title: Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis.
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.
authors.forename: Jessilyn
authors.initials: J
authors.lastname: Dunn
authors.forename: Haiwei
authors.initials: H
authors.lastname: Qiu
authors.forename: Soyeon
authors.initials: S
authors.lastname: Kim
authors.forename: Daudi
authors.initials: D
authors.lastname: Jjingo
authors.forename: Ryan
authors.initials: R
authors.lastname: Hoffman
authors.forename: Chan Woo
authors.initials: CW
authors.lastname: Kim
authors.forename: Inhwan
authors.initials: I
authors.lastname: Jang
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.forename: Chenyi
authors.initials: C
authors.lastname: Pan
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Fan
authors.forename: I King
authors.initials: IK
authors.lastname: Jordan
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D014157:Transcription Factors
chemical_list: D001057:Apolipoproteins E; D018398:Homeodomain Proteins; C059637:Hoxa5 protein, mouse; C529780:Klf3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D001374:Azacitidine