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Flow-dependent regulation of genome-wide mRNA and microRNA expression in endothelial cells in vivo.

ABSTRACT: Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), in part, due to alterations in gene expression in the endothelium. While numerous in vitro studies have shown how anti-atherogenic flow and pro-atherogenic flow differently regulate gene expression of cultured endothelial cells, similar in vivo studies have been scarce. Recently, we developed a mouse model of atherosclerosis that rapidly develops robust atherosclerosis by partially ligating the left carotid artery (LCA) branches, while using the contralateral right carotid (RCA) as control. We also developed a novel method to collect endothelial-enriched RNAs from the carotids of these animals, which enabled us to perform genome-wide expression analyses of mRNAs and miRNAs in the arterial endothelium exposed to either d-flow or s-flow. These microarray results were used to identify novel mechanosensitive genes such as DNA methyltransferase-1 and miR-712 that play key roles in atherosclerosis. Here, we report these endothelial mRNA and miRNA expression profiles with in-depth information on experimental procedures along with an example of usage of these data.

SUBMITTER: Kumar S

PROVIDER: S-EPMC4411008 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Flow-dependent regulation of genome-wide mRNA and microRNA expression in endothelial cells in vivo.

Kumar Sandeep S Kim Chan Woo CW Son Dong Ju DJ Ni Chih Wen CW Jo Hanjoong H

Scientific data 20141028

Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), in part, due to alterations in gene expression in the endothelium. While numerous in vitro studies have shown how anti-atherogenic flow and pro-atherogenic flow differently regulate gene expression of cultured endothelial cells, similar in vivo studies have been scarce. Recently, we developed a mouse model of atherosclerosis that rapidly develops robust atherosclerosis by partially ligating the le ...[more]

PMID: 25977794

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Project description:Rationale: Atherosclerosis is a chronic inflammatory and epigenetic disease that is influenced by different patterns of blood flow. However, the epigenetic mechanism whereby atheroprotective flow controls endothelial gene programming remains elusive. Here, we investigated the possibility that flow alters endothelial gene expression through epigenetic mechanisms. Methods: En face staining and western blot were used to detect protein expression. Real-time PCR was used to determine relative gene expression. RNA-sequencing of human umbilical vein endothelial cells treated with siRNA of enhancer of zeste homolog 2 (EZH2) or laminar flow was used for transcriptional profiling. Results: We found that trimethylation of histone 3 lysine 27 (H3K27me3), a repressive epigenetic mark that orchestrates gene repression, was reduced in laminar flow areas of mouse aorta and flow-treated human endothelial cells. The decrease of H3K27me3 paralleled a reduction in the epigenetic "writer"-EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2). Moreover, laminar flow decreased expression of EZH2 via mechanosensitive miR101. Genome-wide transcriptome profiling studies in endothelial cells treated with EZH2 siRNA and flow revealed the upregulation of novel mechanosensitive gene IGFBP5 (insulin-like growth factor-binding protein 5), which is epigenetically silenced by H3K27me3. Functionally, inhibition of H3K27me3 by EZH2 siRNA or GSK126 (a specific EZH2 inhibitor) reduced H3K27me3 levels and monocyte adhesion to endothelial cells. Adenoviral overexpression of IGFBP5 also recapitulated the anti-inflammatory effects of H3K27me3 inhibition. More importantly, we observed EZH2 upregulation, and IGFBP5 downregulation, in advanced atherosclerotic plaques from human patients. Conclusion: Taken together, our findings reveal that atheroprotective flow reduces H3K27me3 as a chromatin-based mechanism to augment the expression of genes that confer an anti-inflammatory response in the endothelium. Our study exemplifies flow-dependent epigenetic regulation of endothelial gene expression, and also suggests that targeting the EZH2/H3K27me3/IGFBP5 pathway may offer novel therapeutics for inflammatory disorders such as atherosclerosis.

Dataset Information

Flow-dependent regulation of genome-wide mRNA and microRNA expression in endothelial cells in vivo.

Publications

Flow-dependent regulation of genome-wide mRNA and microRNA expression in endothelial cells in vivo.

Similar Datasets

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