期刊
CARDIOVASCULAR RESEARCH
卷 115, 期 10, 页码 1487-1499出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvz027
关键词
Endothelial cells; Shear stress; Regulatory elements; Atherosclerosis; H3K27ac ChIP-Seq; RNA-Seq
资金
- Graduate School of the Cells-in-Motion Cluster of Excellence [EXC 1003 - CiM]
- Westfalische Wilhelms University of Munster
- International Max Planck Research School - Molecular Biomedicine, Munster
- German Research Council (DFG)
- Federal Ministry of Education and Research (BMBF) [SCHN 43076-2, DFG INST 2105/241, 03ZZ0906E, BMBF 03ZZ0902D, SI-1374/4-2, SI-1374/5-1, SI-1374/6-1]
- Excellence Cluster Cells-in-Motion (CiM) flexible fund [FF-2014-15]
Aims Oscillatory shear stress (OSS) is an atheroprone haemodynamic force that occurs in areas of vessel irregularities and is implicated in the pathogenesis of atherosclerosis. Changes in signalling and transcriptional programme in response to OSS have been vigorously studied; however, the underlying changes in the chromatin landscape controlling transcription remain to be elucidated. Here, we investigated the changes in the regulatory element (RE) landscape of endothelial cells under atheroprone OSS conditions in an in vitro model. Methods and results Analyses of H3K27ac chromatin immunoprecipitation-Seq enrichment and RNA-Seq in primary human umbilical vein endothelial cells 6 h after onset of OSS identified 2806 differential responsive REs and 33 differentially expressed genes compared with control cells kept under static conditions. Furthermore, gene ontology analyses of putative RE-associated genes uncovered enrichment of WNT/HIPPO pathway and cytoskeleton reorganization signatures. Transcription factor (TF) binding motif analysis within RE sequences identified over-representation of ETS, Zinc finger, and activator protein 1 TF families that regulate cell cycle, proliferation, and apoptosis, implicating them in the development of atherosclerosis. Importantly, we confirmed the activation of EGR1 as well as the YAP/TAZ complex early (6 h) after onset of OSS in both cultured human vein and artery endothelial cells and, by undertaking luciferase assays, functionally verified their role in RE activation in response to OSS. Conclusions Based on the identification and verification of specific responsive REs early upon OSS exposure, we propose an expanded mechanism of how OSS might contribute to the development of atherosclerosis.
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