Jessilyn Dunn1, Haiwei Qiu1, Soyeon Kim1, Daudi Jjingo2, Ryan Hoffman1, Chan Woo Kim1, Inhwan Jang1, Dong Ju Son1, Daniel Kim1, Chenyi Pan2, Yuhong Fan2, I. King Jordan2 and Hanjoong Jo1,3,*
1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University,
2School of Biology, Georgia Institute of Technology, and
3Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia, USA.
*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.
Authorship note: Jessilyn Dunn, Haiwei Qiu, and Soyeon Kim contributed equally to this work.
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.