Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells.
Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells.
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DOI：
10.1371/journal.pone.0096005
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wada Y
中科院分区：
文献类型：
--
作者：
Maejima T;Inoue T;Kanki Y;Kohro T;Li G;Ohta Y;Kimura H;Kobayashi M;Taguchi A;Tsutsumi S;Iwanari H;Yamamoto S;Aruga H;Dong S;Stevens JF;Poh HM;Yamamoto K;Kawamura T;Mimura I;Suehiro J;Sugiyama A;Kaneki K;Shibata H;Yoshinaka Y;Doi T;Asanuma A;Tanabe S;Tanaka T;Minami T;Hamakubo T;Sakai J;Nozaki N;Aburatani H;Nangaku M;Ruan X;Tanabe H;Ruan Y;Ihara S;Endo A;Kodama T;Wada Y
他汀类药物通过在多个器官中诱导特异性转录因子发挥动脉粥样硬化保护作用。在内皮细胞中，他汀类药物依赖的动脉粥样硬化保护基因上调是由Kruppel样因子（KLF）家族转录因子介导的。为了剖析基因调控的机制，我们试图通过对用匹伐他汀处理的人脐静脉内皮细胞（HUVECs）进行微阵列分析来确定分子靶点，并且KLF 4被确定为最高度诱导的基因。此外，研究表明，用匹伐他汀诱导的动脉粥样硬化保护基因，如一氧化氮合酶3（NOS 3）和血栓调节蛋白（THBD），被KLF 4敲低所抑制。据报道，肌细胞增强因子-2（MEF 2）家族激活参与匹伐他汀依赖性KLF 4诱导。我们专注于MEF 2家族成员中的MEF 2C，并通过染色质免疫沉淀沿着深度测序（ChIP-seq）和荧光素酶测定，在KLF 4基因上游148 kb处鉴定了一个新的功能性MEF 2C结合位点。通过应用全基因组和定量染色质构象分析（染色质相互作用分析与配对末端标签测序（ChIA-PET）和真实的时间染色体构象捕获（3C）分析），我们观察到通过匹伐他汀处理，KLF 4的MEF 2C结合的增强子和转录起始位点（TSS）在空间上变得更接近。三维荧光原位杂交（FISH）成像支持单个细胞的构象变化。两者合计，动态染色质构象变化被证明介导内皮细胞中匹伐他汀应答基因的诱导。
Statins exert atheroprotective effects through the induction of specific transcriptional factors in multiple organs. In endothelial cells, statin-dependent atheroprotective gene up-regulation is mediated by Kruppel-like factor (KLF) family transcription factors. To dissect the mechanism of gene regulation, we sought to determine molecular targets by performing microarray analyses of human umbilical vein endothelial cells (HUVECs) treated with pitavastatin, and KLF4 was determined to be the most highly induced gene. In addition, it was revealed that the atheroprotective genes induced with pitavastatin, such as nitric oxide synthase 3 (NOS3) and thrombomodulin (THBD), were suppressed by KLF4 knockdown. Myocyte enhancer factor-2 (MEF2) family activation is reported to be involved in pitavastatin-dependent KLF4 induction. We focused on MEF2C among the MEF2 family members and identified a novel functional MEF2C binding site 148 kb upstream of the KLF4 gene by chromatin immunoprecipitation along with deep sequencing (ChIP-seq) followed by luciferase assay. By applying whole genome and quantitative chromatin conformation analysis {chromatin interaction analysis with paired end tag sequencing (ChIA-PET), and real time chromosome conformation capture (3C) assay}, we observed that the MEF2C-bound enhancer and transcription start site (TSS) of KLF4 came into closer spatial proximity by pitavastatin treatment. 3D-Fluorescence in situ hybridization (FISH) imaging supported the conformational change in individual cells. Taken together, dynamic chromatin conformation change was shown to mediate pitavastatin-responsive gene induction in endothelial cells.
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影响因子：
12.3
作者：
Li G;Fullwood MJ;Xu H;Mulawadi FH;Velkov S;Vega V;Ariyaratne PN;Mohamed YB;Ooi HS;Tennakoon C;Wei CL;Ruan Y;Sung WK
通讯作者：
Sung WK
影响因子：
11.8
作者：
Arnold, Michael A.;Kim, Yuri;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
20.3
作者：
Dekker, RJ;van Soest, S;Horrevoets, AJG
通讯作者：
Horrevoets, AJG
动脉粥样硬化的炎症。
DOI：
10.1161/atvbaha.108.179705
发表时间：
2012-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Libby P
通讯作者：
Libby P
影响因子：
2.1
作者：
Irizarry, RA;Hobbs, B;Speed, TP
通讯作者：
Speed, TP