About this item:

146 Views | 252 Downloads

Author Notes:

Address correspondence to: Hanjoong Jo, Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Health Sciences Research Building, E170, Atlanta, Georgia 30322, USA. Phone: 404.712.9654; Fax: 404.727.3330; E-mail: hjo@bme.gatech.edu.

H. Jo thanks the Ada Lee and Pete Correll Professorship and the John and Jan Portman Professorship.

Conflict of interest: The authors have declared that no conflict of interest exists.

Subject:

Research Funding:

This work was supported by funding from NIH grants HL095070, HL114772, and HL113451 to H. Jo.

This work was also supported by the National Heart, Lung, and Blood Institute of the NIH through a Program of Excellence in Nanotechnology award (HHSN268201000043C to H. Jo).

J. Dunn is a National Science Foundation Graduate Research Fellowship recipient.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • MEDICINE, RESEARCH & EXPERIMENTAL
  • E-DEFICIENT MICE
  • SHEAR-STRESS
  • DISTURBED FLOW
  • CPG-ISLANDS
  • VASCULAR ENDOTHELIUM
  • GENOMIC DNA
  • IN-VIVO
  • CELLS
  • LEUKEMIA
  • HOXA5

Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis

Show all authors Show less authors

Tools:

Journal Title:

Journal of Clinical Investigation

Volume:

Volume 124, Number 7

Publisher:

, Pages 3187-3199

Type of Work:

Article | Final Publisher PDF

Abstract:

In atherosclerosis, plaques preferentially develop in arterial regions of disturbed blood flow (d-flow), which alters endothelial gene expression and function. Here, we determined that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase-dependent (DNMT-dependent) manner. Induction of d-flow by partial carotid ligation surgery in a murine model induced DNMT1 in arterial endothelium. In cultured endothelial cells, DNMT1 was enhanced by oscillatory shear stress (OS), and reduction of DNMT with either the inhibitor 5-aza-2′-deoxycytidine (5Aza) or siRNA markedly reduced OS-induced endothelial inflammation. Moreover, administration of 5Aza reduced lesion formation in 2 mouse models of atherosclerosis. Using both reduced representation bisulfite sequencing (RRBS) and microarray, we determined that d-flow in the carotid artery resulted in hypermethylation within the promoters of 11 mechanosensitive genes and that 5Aza treatment restored normal methylation patterns. Of the identified genes, HoxA5 and Klf3 encode transcription factors that contain cAMP response elements, suggesting that the methylation status of these loci could serve as a mechanosensitive master switch in gene expression. Together, our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

Copyright information:

© 2014, American Society for Clinical Investigation

Export to EndNote