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J Biol Chem. 2018 Jun 1;293(22):8449-8461. doi: 10.1074/jbc.M117.814699. Epub 2018 Apr 2.

The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells.

Author information

1
From the Translational Medicine Research Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
2
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
3
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada.
4
Department of Cell Biology and Genetics, Erasmus Medical Center, Rotterdam 3015 CN, The Netherlands.
5
Genetics and Genome Biology Research Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
6
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and.
7
Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Ontario M5S 3H2, Canada.
8
From the Translational Medicine Research Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada, paul.delgadoolguin@sickkids.ca.

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.

KEYWORDS:

CTCF; Friedreich's ataxia; development; embryo; endothelial cell; frataxin; gene expression; gene regulation; oxidative stress; placenta; reactive oxygen species (ROS); vascular; vascular biology

PMID:
29610276
PMCID:
PMC5986204
DOI:
10.1074/jbc.M117.814699
[Indexed for MEDLINE]
Free PMC Article

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