Epigenetic control of tissue-type plasminogen activator synthesis in human endothelial cells
| Autor: | Egbert K. O. Kruithof, Sylvie Dunoyer-Geindre |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Tissue Plasminogen Activator/biosynthesis/genetics
RNA Messenger/genetics/metabolism Physiology Histones/metabolism 030204 cardiovascular system & hematology Epigenesis Genetic/drug effects Histone Deacetylases Epigenesis Genetic Histones 03 medical and health sciences 0302 clinical medicine Physiology (medical) Humans RNA Messenger Epigenetics Promoter Regions Genetic Cells Cultured DNA Primers 030304 developmental biology ddc:616 DNA Primers/genetics 0303 health sciences Base Sequence biology T-plasminogen activator Hepatocytes/metabolism Endothelial Cells DNA Methylation Molecular biology Histone Deacetylase Inhibitors Endothelial Cells/drug effects/metabolism Histone PCAF Acetylation Tissue Plasminogen Activator DNA methylation Hepatocytes biology.protein Histone Deacetylases/metabolism Histone deacetylase Cardiology and Cardiovascular Medicine Plasminogen activator Histone Deacetylase Inhibitors/pharmacology |
| Zdroj: | Cardiovascular Research, Vol. 90, No 3 (2011) pp. 457-63 Cardiovascular research |
| ISSN: | 0008-6363 |
| Popis: | Aims Tissue-type plasminogen activator (t-PA) is produced by endothelial cells (EC) and is responsible for the removal of intravascular fibrin deposits. We investigated whether expression of t-PA by EC is under epigenetic control. Methods and results Methylation analysis of the proximal t-PA promoter revealed a stretch of unmethylated CpG dinucleotides from position −121 to +59, while upstream CpG dinucleotides were all methylated. In contrast, in human primary hepatocytes, which express t-PA at much lower levels than EC, the proximal promoter was partially methylated. Treatment of EC with the non-specific histone deacetylase (HDAC) inhibitors butyrate and trichostatin and with MS275, a specific inhibitor of class I HDAC, resulted in a time- and dose-dependent increase in t-PA expression. Garcinol and anacardic acid, inhibitors of the histone acetyl transferases CBP/p300 and PCAF, reduced basal and HDAC inhibitor-induced t-PA expression, whereas curcumin, an inhibitor of CBP/p300 only, had no effect. We performed chromosome immunoprecipitation analysis of the t-PA promoter using antibodies specific for acetylated histone H3 or H4 and observed an increase in H3 acetylation of 10 ± 3 and 44 ± 14-fold in EC treated with trichostatin or MS275, respectively, and in H4 acetylation of 7.7 ± 1.4 and 16 ± 3-fold, respectively. Conclusion The proximal t-PA promoter is unmethylated in human EC and partially methylated in human primary hepatocytes. Expression of t-PA by EC is repressed by HDACs in a mechanism that involves de-acetylation of histone H3 and H4 |
| Databáze: | OpenAIRE |
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