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Series GSE56143 Query DataSets for GSE56143
Status Public on Mar 25, 2014
Title Identification of mechano- and/or 5Aza-sensitive genes in mouse carotid artery endothelium in vivo exposed to disturbed blood flow for 7 days
Organism Mus musculus
Experiment type Expression profiling by array
Summary 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.
Overall design We used 6- to 8-week-old male C57Bl/6 mice (The Jackson Laboratory) according to the approved Institutional Animal Care and Use Committee protocol by Emory University. Mice were subjected to partial carotid ligation surgery under anesthesia. Briefly, 3 of 4 caudal branches of LCA (left external carotid, internal carotid, and occipital artery) were ligated with 6-0 silk suture, although the superior thyroid artery was left intact. Development of low and oscillatory blood flow in the Left Carotid Artery of each mouse was determined by ultrasound measurements. Each sample contained total RNA from 3 pooled RCAs or LCAs. We ran 3 samples of LCA, RCA, AzaLCA, and AzaRCA on 2 microarrays.
Contributor(s) Dunn JP, Jo H, Kim C
Citation(s) 24865430
Submission date Mar 24, 2014
Last update date Jan 16, 2019
Contact name Jessilyn Dunn
Phone 404-727-3223
Organization name Georgia Tech & Emory University
Department Biomedical Engineering
Lab Hanjoong Jp
Street address 1760 Haygood Drive HSRB E197
City Atlanta
State/province GA
ZIP/Postal code 30322
Country USA
Platforms (1)
GPL6887 Illumina MouseWG-6 v2.0 expression beadchip
Samples (12)
GSM1356640 LCA1
GSM1356641 LCA2
GSM1356642 LCA4
BioProject PRJNA242550

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE56143_RAW.tar 15.8 Mb (http)(custom) TAR
GSE56143_non-normalized.txt.gz 3.5 Mb (ftp)(http) TXT
Processed data included within Sample table

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