Mechanism for cardiomyocyte-specific nuclear architecture and disease development by dynamic DNA demethylation system.

• Project/Area Number: 18K08085
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Keio University
• Principal Investigator: ODA Mayumi 慶應義塾大学, 医学部(信濃町), 特任講師 (80567511)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: エピゲノム / DNAメチル化 / 転写伸長活動 / gene body領域 / ヒストンH3K35トリメチル化 / 老化 / 核内構造 / 細胞種特異性 / 5hmC / 遺伝子転写制御 / Gene body領域 / シングルセル解析 / 転写因子 / 心筋細胞 / 細胞成熟 / 病態発生機構 / 転写伸長反応 / スプライシング / DNA脱メチル化 / ゲノム進化 / 細胞種特異的遺伝子発現

Outline of Final Research Achievements

In this project, we investigated the active epigenetic domains that are extensively formed in the gene body region of cardiomyocyte-specific genes, and found that this region has high transcriptional elongation activity, and that it may be formed by genome-wide epigenetic changes specific to cardiomyocytes. In particular, the distribution of histone H3K36 trimethylation in constitutively expressed genes is altered genome-wide, indicating that transcription elongation of many constitutively expressed genes may be repressed. A model was presented in which genome-wide changes benefit a small number of specific gene transcription.

Academic Significance and Societal Importance of the Research Achievements

本研究計画では、マウス心臓における予期せぬ細胞種特異的なエピゲノム変化が観察された。細胞特異的な機能を維持するためのゲノムワイドな転写リソース戦略の変化は遺伝子機能の発現とバランスに大きく影響する要因であり、これが細胞種によって異なることを創薬・治療戦略において想定する必要がある。また、年齢的な変化の可能性については老若の細胞変化の細胞種間の差異とその影響の違い、特にヒトにおいては健康寿命を考える上で細胞種としてのデフォルトと初期老化状態の違いを改めて考慮する必要がある。このような問題提起において本研究は重要な知見を与えることができ、創薬・老化対策研究への応用が期待できる。

Research Products

• [Int'l Joint Research] NIA/NIH(米国)
• [Journal Article] Epigenetics Now and Then: Toward a New Resolution (2021)
  • Author(s): 小田 真由美
  • Journal Title: JSBi Bioinformatics Review Volume: 2 Issue: 1 Pages: 7-14
  • DOI: 10.11234/jsbibr.2021.primer2
  • NAID: 130008101629
  • ISSN: 2435-7022
• [Journal Article] Generation and Profiling of 2,135 Human ESC Lines for the Systematic Analyses of Cell States Perturbed by Inducing Single Transcription Factors (2020)
  • Author(s): Nakatake Y、Ko S B.H.、Sharov A A.、Wakabayashi S、Murakami M、Sakota M、Chikazawa N、Ookura C、Sato S、Ito N、Ishikawa-Hirayama M、Mak Siu S、Jakt Lars M、Ueno T、Hiratsuka K、Matsushita M、Goparaju S K、Akiyama T、Ishiguro K、Oda M、Gouda N、Umezawa A、Akutsu H、Nishimura K、Matoba R、Ohara O、Ko M S.H.
  • Journal Title: Cell Reports Volume: 31 Issue: 7 Pages: 107655-107655
  • DOI: 10.1016/j.celrep.2020.107655
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcriptomic features of trophoblast lineage cells derived from human induced pluripotent stem cells treated with BMP 4 (2020)
  • Author(s): Tsuchida Nanae、Kojima Junya、Fukuda Atsushi、Oda Mayumi、Kawasaki Tomoyuki、Ito Hiroe、Kuji Naoaki、Isaka Keiichi、Nishi Hirotaka、Umezawa Akihiro、Akutsu Hidenori
  • Journal Title: Placenta Volume: 89 Pages: 20-32
  • DOI: 10.1016/j.placenta.2019.10.006
  • Peer Reviewed / Open Access
• [Journal Article] Generation and profiling of 2,135 human ESC lines for the systematic analyses of cell states perturbed by inducing single transcription factors (2020)
  • Author(s): Nakatake Y, Ko SSH,Sharov AA, Wakabayashi S, Murakami M, Sakota M, Chikazawa N, Ookura C, Sato S, Ito N, Ishikawa-Hirayama M, Mak SS, Jakt KN, Ueno T, Hiratsuka K, Matsushita M, Goparaju SK, Akiyama T, Ishiguro K, Oda M, Gouda N, Umezawa A, Akutsu H, Nishimura K, Matoba R, Ohara O, and Ko. MSH
  • Journal Title: Cell Reports Volume: -
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization, and IL-17 expression. (2019)
  • Author(s): Nakatsukasa H, Oda M, Yin J, Chikuma S, Ito M, Koga-Iizuka M, Someya K, Kitagawa Y, Ohkura N, Sakaguchi S, Koya I, Sanosaka T, Kohyama J, Tsukada YI, Yamanaka S, Takamura-Enya T, Lu Q, Yoshimura A
  • Journal Title: International immunology Volume: 31 Issue: 5 Pages: 335-347
  • DOI: 10.1093/intimm/dxz008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients (2019)
  • Author(s): Higashikuse Yuta、Mittal Nishant、Arimura Takuro、Yoon Sung Han、Oda Mayumi、Enomoto Hirokazu、Kaneda Ruri、Hattori Fumiyuki、Suzuki Takeshi、Kawakami Atsushi、Gasch Alexander、Furukawa Tetsushi、Labeit Siegfried、Fukuda Keiichi、Kimura Akinori、Makino Shinji
  • Journal Title: Disease Models & Mechanisms Volume: 12 Pages: 041103-041103
  • DOI: 10.1242/dmm.041103
  • Peer Reviewed / Open Access
• [Journal Article] Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors. (2019)
  • Author(s): Hiratsuka K, Monkawa T, Akiyama T, Nakatake Y, Oda M, Goparaju SK, Kimura H, Chikazawa-Nohtomi N, Sato S, Ishiguro K, Yamaguchi S, Suzuki S, Morizane R, Ko SBH, Itoh H, Ko MSH
  • Journal Title: Scientific reports Volume: 9 Issue: 1 Pages: 913-913
  • DOI: 10.1038/s41598-018-37485-8
  • Peer Reviewed / Open Access
• [Journal Article] Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification. (2018)
  • Author(s): Sadahiro T, Isomi M, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tamura F, Tani H, Tohyama S, Fujita J, Miyoshi H, Kawamura Y, Goshima N, Iwasaki YW, Murano K, Saito K, Oda M, Andersen P, Kwon C, Uosaki H, Nishizono H, Fukuda K, Ieda M
  • Journal Title: Cell stem cell Volume: 23(3) Issue: 3 Pages: 382-395
  • DOI: 10.1016/j.stem.2018.07.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Selective modulation of local linkages between active transcription and oxidative demethylation activity shapes cardiomyocyte-specific gene-body epigenetic status in mice. (2018)
  • Author(s): Oda M, Wakabayashi S, Ari Wijetunga N, Yuasa S, Enomoto H, Kaneda R, Yoon SH, Mittal N, Jing Q, Suzuki M, Greally JM, Fukuda K, Makino S
  • Journal Title: BMC genomics Volume: 19 Issue: 1 Pages: 349-349
  • DOI: 10.1186/s12864-018-4752-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of Mitophagy By O-Linked N-Acetylglucosamine Transferase Is Essential for Hematopoietic Stem Cell Maintenance (2018)
  • Author(s): Murakami K, Kurotaki D, Kawase W, Soma S, Fukuchi Y, Kunimoto H, Yoshimi R, Koide S, Oshima M, Hishiki T, Hayakawa N, Matsuura T, Ko M, Oda M, Yanagisawa K, Kobayashi H, Atobe Y, Funakoshi K, Iwama A, Takubo K, Okamoto S, Tamura T and Nakajima H
  • Journal Title: Blood Volume: 132 Issue: Supplement 1 Pages: 171-171
  • DOI: 10.1182/blood-2018-171
  • Peer Reviewed / Open Access
• [Presentation] 細胞成熟に関与する細胞特異的なゲノム配列的特徴とエピジェネティック状態 (2021)
  • Author(s): 小田真由美
  • Organizer: 第44回 日本分子生物学会年会
• [Presentation] 心筋細胞成熟のGene body領域 エピジェネティクスとスプライシング制御 (2019)
  • Author(s): 小田 真由美
  • Organizer: RNA frontier 2019
• [Presentation] Gene body epigenetics and splicing regulation in cardiomyocyte maturation. (2019)
  • Author(s): Mayumi Oda
  • Organizer: 第42回分子生物学会年会
• [Presentation] The relationship between DNA methylation dynamics and cardiomyocyte- specific epigenetic domain formation in cardiomyocyte maturation (2019)
  • Author(s): Mayumi Oda
  • Organizer: BDR symposium 2019 "Control and Design of Biosystems"
  • Int'l Joint Research
• [Presentation] 試験管内心筋細胞分化における細胞成熟と細胞種特異的エピジェネティック・ドメイン形成 (2018)
  • Author(s): 小田 真由美、魚崎 英毅
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 心筋細胞特異的遺伝子の転写伸長反応と成熟過程における細胞種特異的エピジェネティック・ドメイン構築の影響 (2018)
  • Author(s): 小田真由美
  • Organizer: RNAフロンティアミーティング2018
• [Presentation] Gene bodyエピジェネティック修飾の細胞種特異的不均一性と進化的ゲノム配列要素選択の関与 (2018)
  • Author(s): 小田真由美
  • Organizer: 日本エピジェネティクス研究会第12回年会
• [Remarks] 慶應義塾坂口光洋記念講座 テニュアトラック・プログラム 助教・小田真由美
  • URL: http://www.careerpath-prj.keio.ac.jp/sakaguchi/scholar/m_oda/
• [Remarks] Research gate: Mayumi Oda
  • URL: https://www.researchgate.net/profile/Mayumi_Oda
• [Patent(Industrial Property Rights)] Reagent for differentiating somatic cells into alveolar epithelial cells, and use of said reagent (2020)
  • Inventor(s): Ishii Makoto, Mayumi Oda他7名
  • Industrial Property Rights Holder: Ishii Makoto, Mayumi Oda他7名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Overseas