Chromatin modification and the endothelial-specific activation of the E-selectin gene

E- selectin plays a role in the binding and extravasation of leukocytes from the bloodstream. The E- selectin gene is rapidly and transiently expressed by endothelial cells activated by inflammatory stimuli. Despite the identification of factors critical for cytokine- induced activation of the E- selectin promoter, little is known about the mechanisms that restrict the gene expression to endothelial cells. We used in vivo approaches to characterize the E- selectin promoter in primary cultures of human umbilical vein endothelial cells and umbilical artery smooth muscle cells. In endothelial cells specifically, nucleosomes are remodeled after tumor necrosis factor ( TNF) alpha induction. Chromatin immunoprecipitation analysis demonstrated the binding of the p65 ( RelA) component of nuclear factor- kappa B ( NF- kappa B) to the endogenous E- selectin promoter after TNF alpha stimulation along with I kappa B kinase alpha. Multiple coactivators-1including p300, steroid receptor coactivator- 1, and p300/ cAMP- response element- binding protein ( CREB)- binding protein ( CBP)associated factor localize differentially to the E- selectin promoter. Additionally, TNF alpha induced localized histone hyperacetylation, phosphorylation, and methylation in the E- selectin gene specifically in endothelial cells. Postinduction repression of E- selectin expression is associated with recruitment of multiple deacetylases. Collectively, these studies suggest a model for the selective induction of the E- selectin gene in which the core promoter chromatin architecture is specifically modified in endothelial cells.