Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells

Jin Li, Jiayu Zhu, Olivia Gray, Débora R. Sobreira, David Wu, Ru Ting Huang, Bernadette Miao, Noboru J. Sakabe, Matthew D. Krause, Minna U. Kaikkonen, Casey E. Romanoski, Marcelo A. Nobrega, Yun Fang

Research output: Contribution to journalArticlepeer-review

Abstract

Vascular homeostasis and pathophysiology are tightly regulated by mechanical forces generated by hemodynamics. Vascular disorders such as atherosclerotic diseases largely occur at curvatures and bifurcations where disturbed blood flow activates endothelial cells while unidirectional flow at the straight part of vessels promotes endothelial health. Integrated analysis of the endothelial transcriptome, the 3D epigenome, and human genetics systematically identified the SNP-enriched cistrome in vascular endothelium subjected to well-defined atherosclerosis-prone disturbed flow or atherosclerosis-protective unidirectional flow. Our results characterized the endothelial typical- and super-enhancers and underscored the critical regulatory role of flow-sensitive endothelial super-enhancers. CRISPR interference and activation validated the function of a previously unrecognized unidirectional flow-induced super-enhancer that upregulates antioxidant genes NQO1, CYB5B, and WWP2, and a disturbed flow-induced super-enhancer in endothelium which drives prothrombotic genes EDN1 and HIVEP in vascular endothelium. Our results employing multiomics identify the cis-regulatory architecture of the flow-sensitive endothelial epigenome related to atherosclerosis and highlight the regulatory role of super-enhancers in mechanotransduction mechanisms.

Original languageEnglish (US)
JournalThe Journal of cell biology
Volume223
Issue number3
DOIs
StatePublished - Mar 4 2024
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

Fingerprint

Dive into the research topics of 'Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells'. Together they form a unique fingerprint.

Cite this