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

他汀类药物通过染色质构象变化诱导组成型 KLF 的分子动力学分析

• 批准号: 23659050
• 负责人: WADA Youichiro
• 金额: $ 2.58万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659050/
• 关键词: スタチン; 転写調節; KLFファミリー; 内皮細胞; 動脈硬化

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.

已知3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，即他汀类药物，通过在多个器官中诱导特异性转录因子来发挥动脉粥样硬化保护作用。本文主要研究匹伐他汀对血管壁的有益作用，分析匹伐他汀诱导的综合基因表达谱。通过芯片分析，我们发现KLF4和KLF2是显著诱导基因。利用染色质免疫沉淀与深度测序（ChIP-seq）分析，我们在KLF4基因中发现了一个新的功能重要的MEF2C结合位点。染色质构象分析显示，该mef2c结合增强子与转录起始位点具有空间邻近性，并且经匹伐他汀治疗后频率增加。因此，在他汀类药物处理的内皮中，MEF2C通过MEK5/ERK5通路被激活，并且MEF2C占据的增强子在KLF4诱导中空间邻近性增加，提示他汀类药物介导的基因诱导涉及动态染色质构象改变。

项目成果

Renewal of histone modification during a wave of transcription caused by inflammatory stimulation in endothelial cells

内皮细胞炎症刺激引起的转录波期间组蛋白修饰的更新

• 发表时间: 2011
• 作者: Fox;R.;Kim;H. S.;Reddick;R. L.;Kujoth;G. C.;Prolla;T. A.;Tsutsumi;S.;Wada;Y.;Smithies;O.;and *Maeda;N.;和田洋一郎;和田洋一郎;和田洋一郎;和田洋一郎;和田洋一郎
• 通讯作者: 和田洋一郎

Distribution of histone3 lysine 4 trimethylation at T3-responsive loci in the heart during reversible changes in gene expression.

• DOI: 10.3727/105221612x13372578119698
• 发表时间: 2012
• 期刊: Gene expression
• 作者: Pandya K;Kohro T;Mimura I;Kobayashi M;Wada Y;Kodama T;Smithies O
• 通讯作者: Smithies O

Dynamic change of the chromatin conformation in response to hypoxia enhances the expression of GLUT3(SLC2A3) by cooperative interaction of HIF1 and KDM3A

缺氧时染色质构象的动态变化通过 HIF1 和 KDM3A 的协同相互作用增强 GLUT3(SLC2A3) 的表达

• 发表时间: 2012
• 期刊: Molecular and Cellular Biology, in press
• 作者: Mimura I;Wada Y;et al
• 通讯作者: et al

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

超高速测序仪揭示与转录相关的动态染色体结构变化以及新转录装置的概念

• 发表时间: 2011
• 作者: Fox;R.;Kim;H. S.;Reddick;R. L.;Kujoth;G. C.;Prolla;T. A.;Tsutsumi;S.;Wada;Y.;Smithies;O.;and *Maeda;N.;和田洋一郎;和田洋一郎;和田洋一郎
• 通讯作者: 和田洋一郎

A wave of nascent transcription on activated big genes in human endothelial cells

人内皮细胞中激活的大基因的新生转录波

• 发表时间: 2012
• 作者: Fox;R.;Kim;H. S.;Reddick;R. L.;Kujoth;G. C.;Prolla;T. A.;Tsutsumi;S.;Wada;Y.;Smithies;O.;and *Maeda;N.;和田洋一郎
• 通讯作者: 和田洋一郎