ZONAB Regulates DNA Methylation, Mitochondrial Function, and Entry into Cell Senescence of Endothelial Cells

Regulation of the endothelial stress response is important for blood vessel homeostasis and angiogenesis, processes disrupted in common vascular diseases and ageing. Here, we discovered that the Y-box factor ZONAB (ZO-1-associated nucleic acid binding protein; YBX3), a gene associated with risk loci for severe vascular disorders, regulates endothelial homeostasis and angiogenesis. By combining cell-based assays with primary endothelial cells and genome-wide expression and methylation measurements, we found that ZONAB depletion results in mitochondrial deregulation, increased reactive oxygen species, and a defective oxidative stress response, which correlates with increased promoter methylation of cell cycle genes. ZONAB depletion triggered cellular senescence via a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway, which was attenuated by PIK3 inhibitors, an antioxidant, or by drugs targeting mitochondrial function or fragmentation. Thus, our results reveal that ZONAB repression in endothelial cells leads to genome-wide changes in gene expression and DNA methylation, regulating endothelial proliferation and inflammation, as well as mitochondrial deregulation to promote cellular senescence. Hence, ZONAB supports endothelial homeostasis and may play a role in vascular health.