Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells
Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells
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DOI：
10.7554/elife.22536
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发表时间：
2017-06-06
期刊：
影响因子：
7.7
通讯作者：
Romanoski, Casey E.
中科院分区：
文献类型：
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作者：
Hogan, Nicholas T.;Whalen, Michael B.;Romanoski, Casey E.
内皮细胞（ECs）是血管内稳态和炎症的关键决定因素，但确定其特性和功能状态的转录机制仍知之甚少。在此，我们报告了在基础和激活条件下对原代人主动脉内皮细胞（HAECs）调控区域的全基因组评估，从而能够推断出指导内稳态和促炎程序的转录因子网络。我们证明，检测到的增强子中有43%是内皮细胞特异性的，并且包含与心血管疾病和高血压相关的单核苷酸多态性（SNP）。我们提供的证据表明，AP1、ETS和GATA转录因子通过共同结合与内皮细胞特异性基因相关的增强子，在人主动脉内皮细胞转录中起关键作用。我们进一步证明，人主动脉内皮细胞暴露于氧化磷脂或促炎细胞因子会导致增强子区域发生信号特异性改变，并与CEBPD、IRF1和NFκB的协同结合相关。总之，这些发现确定了有助于内皮细胞特性及其对促炎刺激的特异性反应的顺式调控元件和相应的反式作用因子。
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 NFxB. 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.