今後、DNMT1/UHRF1の複製フォークが、ポリコム群に作用するメカニズムを中心に解析を進めていく。また、PCGF1-PRC1複合体については、造血前駆細胞におけるSWI/SNF複合体と複製フォーク近傍での競合作用を介したクロマチン複製の制御機構を見出した。SWI/SNF複合体も複製フォーク近傍に局在し、ゲノム不安定化を防ぐことで、複製の進行を担保することが知られている。また、SWI/SNF複合体とポリコム群は文脈に応じて、競合あるいは協調することが知られている。今後、複製フォークの適切な機能維持のためにポリコム群とSWI/SNF複合体がどのように相互作用するか、造血系のみならず複数の細胞種で解析を進めて行く。

Research Products

• [Journal Article] Establishment of mouse stem cells that can recapitulate the developmental potential of primitive endoderm (2022)
  • Author(s): Ohinata Yasuhide、Endo Takaho A.、Sugishita Hiroki、Watanabe Takashi、Iizuka Yusuke、Kawamoto Yurie、Saraya Atsunori、Kumon Mami、Koseki Yoko、Kondo Takashi、Ohara Osamu、Koseki Haruhiko
  • Journal Title: Science Volume: 375 Issue: 6580 Pages: 574-578
  • DOI: 10.1126/science.aay3325
  • Peer Reviewed
• [Journal Article] Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis (2022)
  • Author(s): Kanki Yasuharu、Muramatsu Masashi、Miyamura Yuri、Kikuchi Kenta、Higashijima Yoshiki、Nakaki Ryo、Suehiro Jun-ichi、Sasaki Yuji、Kubota Yoshiaki、Koseki Haruhiko、Morioka Hiroshi、Kodama Tatsuhiko、Nakao Mitsuyoshi、Kurotaki Daisuke、Aburatani Hiroyuki、Minami Takashi
  • Journal Title: Cell Reports Volume: 38 Issue: 6 Pages: 110332-110332
  • DOI: 10.1016/j.celrep.2022.110332
  • Peer Reviewed / Open Access
• [Journal Article] The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation (2021)
  • Author(s): Kiuchi Masahiro、Onodera Atsushi、Kokubo Kota、Ichikawa Tomomi、Morimoto Yuki、Kawakami Eiryo、Takayama Naoya、Eto Koji、Koseki Haruhiko、Hirahara Kiyoshi、Nakayama Toshinori
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 4 Pages: 3-8
  • DOI: 10.1084/jem.20201690
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] H2AK119ub1 guides maternal inheritance and zygotic deposition of H3K27me3 in mouse embryos (2021)
  • Author(s): Mei Hailiang、Kozuka Chisayo、Hayashi Ryoya、Kumon Mami、Koseki Haruhiko、Inoue Azusa
  • Journal Title: Nature Genetics Volume: 53 Issue: 4 Pages: 539-550
  • DOI: 10.1038/s41588-021-00820-3
  • Peer Reviewed / Open Access
• [Journal Article] Staphylococcus cohnii is a potentially biotherapeutic skin commensal alleviating skin inflammation (2021)
  • Author(s): Ito Y, Sasaki T, Li Y, et al
  • Journal Title: Cell Reports Volume: 35 Issue: 4 Pages: 109052-109052
  • DOI: 10.1016/j.celrep.2021.109052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maintenance DNA methylation in pre-meiotic germ cells regulates meiotic prophase by facilitating homologous chromosome pairing (2021)
  • Author(s): Takada Yuki、Yaman-Deveci Ruken、Shirakawa Takayuki、Sharif Jafar、Tomizawa Shin-ichi、Miura Fumihito、Ito Takashi、Ono Michio、Nakajima Kuniko、Koseki Yoko、Shiotani Fuyuko、Ishiguro Kei-ichiro、Ohbo Kazuyuki、Koseki Haruhiko
  • Journal Title: Development Volume: 148 Issue: 10
  • DOI: 10.1242/dev.194605
  • Peer Reviewed
• [Journal Article] UV-induced reduction in Polycomb repression promotes epidermal pigmentation (2021)
  • Author(s): Li Meng-Yen、Flora Pooja、Pu Hong、Bar Carmit、Silva Jose、Cohen Idan、Galbo Phillip M.、Liu Hequn、Yu Xufen、Jin Jian、Koseki Haruhiko、D’Orazio John A.、Zheng Deyou、Ezhkova Elena
  • Journal Title: Developmental Cell Volume: 56 Issue: 18 Pages: 2547-2561.e8
  • DOI: 10.1016/j.devcel.2021.08.006
• [Journal Article] Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis (2021)
  • Author(s): Shinoda Daisuke、Nakajima-Takagi Yaeko、Oshima Motohiko、Koide Shuhei、Aoyama Kazumasa、Saraya Atsunori、Harada Hironori、Rahmutulla Bahityar、Kaneda Atsushi、Yamaguchi Kiyoshi、Furukawa Yoichi、Koseki Haruhiko、Shimoda Kazuya、Tanaka Tomoaki、Sashida Goro、Iwama Atsushi
  • Journal Title: Leukemia Volume: 36 Issue: 2 Pages: 452-463
  • DOI: 10.1038/s41375-021-01402-2
  • Peer Reviewed / Open Access
• [Journal Article] Variant PCGF1-PRC1 links PRC2 recruitment with differentiation-associated transcriptional inactivation at target genes (2021)
  • Author(s): Sugishita Hiroki、Kondo Takashi、Ito Shinsuke、Nakayama Manabu、Yakushiji-Kaminatsui Nayuta、Kawakami Eiryo、Koseki Yoko、Ohinata Yasuhide、Sharif Jafar、Harachi Mio、Blackledge Neil P.、Klose Robert J.、Koseki Haruhiko
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 5341-5341
  • DOI: 10.1038/s41467-021-24894-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MORC3, a novel MIWI2 association partner, as an epigenetic regulator of piRNA dependent transposon silencing in male germ cells (2021)
  • Author(s): Kojima-Kita Kanako、Kuramochi-Miyagawa Satomi、Nakayama Manabu、Miyata Haruhiko、Jacobsen Steven E.、Ikawa Masahito、Koseki Haruhiko、Nakano Toru
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 20472-20490
  • DOI: 10.1038/s41598-021-98940-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing (2021)
  • Author(s): Mochizuki K, Sharif J, Shirane K, Uranishi K, Bogutz AB, Janssen SM, Suzuki A, Okuda A, Koseki H, Lorincz MC.
  • Journal Title: Nature Communications Volume: 12(1) Issue: 1 Pages: 7020-7020
  • DOI: 10.1038/s41467-021-27345-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional annotation of human long noncoding RNAs via molecular phenotyping (2020)
  • Author(s): Ramilowski Jordan A.、Yip Chi Wai、Agrawal Saumya、Chang Jen-Chien、Ciani Yari、Kulakovskiy Ivan V.、...、Carninci Piero
  • Journal Title: Genome Research Volume: 30 Issue: 7 Pages: 1060-1072
  • DOI: 10.1101/gr.254219.119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes (2020)
  • Author(s): Ochi Y, Ogawa Seishi., et al.
  • Journal Title: Cancer Discov Volume: - Issue: 6 Pages: 836-853
  • DOI: 10.1158/2159-8290.cd-19-0982
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity (2020)
  • Author(s): Tanaka, S. Ise, W. Inoue, T. Ito, A. Ono, C. Shima, Y. Sakakibara, S. Nakayama, M. Fujii, K. Miura, I. Sharif, J. Koseki, H. Koni, P. A. Raman, I. Li, Q. Z. Kubo, M. Fujiki, K. Nakato, R. Shirahige, K. Araki, H. Miura, F. Ito, T. Kawakami, E. Baba, Y. Kurosaki, T.
  • Journal Title: Nature Immunology Volume: 21 Issue: 8 Pages: 950-961
  • DOI: 10.1038/s41590-020-0700-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status. (2020)
  • Author(s): Shrestha R, Sakata-Yanagimoto M, Maie K, Oshima M, Ishihara M, Suehara Y, Fukumoto K,1 Nakajima-Takagi Y, Matsui H, Kato T, Muto H, Sakamoto T, Kusakabe M, Nannya Y, Makishima H, Ueno H, Saiki R, Ogawa S, Chiba K, Shiraishi Y, Miyano S, Mouly E, Bernard OA, Inaba T, Koseki H, Iwama A, Chiba S
  • Journal Title: Blood Adv. Volume: 4(5) Issue: 5 Pages: 845-854
  • DOI: 10.1182/bloodadvances.2019001324
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis (2020)
  • Author(s): Miyajima Yurina、Ealey Kafi N、Motomura Yasutaka、Mochizuki Miho、Takeno Natsuki、Yanagita Motoko、Economides Aris N、Nakayama Manabu、Koseki Haruhiko、Moro Kazuyo
  • Journal Title: International Immunology Volume: 32 Issue: 6 Pages: 407-419
  • DOI: 10.1093/intimm/dxaa013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon. (2020)
  • Author(s): Hikaru Eto#, Yusuke Kishi#*, Nayuta Yakushiji-Kaminatsu, Hiroki Sugishita, Shun Utsunomiya, Haruhiko Koseki, and Yukiko Gotoh* (#Equal contribution, *Correspondence)
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 5709-5709
  • DOI: 10.1038/s41467-020-19556-5
  • Peer Reviewed / Open Access
• [Journal Article] CDCA7 and HELLS suppress DNA:RNA hybrid-associated DNA damage at pericentromeric repeats (2020)
  • Author(s): Unoki Motoko、Sharif Jafar、Saito Yuichiro、Velasco Guillaume、Francastel Claire、Koseki Haruhiko、Sasaki Hiroyuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 17865-17865
  • DOI: 10.1038/s41598-020-74636-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tet DNA demethylase is required for plasma cell differentiation by controlling expression levels of IRF4 (2020)
  • Author(s): Fujii, K. Tanaka, S. Hasegawa, T. Narazaki, M. Kumanogoh, A. Koseki, H. Kurosaki, T. Ise, W.
  • Journal Title: International Immunology Volume: 32 Issue: 10 Pages: 683-690
  • DOI: 10.1093/intimm/dxaa042
  • Peer Reviewed / Open Access
• [Journal Article] Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice (2019)
  • Author(s): Tamaura Moe、Satoh-Takayama Naoko、Tsumura Miyuki、Sasaki Takaharu、Goda Satoshi、Kageyama Tomoko、Hayakawa Seiichi、Kimura Shunsuke、Asano Takaki、Nakayama Manabu、Koseki Haruhiko、Ohara Osamu、Okada Satoshi、Ohno Hiroshi、Kobayashi Masao
  • Journal Title: International Immunology Volume: － Issue: 4 Pages: 259-272
  • DOI: 10.1093/intimm/dxz079
  • Peer Reviewed / Open Access
• [Journal Article] Synergy between Variant PRC1 Complexes Defines Polycomb-Mediated Gene Repression (2019)
  • Author(s): Fursova NA, Blackledge NP, Nakayama M, Ito S, Koseki Y, Farcas AM, King HW, Koseki H, Klose RJ.
  • Journal Title: Molecular Cell Volume: 印刷中 Issue: 5 Pages: 1020-1036
  • DOI: 10.1016/j.molcel.2019.03.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polycomb Repressive Complex 1 Controls Maintenance of Fungiform Papillae by Repressing Sonic Hedgehog Expression (2019)
  • Author(s): Bar Carmit、Cohen Idan、Zhao Dejian、Pothula Venu、Litskevitch Anna、Koseki Haruhiko、Zheng Deyou、Ezhkova Elena
  • Journal Title: Cell Reports Volume: 28 Issue: 1 Pages: 257-266.e5
  • DOI: 10.1016/j.celrep.2019.06.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity (2019)
  • Author(s): Turberfield Anne H、Kondo Takashi、Nakayama Manabu、Koseki Yoko、King Hamish W、Koseki Haruhiko、Klose Robert J
  • Journal Title: Nucleic Acids Research Volume: 47 Issue: 17 Pages: 9005-9023
  • DOI: 10.1093/nar/gkz607
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phc2 controls hematopoietic stem and progenitor cell mobilization from bone marrow by repressing Vcam1 expression (2019)
  • Author(s): Bae Joonbeom、Choi Sang-Pil、Isono Kyoichi、Lee Ji Yoon、Park Si-Won、Choi Chang-Yong、Han Jihye、Kim Sang-Hoon、Lee Han-Hyoung、Park Kyungmin、Jin Hyun Yong、Lee Suk Jun、Park Chung-Gyu、Koseki Haruhiko、Lee Young Sik、Chun Taehoon
  • Journal Title: Nature Communications Volume: 10 Issue: 1
  • DOI: 10.1038/s41467-019-11386-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis. (2019)
  • Author(s): Isshiki Y, Nakajima-Takagi Y, Oshima M, Aoyama K, Rizk M, Kurosawa S, Saraya A, Kondo T, Sakaida E, Nakaseko C, Yokote K, Koseki H, Iwama A.
  • Journal Title: Blood Adv Volume: 3 Issue: 17 Pages: 2537-2549
  • DOI: 10.1182/bloodadvances.2018028522
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PRC2.1 and PRC2.2 Synergize to Coordinate H3K27 Trimethylation (2019)
  • Author(s): Healy Evan、Mucha Marlena、Glancy Eleanor、Fitzpatrick Darren J.、Conway Eric、Neikes Hannah K.、Monger Craig、Van Mierlo Guido、Baltissen Marijke P.、Koseki Yoko、Vermeulen Michiel、Koseki Haruhiko、Bracken Adrian P.
  • Journal Title: Molecular Cell Volume: 76 Issue: 3 Pages: 437-452.e6
  • DOI: 10.1016/j.molcel.2019.08.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chromatin and epigenetics in development: a Special Issue (2019)
  • Author(s): Bruneau Benoit G.、Koseki Haruhiko、Strome Susan、Torres-Padilla Maria-Elena
  • Journal Title: Development Volume: 146 Issue: 19 Pages: 185025-185025
  • DOI: 10.1242/dev.185025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ポリコム群による抑制ドメインの複製機構の解明 (2020)
  • Author(s): 古関 明彦
  • Organizer: 第１回新学術領域「非ゲノム情報複製」領域会議
• [Presentation] Polycomb in haematipoietic differentiation (2020)
  • Author(s): 古関 明彦
  • Organizer: The Chromatin and Epigenetics biweekly virtual seminar series, Tsinghua University
  • Int'l Joint Research / Invited
• [Presentation] Proteasomal regulation of variant PCGF1-PRC1 contributes to activation of Polycomb target genes via self-ubiquitination (2020)
  • Author(s): Haruhiko Koseki
  • Organizer: U Tokyo's LSBM Symposium 2020 in Hakone
• [Presentation] The role for enhancer of polycomb in chromatin replication and epigenetic inheritance (2019)
  • Author(s): Haruhiko Koseki
  • Organizer: 3rd RIKEN IMS-Stanford ISCBRM Joint Symposium
  • Invited
• [Presentation] Variant PRC1 in cellular differentiation (2019)
  • Author(s): Haruhiko Koseki
  • Organizer: Friedrich Miescher Institute for Biomedical Research
  • Int'l Joint Research / Invited
• [Presentation] Variant PRC1 in cellular differentiation (2019)
  • Author(s): Haruhiko Koseki
  • Organizer: Keble College
  • Int'l Joint Research / Invited
• [Presentation] Variant PCGF1-PRC1 is linked to proteasomal pathway to activate Polycomb target genes during development (2019)
  • Author(s): Haruhiko Koseki
  • Organizer: Gordon Research Conference
  • Int'l Joint Research
• [Presentation] 哺乳類ポリコム群による発生過程の制御 Variant PRC1 in cellular differentiation (2019)
  • Author(s): Haruhiko Koseki
  • Organizer: 日本遺伝学会第91回大会
• [Presentation] ポリコム、分化、複製 (2019)
  • Author(s): Haruhiko Koseki
  • Organizer: 新学術領域「多様かつ堅牢な細胞形質をさせる非ゲノム情報複製機構」第1回領域会議
• [Presentation] 疾患生物学：マウスからヒトへどう読み替えるか？ (2019)
  • Author(s): Haruhiko Koseki
  • Organizer: 千葉大学消化器内科セミナー
  • Invited