2011 Fiscal Year Final Research Report
Analysis of molecular dynamics of constitutive KLF induction through chromatin conformation change by statin
| Project/Area Number |
23659050
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Drug development chemistry
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| Research Institution | The University of Tokyo |
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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)
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| Project Period (FY) |
2011
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| Keywords | スタチン / 転写調節 / KLFファミリー / 内皮細胞 / 動脈硬化 |
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| 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.
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