Transcriptional networks specifying homeostatic and 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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-06-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/22536 |
| _version_ | 1828380983895785472 |
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| author | Nicholas T Hogan Michael B Whalen Lindsey K Stolze Nizar K Hadeli Michael T Lam James R Springstead Christopher K Glass Casey E Romanoski |
| author_facet | Nicholas T Hogan Michael B Whalen Lindsey K Stolze Nizar K Hadeli Michael T Lam James R Springstead Christopher K Glass Casey E Romanoski |
| author_sort | Nicholas T Hogan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T04:06:44Z |
| format | Article |
| id | doaj.art-25b57f160a724bd897fd2d963a30394d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:06:44Z |
| publishDate | 2017-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-25b57f160a724bd897fd2d963a30394d2022-12-22T02:02:49ZengeLife Sciences Publications LtdeLife2050-084X2017-06-01610.7554/eLife.22536Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cellsNicholas T Hogan0Michael B Whalen1Lindsey K Stolze2Nizar K Hadeli3Michael T Lam4James R Springstead5Christopher K Glass6https://orcid.org/0000-0003-4344-3592Casey E Romanoski7https://orcid.org/0000-0002-0149-225XDepartment of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United StatesDepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, United StatesDepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, United StatesDepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, United StatesDepartment of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United StatesDepartment of Chemical and Paper Engineering, University of Western Michigan, Kalamazoo, United StatesDepartment of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United StatesDepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, United StatesEndothelial 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.https://elifesciences.org/articles/22536endothelial cellenhancersinflammationcardiovascular diseaseatherosclerosis |
| spellingShingle | Nicholas T Hogan Michael B Whalen Lindsey K Stolze Nizar K Hadeli Michael T Lam James R Springstead Christopher K Glass Casey E Romanoski Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells eLife endothelial cell enhancers inflammation cardiovascular disease atherosclerosis |
| title | Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells |
| title_full | Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells |
| title_fullStr | Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells |
| title_full_unstemmed | Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells |
| title_short | Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells |
| title_sort | transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells |
| topic | endothelial cell enhancers inflammation cardiovascular disease atherosclerosis |
| url | https://elifesciences.org/articles/22536 |
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