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

Autor: Maejima, T., Inoue, T., Kanki, Y., Kohro, T., Li, G., Ohta, Y., Kimura, Hiroshi, Kobayashi, M., Taguchi, A., Tsutsumi, S., Iwanari, H., Yamamoto, S., Aruga, H., Dong, S., Stevens, J. F., Poh, H. M., 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.
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Microarrays
Thrombomodulin
lcsh:Medicine
Gene Expression
Nitric Oxide Synthase Type III/biosynthesis/genetics
Vascular Medicine
Epithelium
Chromosome conformation capture
Molecular Cell Biology
Medicine and Health Sciences
lcsh:Science
Regulation of gene expression
Multidisciplinary
Chromatin Assembly and Disassembly/*drug effects
Chromosome Biology
MEF2 Transcription Factors
Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
Quinolines/*pharmacology
Genomics
Animal Models
MEF2 Transcription Factors/genetics/metabolism
Chromatin
Bioassays and Physiological Analysis
Thrombomodulin ＜NLM MeSH Terms＞
Gene Knockdown Techniques
Quinolines
Anatomy
Cellular Types
Transcriptome Analysis
Research Article
Mef2
Chromosome Structure and Function
Drug Research and Development
Nitric Oxide Synthase Type III
Thrombomodulin/biosynthesis/genetics
Cardiology
Kruppel-Like Transcription Factors
Mouse Models
Kruppel-Like Transcription Factors/*biosynthesis/genetics
Biology
Research and Analysis Methods
Response Elements
Chromosomes
Kruppel-Like Factor 4
Model Organisms
Genetics
Human Umbilical Vein Endothelial Cells
Humans
Enhancer
Transcription factor
ChIA-PET
Pharmacology
lcsh:R
Biology and Life Sciences
Endothelial Cells
Computational Biology
Epithelial Cells
Cell Biology
Genome Analysis
Atherosclerosis
Chromatin Assembly and Disassembly
Molecular biology
Biological Tissue
Gene Expression Regulation
Cardiovascular Anatomy
Gene Expression Regulation/*drug effects/genetics
Human Umbilical Vein Endothelial Cells/cytology/*metabolism
lcsh:Q
Chromatin/genetics/*metabolism
Clinical Medicine
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Genome Expression Analysis
Chromatin immunoprecipitation
Zdroj: PLoS ONE
PLoS ONE, Vol 9, Iss 5, p e96005 (2014)
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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