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

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    Research article (3.182Mb)
    Date
    2014
    Author
    Dunn, Jessilyn
    Qiu, Haiwei
    Kim, Soyeon
    Jjingo, Daudi
    Hoffman, Ryan
    Kim, Chan Woo
    Jang, Inhwan
    Son, Dong Ju
    Kim, Daniel
    Pan, Chenyi
    Fan, Yuhong
    Jordan, I. King
    Jo, Hanjoong
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    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 hyper-methylation 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.
    Use this URI to cite this item:
    https://hdl.handle.net/20.500.11951/631
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