Quantitative Epigenome Mapping to Identify Therapeutic Target in Heart Failure

• Project/Area Number: 24790757
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: Osaka University
• Principal Investigator: HIGO Shuichiro 大阪大学, 医学(系)研究科(研究院), 助教 (00604034)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: エピゲノム / 高速シークエンサー / 心不全 / 次世代シークエンサー

Research Abstract

To explore a therapeutic target for preventing the progression of heart failure, we established the novel screening method using next generation sequencer. Pressure-overloaded hearts of mice were applied to RNA-sequence and trimethylated histone H3 Lysine 4 (H3K4me3) ChIP-sequence analysis. We developed a quantification algorithm for H3K4me3 marks which enables absolute comparison between control and the pathological conditions. We demonstrate that H3K4me3 accumulated at the genes functionally involved in transcriptional regulation, although the expression levels of these genes were low. We applied the additional H3K4me3 filtering to the transcriptionally upregulated genes in failing hearts and found the genes specifically marked by H3K4me3 under prolonged hypertrophic stimuli. Among them, we identified a transcription factor with significant H3K4me3 enrichment in failing hearts. From these data, now we are currently advancing functional analysis of this molecule.

Research Products

• [Journal Article] Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2 (2014)
  • Author(s): Shintani Y, Drexler HC, Kioka H, Terracciano CM, Coppen SR, Imamura H, Akao M, Nakai J, Wheeler AP, Higo S, Nakayama H, Takashima S, Yashiro K, Suzuki K
  • Journal Title: EMBO Rep Pages: 7-7
• [Journal Article] Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing heart (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: 1870-9
• [Journal Article] Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation (2014)
  • Author(s): Kioka H, Kato H, Fujikawa M, Tsukamoto O, Suzuki T, Imamura H, Nakano A, Higo S, Yamazaki S, Matsuzaki T, Takafuji K, Asanuma H, Asakura M, Minamino T, Shintani Y, Yoshida M, Noji H, Kitakaze M, Komuro I, Asano Y, Takashima S.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 111(1) Pages: 7-7
• [Journal Article] Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2. (2014)
  • Author(s): Shintani Y, Drexler HC, Kioka H, Terracciano CM, Coppen SR, Imamura H, Akao M, Nakai J, Wheeler AP, Higo S, Nakayama H, Takashima S, Yashiro K, Suzuki K.
  • Journal Title: EMBO Reports Volume: 15 Issue: 4 Pages: 438-445
  • DOI: 10.1002/embr.201337945
  • Peer Reviewed / Open Access
• [Journal Article] Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing heart. (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) Issue: 4 Pages: 1870-9
  • DOI: 10.1096/fj.13-245522
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evaluation of intra-mitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation (2013)
  • Author(s): Kioka H, Kato H, Fujikawa M, Tsukamoto O, Suzuki T, Imamura H, Nakano A, Higo S, Yamazaki S, Matsuzaki T, Tkafuji K, Asanuma H, Asakura M, Minamino T, Shintani Y, Yoshida M, Noji H, Kitakaze M, Komuro I, Asano Y and Takashima S
  • Journal Title: PNAS Volume: 111 Issue: 1 Pages: 273-278
  • DOI: 10.1073/pnas.1318547111
  • Peer Reviewed / Open Access
• [Presentation] 定量的エピゲノム解析を用いた心臓線維芽細胞における細胞周期制御因子の同定 (2014)
  • Author(s): 肥後修一朗、朝野仁裕、増村雄喜、坂田泰史、澤芳樹、北風政史、小室一成、高島成二
  • Organizer: 第51回日本臨床分子医学会
• [Presentation] 定量的エピゲノム解析を用いた心臓線維芽細胞における細胞周期制御因子の同定 (2014)
  • Author(s): 肥後 修一朗
  • Organizer: 第51回日本臨床分子医学会学術集会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Comprehensive quantitative epigenome mapping reveals the differential induction of histone H3 lysine 4 trimethylation marks in pressure-overloaded murine hearts (2013)
  • Author(s): 肥後 修一朗
  • Organizer: AHA scientific sessions 2012
  • Place of Presentation: Losangels, USA
• [Presentation] Quantitative ChIP-sequence Analysis Reveals the Differentially Altered Active Epigenomic States in Murine Pressure-overloaded Failing Hearts. (2012)
  • Author(s): Shuichiro Higo, Yoshihiro Asano, Seiji Takashima, Masafumi Kitakaze, Issei Komuro
  • Organizer: 第29回ISHR日本部会総会
  • Place of Presentation: 九州大学福岡
  • Year and Date: 2012-10-26
• [Presentation] Comprehensive quantitative epigenome mapping reveals the differential induction of histone H3 lysine 4 trimethylation. (2012)
  • Author(s): Shuichiro Higo, Yoshihiro Asano, Seiji Takashima, Masafumi Kitakaze, Issei Komuro
  • Organizer: AHA scientific sessions
  • Place of Presentation: Losangels, USA
• [Presentation] Quantitative Epigenome Mapping Reveals the Differentially Induced Histone H3 Lysine 4 Trimethylation Marks in Pressure-overloaded Failing Hearts. (2012)
  • Author(s): Shuichiro Higo, Yoshihiro Asano, Seiji Takashima, Issei Komuro
  • Organizer: Molecular CardiovascularConference II
  • Place of Presentation: 北海道赤井川村キロロ
• [Presentation] Quantitative Epigenome Mapping Reveals the Differentially Induced Histone H3 Lysine 4 Trimethylation Marks in Pressure-overloaded Failing Hearts (2012)
  • Author(s): 肥後 修一朗
  • Organizer: Molecular Cardiovascular Conference II
  • Place of Presentation: 北海道赤井川村キロロ
• [Presentation] Quantitative ChIP-sequence Analysis Reveals the Differentially Altered Active Epigenomic States in Murine Pressure-overloaded Failing Hearts (2012)
  • Author(s): 肥後 修一朗
  • Organizer: 第29回ISHR日本部会総会
  • Place of Presentation: 九州大学 福岡