Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells.
Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells.
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DOI：
10.1083/jcb.202211125
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发表时间：
2024-03-04
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--
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机械力在血液流动中的作用对血管健康和动脉粥样硬化等疾病的发展至关重要。这项研究使用多组学方法来阐明不同的流动模式如何影响内皮细胞的基因调控，准确地定位参与机械转导的关键超级增强子。血管动态平衡和病理生理学受到血流动力学产生的机械力的严格调控。血管疾病，如动脉粥样硬化性疾病，主要发生在弯曲处和分叉处，紊乱的血流激活内皮细胞，而血管直段的单向血流促进内皮健康。对内皮转录组、3D表观基因组和人类遗传学的综合分析系统地鉴定了血管内皮细胞中SNP富含的胞浆受到明确定义的动脉粥样硬化倾向扰乱流或动脉粥样硬化保护性单向流的影响。我们的结果描述了内皮细胞典型和超级增强剂的特征，并强调了血流敏感型内皮超级增强剂的关键调节作用。CRISPR干扰和激活验证了先前未知的单向流动诱导的超级增强子的功能，该超级增强子上调抗氧化基因NQO1、CYB5B和WWP2，以及内皮细胞中干扰的流动诱导的超级增强子，驱动血管内皮细胞中的血栓前基因EDN1和HIVEP。我们利用多组学的结果确定了与动脉粥样硬化相关的血流敏感型内皮表观基因组的顺式调控结构，并强调了超级增强子在机械转导机制中的调节作用。
The role of mechanical forces in blood flow is pivotal in vascular health and the development of diseases like atherosclerosis. This study employs multiomics approaches to elucidate how various flow patterns influence gene regulation in endothelial cells, pinpointing critical super-enhancers involved in mechanotransduction. 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.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
20.3
作者：
Bruzelius, Maria;Iglesias, Maria Jesus;Odeberg, Jacob
通讯作者：
Odeberg, Jacob
影响因子：
4.8
作者：
Chen, XL;Varner, SE;Kunsch, C
通讯作者：
Kunsch, C
影响因子：
20.1
作者：
Dai, Guohao;Vaughn, Saran;Gimbrone, Michael A., Jr.
通讯作者：
Gimbrone, Michael A., Jr.
影响因子：
5.8
作者：
Fang, Yun;Wu, David;Birukov, Konstantin G.
通讯作者：
Birukov, Konstantin G.