Abstract
The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 because of defective yolk sac and placental vascular development. Analysis of global gene expression revealed Frataxin (Fxn), the gene mutated in Friedreich's ataxia (FRDA), as the most strongly down-regulated gene in Ctcf-deficient placental endothelial cells. Moreover, in vitro reporter assays showed that Ctcf activates the Fxn promoter in endothelial cells. ROS are known to accumulate in the endothelium of FRDA patients. Importantly, Ctcf deficiency induced ROS-mediated DNA damage in endothelial cells in vitro, and in placental endothelium in vivo Taken together, our findings indicate that Ctcf promotes vascular development and limits oxidative stress in endothelial cells. These results reveal a function for Ctcf in vascular development, and suggest a potential mechanism for endothelial dysfunction in FRDA.
Highlights
The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood
Data shown are CTCF normalized to GAPDH Ϯ S.E., of three biological replicates. *, p Ͻ 0.05 compared with negative control
F, expression of FXN mRNA in human umbilical vein endothelial cells (HUVECs) transfected with negative control, anti-CTCF, or anti-FXN siRNAs
Summary
The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells. Our findings indicate that Ctcf promotes vascular development and limits oxidative stress in endothelial cells. Transcriptional misregulation in endothelial cells in embryonic and extra embryonic vasculanitric-oxide synthase; BAEC, bovine aortic endothelial cell; HUVEC, human umbilical vein endothelial cells; 8-OHG, 8-hydroxyguanosine; 4HNA, 4-hydroxynonenal; PFA, paraformaldehyde; qPCR, quantitative PCR In FRDA patients’ cells and mouse models, histones located near the expanded GAA repeats are occupied with the repressive mark histone H3 lysine 9 trimethylation (H3K9me3), and have reduced levels of acetylated core histones, which mark transcriptionally active genes (34 –36) These modifications might interfere with the activity of transcriptional regulators controlling FXN expression. Whether CTCF controls FXN gene expression in endothelial cells, and regulates vascular development is unknown
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