Abstract
Endothelial cells (ECs) are critical determinants of vascular homeostasis and inflammation, but transcriptional mechanisms specifying their identities and functional states remain poorly understood. Here, we report a genome-wide assessment of regulatory landscapes of primary human aortic endothelial cells (HAECs) under basal and activated conditions, enabling inference of transcription factor networks that direct homeostatic and pro-inflammatory programs. We demonstrate that 43% of detected enhancers are EC-specific and contain SNPs associated to cardiovascular disease and hypertension. We provide evidence that AP1, ETS, and GATA transcription factors play key roles in HAEC transcription by co-binding enhancers associated with EC-specific genes. We further demonstrate that exposure of HAECs to oxidized phospholipids or pro-inflammatory cytokines results in signal-specific alterations in enhancer landscapes and associate with coordinated binding of CEBPD, IRF1, and NFκB. Collectively, these findings identify cis-regulatory elements and corresponding trans-acting factors that contribute to EC identity and their specific responses to pro-inflammatory stimuli.
Highlights
Atherosclerosis is an inflammatory disease of large arteries mediated by the accumulation of plaque within the vessel wall
We demonstrate that many enhancers identified in Endothelial cells (ECs) are cell type-specific and several enhancers overlap with SNPs that have been associated to coronary artery disease (CAD) and hypertension
A total of 16,929 high-confidence enhancer-like elements were mapped in human aortic endothelial cells (HAECs) (Figure 1a) using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to identify promoter-distal elements marked by significant levels of histone H3 di-methylation of lysine 4 (H3K4me2) and acetylation of lysine 27 (H3K27ac) that together mark active enhancers (Heintzman et al, 2007; Creyghton et al, 2010; Rada-Iglesias et al, 2011)
Summary
Atherosclerosis is an inflammatory disease of large arteries mediated by the accumulation of plaque within the vessel wall. Through sequelae such as heart attack, stroke, and peripheral vascular disease, it is responsible for an immense burden of morbidity and mortality. The onset of atherosclerosis involves the activation of ECs by pro-inflammatory micro-environmental exposures including hemodynamic turbulence, oxidized-specific epitopes, and inflammatory cytokines (Tabas et al, 2015). These inflammatory stimuli result in the expression of adhesion molecules on the luminal EC surface and rolling, attachment, and migration of leukocytes into the vessel wall. Acute plaque rupture can result in sudden vascular occlusion, leading to heart attack or stroke
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