Analysis of molecular dynamics of constitutive KLF induction through chromatin conformation change by statin

• Project/Area Number: 23659050
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: WADA Youichiro 東京大学, 先端科学技術研究センター, 特任准教授 (10322033)
• Project Period (FY): 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: スタチン / 転写調節 / KLFファミリー / 内皮細胞 / 動脈硬化

Research Abstract

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, are known to exert athero-protective effects through the induction of specific transcriptional factors in multiple organs. Here, we focus on the beneficial effect in vascular wall, and analyzed comprehensive gene expression profile induced by pitavastatin. Through microarray analysis, we identified KLF4 and KLF2 as significantly induced genes. Using the chromatin immunoprecipitation with deep sequencing(ChIP-seq) analysis, we identified a novel functionally important MEF2C binding site within KLF4 gene. Chromatin conformation analysis revealed this MEF2C-bound enhancer had spacial proximity to transcription start site and the frequency was increased by pitavastatin treatment. Thus, in statin treated endothelium, MEF2C was activated through MEK5/ERK5 pathway, and spacial proximity of MEF2C occupied enhancer was increased in KLF4 induction, suggesting dynamic chromatin conformation change was involved in statin mediated gene induction.

Research Products

• [Journal Article] Distribution of histone3 lysine4 trimethylation at T3-responsive loci in the heart during reversible changes in gene expression (2012)
  • Author(s): Pandya K, Kohro T, Wada Y, et al
  • Journal Title: Gene Expression, in press
• [Journal Article] Dynamic change of the chromatin conformation in response to hypoxia enhances the expression of GLUT3(SLC2A3) by cooperative interaction of HIF1 and KDM3A (2012)
  • Author(s): Mimura I, Wada Y, et al
  • Journal Title: Molecular and Cellular Biology, in press
• [Journal Article] Distribution of histone3 lysine4 trimethylation at T3-responsive loci in the heart during reversible changes in gene expression (2012)
  • Author(s): Pandya K, Kohro T, Wada Y, et al
  • Journal Title: Gene Expression Volume: (In press)
  • Peer Reviewed
• [Journal Article] Epigenetically coordinated GATAT2 binding is necessary for endothelium-specific endomucin expression (2011)
  • Author(s): Kanki Y, Kohro T, Jiang S, Tsutsumi S, Mimura I, Suehiro J, Wada Y, Ohta Y, Ihara S, Iwanari H, Naito M, Hamakubo T, Aburatani H, Kodama T, Minami T
  • Journal Title: EMBO J Volume: 30 Issue: 13 Pages: 2582-95
  • DOI: 10.1038/emboj.2011.173
  • Peer Reviewed
• [Journal Article] Genome-wide approaches reveal functional interleukin-4-inducible STAT6 binding to the vascular cell adhesion molecule 1 promoter. (2011)
  • Author(s): Tozawa H, Kanki Y, Wada Y, et al.
  • Journal Title: Molecular and Cellular Biology Volume: vol.31 Issue: 11 Pages: 2196-209
  • DOI: 10.1128/mcb.01430-10
  • Peer Reviewed
• [Journal Article] Mitochondrial DNA polymerase editing mutation, PolgD257A, reduces the diabetic phenotype of Akita male mice by suppressing appetite. (2011)
  • Author(s): Fox, R., Kim, H. S., Reddick, R. L., Kujoth, G. C., Prolla, T. A., Tsutsumi, S., Wada, Y., Smithies, O., and *Maeda, N.
  • Journal Title: Proceedings of the National Academy ofSciences of the United States of America Volume: 108 Issue: 21 Pages: 8779-8784
  • DOI: 10.1073/pnas.1106344108
  • Peer Reviewed
• [Presentation] A wave of nascent transcription on activated big genes in human endothelial cells (2012)
  • Author(s): 和田洋一郎
  • Organizer: Keystone Symposia 2012 Chromatin Dynamics
• [Presentation] A wave of nascent transcription on activated big genes in human endothelial cells (2012)
  • Author(s): 和田洋一郎
  • Organizer: Keystone Symposia 2012 Chromation Dynamics
  • Place of Presentation: Keystone Colorado, U.S.A
• [Presentation] 超高速シーケンサーが明らかにした転写に伴うダイナミックな染色体構造変化と新たな転写装置の概念 (2011)
  • Author(s): 和田洋一郎
  • Organizer: 第2回ARTセミナー
  • Place of Presentation: 岡山大学
  • Year and Date: 2011-05-25
• [Presentation] 超高速シーケンサーが明らかにした転写に伴うダイナミックな染色体構造変化と新たな転写装置の概念 (2011)
  • Author(s): 和田洋一郎
  • Organizer: 第2回ARTセミナー
  • Place of Presentation: 岡山大学(招待講演)
  • Year and Date: 2011-05-25
• [Presentation] Renewal of histone modification during a wave of transcription caused by inflammatory stimulation in endothelial cells (2011)
  • Author(s): 和田洋一郎
  • Organizer: 第5回日本エピジェネティクス研究会
• [Presentation] Identification of novel MEF2C binding site indispensable for KLF4 induction in endothelial cells by statin treatment (2011)
  • Author(s): 前島崇司、和田洋一郎
  • Organizer: 第19回日本血管生物医学会学術集会
  • Place of Presentation: 東京ステーションコンファレンス、東京