1. Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells.
- Author
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Hogan NT, Whalen MB, Stolze LK, Hadeli NK, Lam MT, Springstead JR, Glass CK, and Romanoski CE
- Subjects
- Cells, Cultured, Humans, Polymorphism, Single Nucleotide, Regulatory Elements, Transcriptional, Endothelial Cells physiology, Gene Regulatory Networks
- 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.
- Published
- 2017
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