Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension

Armando Reyes-Palomares, Mingxia Gu, Fabian Grubert, Ivan Berest, Silin Sa, Maya Kasowski, Christian Arnold, Mao Shuai, Rohith Srivas, Simon Miao, Dan Li, Michael P. Snyder (), Marlene Rabinovitch () and Judith B. Zaugg ()
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Armando Reyes-Palomares: Structural and Computational Biology Unit
Mingxia Gu: Stanford University School of Medicine
Fabian Grubert: Stanford University School of Medicine
Ivan Berest: Structural and Computational Biology Unit
Silin Sa: Stanford University School of Medicine
Maya Kasowski: Stanford University School of Medicine
Christian Arnold: Structural and Computational Biology Unit
Mao Shuai: Stanford University School of Medicine
Rohith Srivas: Stanford University School of Medicine
Simon Miao: Stanford University School of Medicine
Dan Li: Stanford University School of Medicine
Michael P. Snyder: Stanford University School of Medicine
Marlene Rabinovitch: Stanford University School of Medicine
Judith B. Zaugg: Structural and Computational Biology Unit

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Environmental and epigenetic factors often play an important role in polygenic disorders. However, how such factors affect disease-specific tissues at the molecular level remains to be understood. Here, we address this in pulmonary arterial hypertension (PAH). We obtain pulmonary arterial endothelial cells (PAECs) from lungs of patients and controls (n = 19), and perform chromatin, transcriptomic and interaction profiling. Overall, we observe extensive remodeling at active enhancers in PAH PAECs and identify hundreds of differentially active TFs, yet find very little transcriptomic changes in steady-state. We devise a disease-specific enhancer-gene regulatory network and predict that primed enhancers in PAH PAECs are activated by the differentially active TFs, resulting in an aberrant response to endothelial signals, which could lead to disturbed angiogenesis and endothelial-to-mesenchymal-transition. We validate these predictions for a selection of target genes in PAECs stimulated with TGF-β, VEGF or serotonin. Our study highlights the role of chromatin state and enhancers in disease-relevant cell types of PAH.

Date: 2020
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DOI: 10.1038/s41467-020-15463-x

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