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

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dc.contributor.authorDunn, Jessilyn
dc.contributor.authorQiu, Haiwei
dc.contributor.authorKim, Soyeon
dc.contributor.authorJjingo, Daudi
dc.contributor.authorHoffman, Ryan
dc.contributor.authorKim, Chan Woo
dc.contributor.authorJang, Inhwan
dc.contributor.authorSon, Dong Ju
dc.contributor.authorKim, Daniel
dc.contributor.authorPan, Chenyi
dc.contributor.authorFan, Yuhong
dc.contributor.authorJordan, I. King
dc.contributor.authorJo, Hanjoong
dc.date.accessioned2018-12-17T13:18:58Z
dc.date.accessioned2021-12-21T08:58:54Z
dc.date.available2018-12-17T13:18:58Z
dc.date.available2021-12-21T08:58:54Z
dc.date.issued2014
dc.description.abstractIn 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.en_US
dc.identifier.citationJ Clin Invest. 2014;124(7):3187-3199. https://doi.org/10.1172/JCI74792.en_US
dc.identifier.issn1558-8238
dc.identifier.urihttps://hdl.handle.net/20.500.11951/631
dc.language.isoenen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.subjectEpigenetic DNA methylation and endothelial gene expressionen_US
dc.subjectEpigenetic DNA methylation and atherosclerosisen_US
dc.subjectAtherosclerosisen_US
dc.subjectAtherosclerosis, d-flow epigenomic DNA methylationen_US
dc.subjectFlow-dependent DNA methylation and atherosclerosisen_US
dc.subjectDNA methyltransferasesen_US
dc.subjectDisturbed blood flow (d-flow) and atherosclerosisen_US
dc.titleFlow-Dependent Epigenetic DNA Methylation Regulates Endothelial Gene Expression and Atherosclerosisen_US
dc.typeArticleen_US
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