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Direct Evidence for Pitavastatin Induced Chromatin Structure Change in the KLF4 Gene in Endothelial Cells
| Content Provider | PubMed Central |
|---|---|
| Author | Maejima, Takashi Inoue, Tsuyoshi Kanki, Yasuharu Takahide, Kohro Li, Guoliang Ohta, Yoshihiro Kimura, Hiroshi Kobayashi, Mika Taguchi, Akashi Tsutsumi, Shuichi Iwanari, Hiroko Yamamoto, Shogo Aruga, Hirofumi Dong, Shoulian Stevens, Junko F. Poh, Huay Mei Yamamoto, Kazuki Kawamura, Takeshi Mimura, Imari Suehiro, Jun-ichi Sugiyama, Akira Kaneki, Kiyomi Shibata, Haruki Yoshinaka, Yasunobu Doi, Takeshi Asanuma, Akimune Tanabe, Sohei Tanaka, Toshiya Minami, Takashi Takao, Hamakubo Sakai, Juro Nozaki, Naohito Hiroyuki, Aburatani Nangaku, Masaomi Ruan, Xiaoan Tanabe, Hideyuki Ruan, Yijun Ihara, Sigeo Endo, Akira Kodama, Tatsuhiko Wada, Youichiro |
| Editor | Aikawa, Masanori |
| Copyright Year | 2014 |
| Abstract | 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. |
| Related Links | http://dx.doi.org/10.1371/journal.pone.0096005 |
| Starting Page | 96005 |
| File Format | |
| ISSN | 19326203 |
| e-ISSN | 19326203 |
| Journal | PLoS ONE |
| Issue Number | 5 |
| Volume Number | 9 |
| Language | English |
| Publisher | Public Library of Science |
| Access Restriction | Open |
| Rights Holder | Public Library of Science |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
