Epigenome analysis in cardiomyocyte differentiation and failure

• Project/Area Number: 26253049
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Komuro Issei 東京大学, 医学部附属病院, 教授 (30260483)
• Co-Investigator(Kenkyū-buntansha): 内藤 篤彦 東京大学, 医学部附属病院, 助教 (10588891) ; 野村 征太郎 東京大学, 医学部附属病院, 助教 (10722118)
• Co-Investigator(Renkei-kenkyūsha): NOMURA Seitaro 東京大学, 医学部附属病院, 特任助教 (10722118)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥41,600,000 (Direct Cost: ¥32,000,000、Indirect Cost: ¥9,600,000); Fiscal Year 2016: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000); Fiscal Year 2015: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2014: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000)
• Keywords: 分子心臓学 / エピゲノム / 遺伝子制御 / 分子心臓病学 / 転写制御 / 循環器 / ゲノム / 心不全 / 心筋細胞分化

Outline of Final Research Achievements

We analyzed epigenomic regulation of cardiomyocyte differentiation and heart failure. Genome-wide enhancer analysis revealed that β-catenin, which is activated by Wnt signaling upon differentiation, forms a complex with epigenomic regulators to activate mesodermal enhancers and provokes the down-stream gene program. Through integrative analysis of single-cell transcriptomes and epigenomes, we also unveiled that transcription factors which are induced upon pressure overload activates enhancers regulating the heart failure gene program. These results indicate that the epigenome regulates cardiomyocyte differentiation and failure.

Research Products

• [Journal Article] Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure (2017)
  • Author(s): Kamo T, Akazawa H, Suda W, Saga-Kamo A, Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT, Takeda N, Harada M, Toko H, Kumagai H, Ikeda Y, Takimoto E, Suzuki JI, Honda K, Morita H, Hattori M, Komuro I.
  • Journal Title: Plos One. Volume: 12 Pages: 0174099-0174099
  • DOI: 10.1371/journal.pone.0174099
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity (2017)
  • Author(s): Semba, H., Takeda, N., Isagawa, T., Sugiura, Y., Honda, K., Wake, M., Miyazawa, H., Yamaguchi, Y., Miura, M., Jenkins, DM., Choi, H., Kim, JW., Asagiri, M., Cowburn, AS., Abe, H., Soma, K., Koyama, K., Katoh, M., Sayama, K., Goda, N., Johnson, RS., Manabe, I., Nagai, R., Komuro, I.
  • Journal Title: Nat Commun. 2016 May 18;7:11635. Volume: 7 Pages: 11635-11635
  • DOI: 10.1038/ncomms11635
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A strategy for genomic research on common cardiovascular diseases aiming at the realization of precision medicine; Personal insights and perspectives. (2016)
  • Author(s): Morita H, Komuro I.
  • Journal Title: Circ Res. Volume: 119 Pages: 900-903
  • DOI: 10.1161/circresaha.116.309802
  • Peer Reviewed
• [Journal Article] Fukutin gene mutations that cause left ventricular noncompaction (2016)
  • Author(s): Amiya E, Morita H, Hatano M, Nitta D, Hosoya Y, Maki H, Motozawa Y, Sato N, Ishiura H, Numakura S, Shintani Y, Kinugawa K, Takeda N, Shimizu J, Tsuji S, Komuro I.
  • Journal Title: Int J Cardiol Volume: 222 Pages: 727-729
  • DOI: 10.1016/j.ijcard.2016.08.011
  • Peer Reviewed
• [Journal Article] Novel molecular mechanisms and regeneration therapy for heart failure. (2016)
  • Author(s): Oka T, Morita H, Komuro I.
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 92 Pages: 46-51
  • DOI: 10.1016/j.yjmcc.2016.01.028
  • Peer Reviewed
• [Journal Article] Generation of Induced Pluripotent Stem Cells From Patients With Duchenne Muscular Dystrophy and Their Induction to Cardiomyocytes (2016)
  • Author(s): Hashimoto A, Naito AT, Lee JK, Kitazume-Taneike R, Ito M, Yamaguchi T, Nakata R, Sumida T, Okada K, Nakagawa A, Higo T, Kuramoto Y, Sakai T, Tominaga K, Okinaga T, Kogaki S, Ozono K, Miyagawa S, Sawa Y, Sakata Y, Morita H, Umezawa A, Komuro I.
  • Journal Title: Int. Heart J. Volume: 57 Issue: 1 Pages: 112-117
  • DOI: 10.1536/ihj.15-376
  • NAID: 130005120987
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Higd1a is a positive regulator of Cytochrome c Oxidase (2015)
  • Author(s): T. Hayashi, Y. Asano, Y. Shintani, H. Aoyama, H. Kioka, O. Tsukamoto, M. Hikita, K. Shinzawa-Itoh, K. Takajuji, S. Higo, H. Kato, S. Yamazaki, K. Matsuoka, A. Nakano, H. Asanuma, M. Asakura, T. Minamino, Y. Goto, T. Ogura, M. Kitakaze, I. Komuro, Y. Sakata, T. Tsukihara, S. Yoshikawa, S. Takashima
  • Journal Title: Proc Natl Acad Sci U SA Volume: 112 Pages: 1553-1553
  • DOI: 10.1073/pnas.1419767112
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Complement C1q-induced activation of β-cateninsignalling causes hypertensive arterial remodelling. (2015)
  • Author(s): Sumida T, Naito AT, Nomura S, Nakagawa A, Higo T, Hashimoto A, Okada K, Sakai T, Ito M, Yamaguchi T, Oka T, Akazawa H, Lee JK, Minamino T, Offermanns S, Noda T, Botto M, Kobayashi Y, Morita H, Manabe I, Nagai T, Shiojima I, Komuro I.
  • Journal Title: Nature Communications Volume: 6 Pages: 1-12
  • DOI: 10.1038/ncomms7241
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Wnt/β-catenin signaling contributes to skeletal myopathy in heart failure via direct interaction with FoxO. (2015)
  • Author(s): Okada K, Naito AT, Higo T, Nakagawa A, Shibamoto M, Sakai T, Hashimoto A, Kuramoto Y, Sumida T, Nomura S, Ito M, Yamaguchi T, Oka T, Akazawa H, Lee JK, Morimoto S, Sakata Y, Shiojima I, Komuro I.
  • Journal Title: Circ Heart Fail Volume: 8 Pages: 799-808
  • DOI: 10.1161/circheartfailure.114.001958
  • Peer Reviewed
• [Journal Article] Monitoring ß-arrestin recruitment via ß-lactamase enzyme fragment complementation: purification of peptide E as a low-affinity ligand for mammalian bombesin receptors. (2015)
  • Author(s): Ikeda Y*, Kumagai H*, Okazaki H, Fujishiro M, Motozawa Y, Nomura S, Takeda N, Toko H, Takimoto E, Akazawa H, Morita H, Suzuki J, Yamazaki T, Komuro I, Yanagisawa M (co-first author)
  • Journal Title: PLoS One. Volume: 10
  • DOI: 10.1371/journal.pone.0127445
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Quantitative measurement of GPCR endocytosis via pulse-chase covalent labeling. (2015)
  • Author(s): Kumagai H, Ikeda Y, Motozawa Y, Fujishiro M, Okamura T, Fujio K, Okazaki H, Nomura S, Takeda N, Harada M, Toko H, Takimoto E, Akazawa H, Morita H, Suzuki J, Yamazaki T, Yamamoto K, Komuro I, Yanagisawa M
  • Journal Title: PLoS One. Volume: 10
  • DOI: 10.1371/journal.pone.0129394
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Angiotensin II receptor blockade promotes repair of skeletal muscle through down-regulation of aging-promoting C1q expression. (2015)
  • Author(s): Yabumoto C, Akazawa H, Yamamoto R, Yano M, Kudo-Sakamoto Y, Sumida T, Kamo T, Yagi H, Shimizu Y, Saga-Kamo A, Naito AT, Oka T, Lee JK, Suzuki J, Sakata Y, Uejima E, Komuro I.
  • Journal Title: Sci Rep. Volume: 5 Pages: 14453-14453
  • DOI: 10.1038/srep14453
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Monocyte-derived extracellular Nampt-dependent biosynthesis of NAD+ protects the heart against pressure overload. (2015)
  • Author(s): Yano M, Akazawa H, Oka T, Yabumoto C, Kudo-Sakamoto Y, Kamo T, Shimizu Y, Yagi H, Naito AT, Lee JK, Suzuki J, Sakata Y, Komuro I.
  • Journal Title: Sci Rep. Volume: 5 Pages: 15857-15857
  • DOI: 10.1038/srep15857
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 【再生医療-新たな医療を求めて-】 臨床応用を目指した基礎研究 疾患モデル細胞、iPS細胞を用いた毒性評価と創薬研究 iPS細胞を用いた遺伝性心筋疾患の病態解明と治療法開発 (2015)
  • Author(s): 伊藤 正道、内藤 篤彦、小室 一成
  • Journal Title: 日本臨床 Volume: 73 Pages: 411-415
• [Journal Article] 【疾患特異的iPSの基礎と臨床】 疾患特異的iPSの臨床 循環器疾患における現況 (2015)
  • Author(s): 伊藤 正道、内藤 篤彦、小室 一成
  • Journal Title: Surgery Frontier Volume: 22 Pages: 137-141
• [Journal Article] 【心筋再生の現状と展望】 iPS細胞を用いた拡張型心筋症の病態解析 (2015)
  • Author(s): 伊藤 正道、内藤 篤彦、小室 一成
  • Journal Title: 最新医学 Volume: 70 Pages: 1683-1688
• [Journal Article] 心不全における心筋細胞の1細胞heterogeneityとその意義 (2015)
  • Author(s): 野村 征太郎、佐藤 真洋、藤田 隆教、山口 敏弘、住田 智一、内藤 篤彦、東口 治弘、油谷 浩幸、小室 一成
  • Journal Title: 日本内分泌学会雑誌 Volume: 91 Pages: 636-636
• [Journal Article] Anti-inflammatory peptides from cardiac progenitors ameliorate dysfunction after myocardial infarction. (2014)
  • Author(s): Liu ML, Nagai T, Tokunaga M, Iwanaga K, Matsuura K, Takahashi T, Kanda M, Kondo N, Naito AT, Komuro I, Kobayashi Y.
  • Journal Title: J Am Heart Assoc. Volume: 3
  • DOI: 10.1161/jaha.114.001101
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Calpain-dependent cleavage of N-cadherin is involved in the progression of post-myocardial infarction remodeling. (2014)
  • Author(s): Yoko Kudo-Sakamoto, Hiroshi Akazawa, Kaoru Ito, Jiro Takano, Masamichi Yano, Chizuru Yabumoto, Atsuhiko T. Naito, Toru Oka, Jong-Kook Lee, Yasushi Sakata, Jun-ichi Suzuki, Takaomi C. Saido and Issei Komuro
  • Journal Title: J Biol Chem. Volume: 289 Pages: 19408-19
  • DOI: 10.1074/jbc.m114.567206
  • Peer Reviewed
• [Journal Article] Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing hear (2014)
  • Author(s): Matsuoka K, Asano Y, Higo S, Tsukamoto O, Yan Y, Yamazaki S, Matsuzaki T, Kioka H, Kato H, Uno Y, Asakura M, Asanuma H, Minamino T, Aburatani H, Kitakaze M, Komuro I, Takashima S.
  • Journal Title: FASEB J Volume: 28(4) Pages: 1870-1870
  • DOI: 10.1096/fj.13-245522
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitochondrial aldehyde dehydrogenase 2 plays protective roles in heart failure after myocardial infarction via suppression of the cytosolic JNK/p53 pathway in mice (2014)
  • Author(s): Sun A, Zou Y, Wang P, Xu D, Gong H, Wang S, Qin Y, Zhang P, Chen Y, Harada M, Isse T, Kawamoto T, Fan H, Yang P, Akazawa H, Nagai T, Ping P, Komuro I, Ge J.
  • Journal Title: J Am Heart Assoc. Volume: 3
  • DOI: 10.1161/jaha.113.000779
  • Peer Reviewed / Open Access
• [Presentation] 臨床・基礎研究の強化 (2017)
  • Author(s): 小室一成
  • Organizer: 第81回 日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-18
  • Invited
• [Presentation] Genetics of Cardiomyopathy (2017)
  • Author(s): 野村征太郎
  • Organizer: 第81回 日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
  • Invited
• [Presentation] 若者を心血管病から守る：金沢宣言への提言 Introduction (2017)
  • Author(s): 小室一成
  • Organizer: 第81回 日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
  • Invited
• [Presentation] システム生物学的アプローチによる心不全１細胞モデリング (2016)
  • Author(s): 野村征太郎、佐藤真洋、候聡志、藤田隆教、油谷浩幸、小室一成
  • Organizer: 第20回日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] 心筋症のハイスルーブットな遺伝子解析技術の構築とその応用 (2016)
  • Author(s): 野村征太郎、飛田尚重、藤田隆教、油谷浩幸、小室一成
  • Organizer: 第20回日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] Angiogenesis has two merits heart failure (2016)
  • Author(s): Issei Komuro
  • Organizer: The 60th Annual Scientific Meeting of The Korean Society of Cardiology 2016
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-09-26
  • Invited
• [Presentation] Inflammation, ageing and heart failure. (2016)
  • Author(s): Issei Komuro
  • Organizer: ESC Congress 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Invited
• [Presentation] Mechanisms for heart failure (2016)
  • Author(s): Issei Komuro
  • Organizer: World Congress of Cardiology and Cardiovascular Health
  • Place of Presentation: Mexico City, Mexico
  • Year and Date: 2016-06-04
  • Invited
• [Presentation] Mechanisms of Heart Failure - crosstalks among ischemia, inflammation and senescence- (2016)
  • Author(s): Issei Komuro
  • Organizer: The 11th IHA International Elite Forum
  • Place of Presentation: Shanghai, China
  • Year and Date: 2016-05-26
  • Invited
• [Presentation] Plenary Lecture : Molecular Mechanism of Heart Failure (2016)
  • Author(s): Issei Komuro
  • Organizer: The 4th Wuhan International Conference on Cardiometabolic Science
  • Place of Presentation: Wuhan, China
  • Year and Date: 2016-05-12
  • Invited
• [Presentation] Cardiac DNA damage causes heart failure. (2016)
  • Author(s): Issei Komuro
  • Organizer: ISHR XXII World Congress
  • Place of Presentation: Buenos Aires, Argentina
  • Year and Date: 2016-04-18
  • Invited
• [Presentation] Molecular mechanisms of heart failure (2016)
  • Author(s): Issei Komuro
  • Organizer: New Frontiers in Cell Death Signaling and Heart Failure
  • Place of Presentation: ハワイ（アメリカ）
  • Year and Date: 2016-02-19
  • Invited
• [Presentation] 心不全における心筋細胞の1細胞heterogeneityとその意義 (2015)
  • Author(s): 野村 征太郎、佐藤 真洋、藤田 隆教、山口 敏弘、住田 智一、内藤 篤彦、東口 治弘、油谷 浩幸、小室 一成
  • Organizer: 第19回 日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-10
• [Presentation] 心不全治療と研究の最前線 (2015)
  • Author(s): 小室一成
  • Organizer: 第114回日本循環器学会 北海道地方会
  • Place of Presentation: 北海道大学学術交流会館（北海道札幌市）
  • Year and Date: 2015-11-28
  • Invited
• [Presentation] Science Highlights From the Japanese Circulation Society (2015)
  • Author(s): Issei Komuro
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: オーランド（アメリカ）
  • Year and Date: 2015-11-07
  • Int'l Joint Research / Invited
• [Presentation] 心不全の先制医療を目指して (2015)
  • Author(s): 小室一成
  • Organizer: 第29回日本医学会総会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2015-04-11
  • Invited
• [Presentation] Epigenomic switch by Wnt/b-catenin signaling directs cardiomyocyte differentiation (2015)
  • Author(s): Seitaro Nomura, Takanori Fujita, Atsuhiko T. Naito, Hiroyuki Aburatani, and Issei Komuro
  • Organizer: Keystone Symposia 2015 Heart Disease and Regeneration
  • Place of Presentation: Copper Mountain, Colorado
  • Year and Date: 2015-03-01 – 2015-03-06
• [Presentation] Epigenomic switch by Wnt/b-catenin signaling directs cardiomyocyte differentiation (2014)
  • Author(s): Seitaro Nomura, Takanori Fujita, Atsuhiko T. Naito, Hiroyuki Aburatani, and Issei Komuro
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: Chicago
  • Year and Date: 2014-11-16 – 2014-11-19
• [Presentation] Molecular Mechanisms of Heart Failure (2014)
  • Author(s): Issei Komuro
  • Organizer: The 12th China Congress of ISHR
  • Place of Presentation: China
  • Year and Date: 2014-08-15
  • Invited
• [Presentation] PI3 Kinase signaling and heart failure (2014)
  • Author(s): Issei Komuro
  • Organizer: Heart Failure 2014
  • Place of Presentation: Greece
  • Year and Date: 2014-05-19
  • Invited
• [Presentation] 心不全の新しい治療 (2014)
  • Author(s): 小室一成
  • Organizer: 日本麻酔科学会第61回学術集会
  • Place of Presentation: 神奈川
  • Year and Date: 2014-05-16
  • Invited