Epigenetic mechanism in regulation of endothelial function by disturbed flow: Induction of DNA hypermethylation by DNMT1

Jing Zhou, Yi Shuan Li, Kuei Chun Wang, Shu Chien

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

There is increasing evidence that epigenetic mechanisms such as changes in DNA methylation and histone modification play an important role in regulating cellular functions in physiological and pathophysiological states. We investigated the effects of hemodynamic force disturbance, one of the risk factors for atherogenesis, on DNA methylation in HUVECs and rat carotid arteries. Our results demonstrated that athero-prone oscillatory shear flow (OS) without a clear direction induces DNA hypermethylation in comparison to the athero-protective pulsatile shear flow (PS) with a definite direction. Furthermore, OS increases the expression and nuclear translocation of DNA methyltransferase 1 (DNMT1), which is a major maintenance DNA methyltransferase that adds methyl groups to hemi-methylated DNA to repress gene expression. Pharmacological inhibition of DNMT1 by 5-Aza-2′-deoxycytidine abolished the OS-induced DNA hypermethylation. In vivo experiments also showed increases of DNMT1 expression and DNA methylation in the partially-ligated rat carotid arteries where the shear flow is disturbed. These in vitro and in vivo findings have provided novel evidence of the differential regulation of DNA methylation by different hemodynamic forces acting on vascular endothelium and identified DNMT1 as a key protein that governs the epigenetic changes in response to the pathophysiological stimuli due to disturbed flow.

Original languageEnglish (US)
Pages (from-to)218-224
Number of pages7
JournalCellular and Molecular Bioengineering
Volume7
Issue number2
DOIs
StatePublished - Jun 2014
Externally publishedYes

Keywords

  • DNA methylation
  • DNMT1
  • Endothelial cells
  • Oscillatory shear flow

ASJC Scopus subject areas

  • Modeling and Simulation
  • Biochemistry, Genetics and Molecular Biology(all)

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