Identification of mechano- and/or 5Aza-sensitive genes in mouse carotid artery endothelium in vivo exposed to disturbed blood flow for 7 days

ABSTRACT: Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. D-flow induced expression of DNMT1 in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two ApoE-/- mouse atherosclerosis models. To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and microarray using endothelial-enriched gDNA and RNA, respectively, from the partially-ligated left carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA) of mice treated with 5Aza or vehicle. Systems biological analyses using RRBS and transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated under d-flow conditions, but rescued by 5Aza treatment. Of those, the two transcription factors HoxA5 and Klf3 contain cAMP- response-elements, and their methylation status could serve as a mechanosensitive master switch in gene expression. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE56143 | GEO | 2014/03/25

SECONDARY ACCESSION(S): PRJNA242550

REPOSITORIES: GEO