Format

Send to

Choose Destination
See comment in PubMed Commons below
PLoS One. 2014 May 5;9(5):e96005. doi: 10.1371/journal.pone.0096005. eCollection 2014.

Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells.

Author information

1
Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan; Tokyo New Drug Research Laboratories, Kowa Company Ltd., Higashimurayama, Tokyo, Japan.
2
Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan; Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan.
3
Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan.
4
Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan; Department of Translational Research for Healthcare and Clinical Science, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
5
Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, United States of America.
6
Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
7
Thermo Fisher Scientific, South San Francisco, California, United States of America.
8
Tokyo New Drug Research Laboratories, Kowa Company Ltd., Higashimurayama, Tokyo, Japan.
9
Mab Institute Inc., North Advancement Center for Science & Technology, Sapporo, Hokkaido, Japan.
10
Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan.
11
Genome Institute of Singapore, Singapore, Singapore.
12
Department of Evolutionary Studies of Biosystems, School of Advanced Sciences, The Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa, Japan.
13
Biopharm Research Laboratories, Inc., Koganei, Tokyo, Japan.
14
Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan; Radioisotope Center, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Erratum in

  • PLoS One. 2014;9(6):e99749.

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.

PMID:
24797675
PMCID:
PMC4010393
DOI:
10.1371/journal.pone.0096005
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Support Center