Characterization of chromatin replication associated with stem cell fate decision

• Project Area: Mechanisms underlying replication of non-genomic codes that mediate plasticity and robustness for cellular inheritance
• Project/Area Number: 19H05746
• 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: The University of Tokyo
• Principal Investigator: Iwama Atsushi 東京大学, 医科学研究所, 教授 (70244126)
• Co-Investigator(Kenkyū-buntansha): 北村 俊雄 東京大学, 大学院薬学系研究科(薬学部), 名誉教授 (20282527)
• Project Period (FY): 2019-06-28 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥168,220,000 (Direct Cost: ¥129,400,000、Indirect Cost: ¥38,820,000); Fiscal Year 2023: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000); Fiscal Year 2022: ¥31,850,000 (Direct Cost: ¥24,500,000、Indirect Cost: ¥7,350,000); Fiscal Year 2021: ¥30,030,000 (Direct Cost: ¥23,100,000、Indirect Cost: ¥6,930,000); Fiscal Year 2020: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000); Fiscal Year 2019: ¥39,000,000 (Direct Cost: ¥30,000,000、Indirect Cost: ¥9,000,000)
• Keywords: 造血幹細胞 / 運命制御 / 自己複製 / エピジェネティクス / クロマチン複製 / 幹細胞 / 運命決定 / クロマチン高次構造 / 非ゲノム情報

Outline of Research at the Start

造血幹細胞とその分裂によって生じる2 つの娘細胞のシングルセル解析を行い、それらのクロマチン複製様式を明らかにする。シングルセルATAC-Seq によるオープンクロマチン領域解析、シングルセルHi-C 解析によるトポロジカル関連ドメイン解析、ならびにシングルセルRNA-seq を行い、造血幹細胞の分裂様式をクロマチン複製と遺伝子発現の観点から理解し、娘細胞のシングルセル骨髄移植によって規定される造血幹細胞の生物学的な自己複製・分化との対応を明らかにする。さらに、本領域研究において同定されるクロマチン複製制御因子群の生物学的意義を、造血幹細胞の自己複製における機能の検証を通して理解する。

Outline of Final Research Achievements

We succeeded to perform Hi-C and RNA-seq analysis using the same single cells. We applied this method to two daughter cells from hematopoietic cells. The obtained data suggested the combination of transcriptome and higher order chromatin structure data is powerful to define symmetric versus asymmetric stem cell division. Further analysis would clarify the epigenetic mechanism that determines the fate decision of hematopoietic stem cells: self-renewal versus differentiation.

Academic Significance and Societal Importance of the Research Achievements

造血幹細胞の分裂により生じる2つの娘細胞の解析において、Hi-CとRNA-seqデータを同一１細胞から同時取得が可能となった。RNA-seqと高次クロマチン構造データの統合を進めることにより、造血幹細胞のクロマチン複製様式とその自己複製・分化の運命制御機構が明らかになるものと期待される。また、骨髄系血液腫瘍において頻用されるDNAメチル化阻害剤の耐性に関わる分子として、ユビキチンE3リガーゼTOPORSを同定した。DNAメチル化阻害剤とTOPORSの機能抑制の併用が有望な新規治療戦略となりうることが示され、新規創薬につながることが期待される。

Research Products

• [Int'l Joint Research] オックスフォード大学/ロンドンがん研究所(英国)
• [Int'l Joint Research] マルセイユがんセンター(フランス)
• [Int'l Joint Research] コロンビア大学(米国)
• [Int'l Joint Research] McGill University(カナダ)
• [Int'l Joint Research] Marseille University(フランス)
• [Int'l Joint Research] Oxford University(英国)
• [Int'l Joint Research] マルセイユがんセンター(フランス)
• [Int'l Joint Research] PTC Therapeutics/Memorial Sloan-Kettering Cancer Center(米国)
• [Int'l Joint Research] マルセイユがんセンタ-/Cleveland Clinic(フランス)
• [Int'l Joint Research] ルンド大学(スウェーデン)
• [Journal Article] Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis (2023)
  • Author(s): Nakajima-Takagi Yaeko、Oshima Motohiko、Takano Junichiro、Koide Shuhei、Itokawa Naoki、Uemura Shun、Yamashita Masayuki、Andoh Shohei、Aoyama Kazumasa、Isshiki Yusuke、Shinoda Daisuke、Saraya Atsunori、Arai Fumio、Yamaguchi Kiyoshi、Furukawa Yoichi、Koseki Haruhiko、Ikawa Tomokatsu、Iwama Atsushi
  • Journal Title: eLife Volume: 12
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• [Journal Article] UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease (2023)
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  • Journal Title: Leukemia Volume: 37 Issue: 9 Pages: 1895-1907
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• [Journal Article] Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs (2023)
  • Author(s): Yokomizo-Nakano T, Hamashima A, Kubota S, Bai J, Sorin S, Sun Y, Kikuchi K, Iimori M, Morii M, Kanai A, Iwama A, Huang G, Kurotaki D, Takizawa H, Matsui H, Sashida G.
  • Journal Title: Journal of Experimental Medicine (JEM) Volume: 220 (7) Issue: 7 Pages: 9999-9999
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• [Journal Article] Mesenchymal loss of p53 alters stem cell capacity and models human soft tissue sarcoma traits. (2023)
  • Author(s): Sorimachi Y, Kobayashi H, Shiozawa Y, Koide S, Nakato R, Shimizu Y, Okamura T, Shirahige K, Iwama A, Goda N, Takubo K, Takubo K.
  • Journal Title: Stem Cell Reports Volume: S2213-6711(23) Issue: 5 Pages: 00097-8
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• [Journal Article] The pathogenetic significance of exhausted T cells in a mouse model of mature B cell neoplasms (2023)
  • Author(s): 1.Shibamiya A, Miyamoto-Nagai Y, Koide S, Oshima M, Rizq O, Aoyama K, Nakajima-Takagi Y, Kato R, Kayamori K, Isshiki Y, Oshima-Hasegawa N, Muto T, Tsukamoto S, Takeda Y, Koyama-Nasu R, Chiba T, Honda H, Yokote K, Iwama A, Sakaida E, Mimura N.
  • Journal Title: Cancer Immunol Immunother Volume: － Issue: 8 Pages: 2635-2648
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• [Journal Article] Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells (2022)
  • Author(s): Itokawa Naoki、Oshima Motohiko、Koide Shuhei、Takayama Naoya、Kuribayashi Wakako、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Yamazaki Satoshi、Yamaguchi Kiyoshi、Furukawa Yoichi、Eto Koji、Iwama Atsushi
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 2691-2691
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• [Journal Article] YAP1/TAZ activity maintains vascular integrity and organismal survival (2022)
  • Author(s): Uemura Shun、Yamashita Masayuki、Aoyama Kazumasa、Yokomizo-Nakano Takako、Oshima Motohiko、Nishio Miki、Masuko Masayoshi、Takizawa Jun、Sone Hirohito、Yamada Yasuhiro、Suzuki Akira、Iwama Atsushi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 619 Pages: 117-123
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  • Peer Reviewed / Open Access
• [Journal Article] A high prevalence of myeloid malignancies in progeria with Werner syndrome is associated with p53 insufficiency (2022)
  • Author(s): Kato Hisaya、Ogawa Seishi, et al.
  • Journal Title: Experimental Hematology Volume: 109 Pages: 11-17
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• [Journal Article] Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis. (2022)
  • Author(s): Isshiki Y, Oshima M, Mimura N, Kayamori K, Miyamoto-Nagai Y, Seki M, Nakajima-Takagi Y, Kanamori T, Iwamoto E, Muto T, Tsukamoto S, Takeda Y, Ohwada C, Misawa S, Ikeda JI, Sanada M, Kuwabara S, Suzuki Y, Sakaida E, Nakaseko C, Iwama A.
  • Journal Title: JCI Insight Volume: 7 Issue: 20 Pages: 1-13
  • DOI: 10.1172/jci.insight.151482
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment (2022)
  • Author(s): Takano J, Ito S, Dong Y, Sharif J, Nakajima-Takagi Y, Umeyama T, Han YW, Isono K, Kondo T, Iizuka Y, Miyai T, Koseki Y, Ikegaya M, Sakihara M, Nakayama M, Ohara O, Hasegawa Y, Hashimoto K, Arner E, Klose RJ, Iwama A, Koseki H, Ikawa T
  • Journal Title: Nat Commun. Volume: 13 (1) Issue: 1 Pages: 7159-7159
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• [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
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• [Journal Article] Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche (2021)
  • Author(s): Kuribayashi W, Oshima M, Itokawa N, Koide S, Nakajima-Takagi Y, Yamashita M, Yamazaki S, Rahmutulla B, Miura F, Ito T, Kaneda A, Iwama A.
  • Journal Title: J Exp Med Volume: 218 Issue: 3
  • DOI: 10.1084/jem.20192283
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• [Journal Article] DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes (2021)
  • Author(s): Kayamori Kensuke、Nagai Yurie、Zhong Cheng、Kuribayashi Wakako、Oshima Motohiko、Nakajima-Takagi Yaeko、Yamashita Masayuki、Mimura Naoya、Becker Hans Jiro、Izawa Kiyoko、Yamazaki Satoshi、Iwano Satoshi、Ito Ryoji、Lennox William、Sheedy Josephine、Yokote Koutaro、Iwama Atsushi
  • Journal Title: Blood Advances Volume: 5 Issue: 2 Pages: 438-450
  • DOI: 10.1182/bloodadvances.2020001461
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• [Journal Article] Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway (2021)
  • Author(s): Fujino Takeshi、Goyama Susumu、Sugiura Yuki、Inoue Daichi、Asada Shuhei、Yamasaki Satoshi、Matsumoto Akiko、Yamaguchi Kiyoshi、Isobe Yumiko、Tsuchiya Akiho、Shikata Shiori、Sato Naru、Morinaga Hironobu、Fukuyama Tomofusa、Tanaka Yosuke、Fukushima Tsuyoshi、Takeda Reina、Yamamoto Keita、Honda Hiroaki et al
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1826-1826
  • DOI: 10.1038/s41467-021-22053-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HHEX promotes myeloid transformation in cooperation with mutant ASXL1. (2020)
  • Author(s): Takeda R, Asada S, Park SJ, Yokoyama A, Becker H, Kanai A, Visconte V, Hershberger C, Hayashi Y, Yonezawa T, Tamura M, Fukushima T, Tanaka Y, Fukuyama T, Matsumoto A, Yamasaki S, Nakai K, Yamazaki S, Inaba T, Shibata T, Inoue D, Honda H, Goyama S, Maciejewski J, Kitamura T.
  • Journal Title: Blood Volume: 136 Pages: 1670-1684
  • DOI: 10.1182/blood.2019004613
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plant homeodomain finger protein 6 in the regulation of normal and malignant hematopoiesis. (2020)
  • Author(s): Miyagi S, Iwama A.
  • Journal Title: Curr Opin Hematol. Volume: - Issue: 4 Pages: 248-253
  • DOI: 10.1097/moh.0000000000000588
  • Peer Reviewed
• [Journal Article] Bmi1 counteracts hematopoietic stem cell aging by repressing target genes and enforcing the stem cell gene signature. (2020)
  • Author(s): Nitta E, Itokawa N, Yabata S, Koide S, Hou LB, Oshima M, Aoyama K, Saraya A, Iwama A.
  • Journal Title: Biochem Biophys Res Commun Volume: 521 Issue: 3 Pages: 612-619
  • DOI: 10.1016/j.bbrc.2019.10.153
  • Peer Reviewed / Open Access
• [Journal Article] Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma. (2019)
  • Author(s): Rizk M, Rizq O, Oshima M, Nakajima-Takagi Y, Koide S, Saraya A, Isshiki Y, Chiba T, Yamazaki S, Ma A, Jin J, Iwama A, Mimura N.
  • Journal Title: Cancer Sci Volume: 110 Issue: 12 Pages: 3695-3707
  • DOI: 10.1111/cas.14207
  • 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] The chromatin binding protein Phf6 restricts the self-renewal of hematopoietic stem cells. (2019)
  • Author(s): Miyagi S, Sroczynska P, Kato Y, Nakajima-Takagi Y, Oshima M, Rizq O, Takayama N, Saraya A, Mizuno S, Sugiyama F, Takahashi S, Matsuzaki Y, Christensen J, Helin K, and Iwama A.
  • Journal Title: Blood Volume: - Issue: 23 Pages: 2495-2506
  • DOI: 10.1182/blood.2019000468
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Aging of hematopoietic stem cells (2024)
  • Author(s): Atsushi Iwama
  • Organizer: International Symposium on “Signals for Human, Animal and Planetary Health: From Metabolites To Biological Interactions”
  • Int'l Joint Research / Invited
• [Presentation] Targeting Hippo pathway in bone marrow niche promotes hematopoietic regeneration. (2024)
  • Author(s): Atsushi Iwama
  • Organizer: The 21st IRCMS Symposium on The Dynamics and Development of Normal and Malignant Hematopoietic Stem Cells.
  • Int'l Joint Research / Invited
• [Presentation] TOPORS ubiquitin ligase promotes degradation of DNMT1 in the presence of DNA hypomethylating agents (2023)
  • Author(s): Atsushi Iwama
  • Organizer: Tsuruoka Conference “Role of epigenetic factors in cancer”
  • Int'l Joint Research / Invited
• [Presentation] Chromatin accessibility in stem cells unveils progressive transcriptional reprogramming in myelodysplastic syndrome (2023)
  • Author(s): Atsushi Iwama
  • Organizer: Symposia ”Revisiting epigenetics in cancer” The 82th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research / Invited
• [Presentation] TOPORS ubiquitin ligase promotes DNMT1 degradation upon DNA hypomethylating agents (2023)
  • Author(s): Atsushi Iwama
  • Organizer: The 2nd International Symposium on REPLICATION of NON GENOME 2023
  • Int'l Joint Research / Invited
• [Presentation] Chromatin accessibility in MDS stem and progenitor cells. Symposium “Recent advances in leukemia stem cell research” (2022)
  • Author(s): Iwama A
  • Organizer: The 84th Annual Meeting of the Japanese Society of Hematology
  • Invited
• [Presentation] 「造血幹細胞特性の加齢変化とエピジェネティックメモリー」シンポジウム「100歳を目指した健康寿命延伸医療の実現」 (2022)
  • Author(s): 岩間厚志
  • Organizer: 日本心血管作動部質学会
  • Invited
• [Presentation] Chromatin accessibility in MDS stem and progenitor cells. Hematopoiesis (2021)
  • Author(s): Atsushi Iwama
  • Organizer: Keystone Symposia
  • Int'l Joint Research / Invited
• [Presentation] Non-canonical PRC1 regulates homeostatic and emergency hematopoiesis by restricting myeloid differentiation program (2021)
  • Author(s): Atsushi Iwama
  • Organizer: The Hematologic Malignancies Conference, FASEB Meeting
  • Int'l Joint Research / Invited
• [Presentation] KDM6A inactivation in germinal center B cells promotes the development of plasma cell neoplasms (2020)
  • Author(s): Atsushi Iwama
  • Organizer: 日本がん学会総会
  • Invited
• [Presentation] 造血幹細胞のエピジェネティックプロファイリング (2020)
  • Author(s): 岩間厚志
  • Organizer: 共同利用・共同研究拠点「マルチオミックスによる遺伝子発現制御の先端的医学共同研究拠点」シンポジウム
  • Invited
• [Presentation] Epigenetic alterations in aged hematopoietic stem cells and age-associated malignancies (2019)
  • Author(s): Iwama A
  • Organizer: 第13回日本エピジェネティクス研究会年会
  • Invited
• [Presentation] 造血幹細胞の加齢変化を規定するエピゲノム特性 (2019)
  • Author(s): 岩間厚志
  • Organizer: 第42回日本基礎老化学会大会
  • Invited
• [Presentation] Epigenetic alterations in aged hematopoietic stem cells and age-associated malignancies (2019)
  • Author(s): Iwama A
  • Organizer: 第62回日本放射線影響学会大会
  • Invited
• [Presentation] Epigenetic alterations in aged hematopoietic stem cells and age-associated malignancies (2019)
  • Author(s): 岩間厚志
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Remarks] https://www.ims.u-tokyo.ac.jp/molmed/
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