Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells.
Nicholas T HoganMichael B WhalenLindsey K StolzeNizar K HadeliMichael T LamJames R SpringsteadChristopher K GlassCasey E RomanoskiPublished in: eLife (2017)
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.
Keyphrases
- transcription factor
- endothelial cells
- dna binding
- genome wide
- gene expression
- genome wide identification
- high glucose
- cardiovascular disease
- oxidative stress
- dna methylation
- vascular endothelial growth factor
- aortic valve
- blood pressure
- public health
- signaling pathway
- heart failure
- type diabetes
- induced pluripotent stem cells
- cell proliferation
- coronary artery disease
- cardiovascular risk factors
- pulmonary arterial hypertension
- nuclear factor
- anti inflammatory
- arterial hypertension