Flow-Dependent Epigenetic DNA Methylation in Endothelial Gene Expression and Atherosclerosis

• Type of Material: Article
• Authors: Jessilyn Dunn, Georgia Institute of Technology; Salim Thabet, Emory University; Hanjoong Jo, Emory University
• Language: English
• Date: 2015-07-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/ATVBAHA.115.305042
• Title of Journal or Parent Work: Arteriosclerosis, Thrombosis, and Vascular Biology
• ISSN: 1079-5642
• Volume: 35
• Issue: 7
• Start Page: 1562
• End Page: 1569
• Grant/Funding Information: JD is a National Science Foundation pre-doctoral fellow.; This work was supported by funding from National Institutes of Health grants HL119798, HL113451, HL095070 and HL124879 to H. Jo.
• Keywords: epigenetics; DNA methyltransferases; endothelial cells; Life Sciences & Biomedicine; HOMEOBOX GENES; HISTONE MODIFICATION; DISTURBED FLOW; flow; atherosclerosis; CPG-ISLANDS; gene expression; VASCULAR ENDOTHELIUM; Cardiovascular System & Cardiology; KRUPPEL-LIKE FACTORS; LAMINAR SHEAR-STRESS; Peripheral Vascular Disease; NITRIC-OXIDE SYNTHASE; DNA methylation; shear stress; EMBRYONIC LETHALITY; ADHESION MOLECULE-1 EXPRESSION; Hematology; Science & Technology
• Research Categories: Biology, Genetics; Health Sciences, General; Engineering, Biomedical

Abstract

Epigenetic mechanisms that regulate endothelial cell gene expression are now emerging. DNA methylation is the most stable epigenetic mark that confers persisting changes in gene expression. Not only is DNA methylation important in rendering cell identity by regulating cell type-specific gene expression throughout differentiation, but it is becoming clear that DNA methylation also plays a key role in maintaining endothelial cell homeostasis and in vascular disease development. Disturbed blood flow causes atherosclerosis, whereas stable flow protects against it by differentially regulating gene expression in endothelial cells. Recently, we and others have shown that flow-dependent gene expression and atherosclerosis development are regulated by mechanisms dependent on DNA methyltransferases (1 and 3A). Disturbed blood flow upregulates DNA methyltransferase expression both in vitro and in vivo, which leads to genome-wide DNA methylation alterations and global gene expression changes in a DNA methyltransferase-dependent manner. These studies revealed several mechanosensitive genes, such as HoxA5, Klf3, and Klf4, whose promoters were hypermethylated by disturbed blood flow, but rescued by DNA methyltransferases inhibitors such as 5Aza-2-deoxycytidine. These findings provide new insight into the mechanism by which flow controls epigenomic DNA methylation patterns, which in turn alters endothelial gene expression, regulates vascular biology, and modulates atherosclerosis development.