Transcriptional Profiling of Hypoxia-Regulated Non-coding RNAs in Human Primary Endothelial Cells

Abstract

Hypoxia occurs in human atherosclerotic lesions and has multiple adverse effects on endothelial cell metabolism. Recently, key roles of long non-coding RNAs (lncRNAs) in the development of atherosclerosis have begun to emerge. In this study, we investigate the lncRNA profiles of human umbilical vein endothelial cells subjected to hypoxia using global run-on sequencing (GRO-Seq). We demonstrate that hypoxia regulates the nascent transcription of ~1800 lncRNAs. Interestingly, we uncover evidence that promoter-associated lncRNAs are more likely to be induced by hypoxia compared to enhancer-associated lncRNAs, which exhibit an equal distribution of up- and downregulated transcripts. We also demonstrate that hypoxia leads to a significant induction in the activity of super-enhancers next to transcription factors and other genes implicated in angiogenesis, cell survival and adhesion, whereas super-enhancers near several negative regulators of angiogenesis were repressed. Despite the majority of lncRNAs exhibiting low detection in RNA-Seq, a subset of lncRNAs were expressed at comparable levels to mRNAs. Among these, MALAT1, HYMAI, LOC730101, KIAA1656, and LOC339803 were found differentially expressed in human atherosclerotic lesions, compared to normal vascular tissue, and may thus serve as potential biomarkers for lesion hypoxia.

MALAT1/miR-15b-5p/MAPK1 mediates endothelial progenitor cells autophagy and affects coronary atherosclerotic heart disease via mTOR signaling pathway

“…Among the differentially expressed genes and lncRNAs in CAD tissues which from microarray analysis, MAPK1 and MALAT1 were chosen for our research because they were found to be related to CAD in previous studies [45–47]. Furthermore, MALAT1 may serve as potential biomarkers of atherosclerosis [48, 49]. MAPK pathways were found playing roles in stroke progression [50, 51].…”

The emerging role of super enhancer-derived noncoding RNAs in human cancer

“…This forces the tumor cell to produce ATP through glycolysis and create a lower pH to prevent drug entry 82 . Moreau et al 83 reported that hypoxia can induce the activation of 358 SE regions in tumor cells, and database analysis showed that for 20% of SEs, the closest RefSeq gene was a lncRNA, as exemplified by MALAT1 and LUCAT1. MALAT1 can not only achieve chemoresistance by competitively inhibiting miR-23b-3p or miR-203, but can also bind with EZH2 to regulate CDH1 transcription expression and promote E-cadherin expression and oxaliplatin-induced EMT 84 - 86 .…”

“…Lin et al 70 found that after SE-UCA1 activates the Hippo/YAP1 pathway, proliferation and cell survival are simultaneously promoted in ovarian cancer cells, showing some anti-apoptosis characteristics. In addition, Moreau et al 83 found that hypoxia can regulate SE activity, which in turn, mediates tumor apoptosis, and can also activate the expression of some lncRNAs. However, whether SE regulates apoptosis by regulating the expression of lncRNAs has not been further analyzed.…”

The Regulatory Roles of Non-coding RNAs in Angiogenesis and Neovascularization From an Epigenetic Perspective

“…This group aimed to discover changes in the expression patterns of lncRNAs in HUVEC cells exposed to hypoxia and demonstrated that hypoxia affects the transcription of ~1,800 lncRNAs. Among the most relevant lncRNAs identified were MALAT1, HYMAI, LOC730101, KIAA1656, and LOC339803, which were differentially expressed in human atherosclerotic lesions compared to normal vascular tissue (116).…”