Transcriptional networks specifying homeostatic and pro-inflammatory programs of gene expression in human aortic endothelial cells

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 of gene expression. We demonstrate that 43% of detected enhancers are specific to ECs and contain SNPs associated to coronary artery disease (CAD) and hypertension. We provide evidence that AP1, ETS, and GATA transcription factors play key roles in establishing HAEC identity by co-binding at many 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 that are associated with coordinated binding of CEBPD, IRF1 and NF?B. Collectively, these findings identify cis-regulatory elements and corresponding trans-acting factors that contribute to endothelial cell identity and their specific responses to pro-inflammatory stimuli.

内皮细胞（Endothelial cells, ECs）是血管稳态与炎症反应的关键调控因素，但界定其细胞身份与功能状态的转录调控机制目前仍知之甚少。本研究对原代人主动脉内皮细胞（Primary human aortic endothelial cells, HAECs）在基础状态与激活状态下的全基因组调控图谱开展了系统性分析，借此推演调控稳态与促炎基因表达程序的转录因子网络。我们证实，本次检测到的增强子中有43%为内皮细胞特异性增强子，且携带有与冠状动脉疾病（Coronary artery disease, CAD）及高血压相关的单核苷酸多态性（Single Nucleotide Polymorphism, SNPs）位点。研究证据表明，AP1、ETS与GATA转录因子可通过在内皮细胞特异性基因相关的大量增强子区域共同结合，在确立原代人主动脉内皮细胞的细胞身份过程中发挥核心作用。我们进一步发现，将原代人主动脉内皮细胞暴露于氧化磷脂或促炎细胞因子后，会引发信号特异性的增强子图谱改变，这类改变与CEBPD、IRF1及核因子κB（NF-κB）的协同结合密切相关。综上，本研究明确了参与调控内皮细胞身份及其对促炎刺激产生特异性应答的顺式调控元件与相应反式作用因子。