Dataset Information

LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus.

ABSTRACT: In an effort to identify human endothelial cell (EC)-enriched lncRNAs,~500 lncRNAs were shown to be highly restricted in primary human ECs. Among them, lncEGFL7OS, located in the opposite strand of the EGFL7/miR-126 gene, is regulated by ETS factors through a bidirectional promoter in ECs. It is enriched in highly vascularized human tissues, and upregulated in the hearts of dilated cardiomyopathy patients. LncEGFL7OS silencing impairs angiogenesis as shown by EC/fibroblast co-culture, in vitro/in vivo and ex vivo human choroid sprouting angiogenesis assays, while lncEGFL7OS overexpression has the opposite function. Mechanistically, lncEGFL7OS is required for MAPK and AKT pathway activation by regulating EGFL7/miR-126 expression. MAX protein was identified as a lncEGFL7OS-interacting protein that functions to regulate histone acetylation in the EGFL7/miR-126 promoter/enhancer. CRISPR-mediated targeting of EGLF7/miR-126/lncEGFL7OS locus inhibits angiogenesis, inciting therapeutic potential of targeting this locus. Our study establishes lncEGFL7OS as a human/primate-specific EC-restricted lncRNA critical for human angiogenesis.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC6370342 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus.

Zhou Qinbo Q Yu Bo B Anderson Chastain C Huang Zhan-Peng ZP Hanus Jakub J Zhang Wensheng W Han Yu Y Bhattacharjee Partha S PS Srinivasan Sathish S Zhang Kun K Wang Da-Zhi DZ Wang Shusheng S

eLife 20190211

In an effort to identify human endothelial cell (EC)-enriched lncRNAs,~500 lncRNAs were shown to be highly restricted in primary human ECs. Among them, <i>lncEGFL7OS</i>, located in the opposite strand of the <i>EGFL7/miR-126</i> gene, is regulated by ETS factors through a bidirectional promoter in ECs. It is enriched in highly vascularized human tissues, and upregulated in the hearts of dilated cardiomyopathy patients. LncEGFL7OS silencing impairs angiogenesis as shown by EC/fibroblast co-cultu ...[more]

PMID: 30741632

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Project description:BackgroundThe abnormal expression of long noncoding RNA (LncRNA) HOTAIR has been associated with synovial angiogenesis in rheumatoid arthritis (RA). The aim of this study is to investigate whether LncRNA HOTAIR plays a role in synovial angiogenesis in RA by regulating the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway through the miR-126-3p/PIK3R2 axis.MethodsIn this study, we conducted in vitro experiments by designing overexpression plasmids and small interfering RNAs targeting LncRNA HOTAIR and then transfected them into rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). We then co-cultured the RA-FLS with human umbilical vein endothelial cells (HUVEC) to establish a RA-FLS-induced HUVEC model. We investigated the effects of LncRNA HOTAIR on the proliferation, migration, lumen forming ability of HUVEC, as well as the expression of synovial endothelial cell markers, angiogenic factors, and the PI3K/AKT pathway. To validate the interactions between LncRNA HOTAIR, miR-126-3p, and PIK3R2, we used bioinformatics and luciferase reporter experiments. We also employed real-time fluorescence quantitative, Western blotanalysis, and immunofluorescence techniques to analyze the target genes and proteins.ResultsThe expression of LncRNA HOTAIR was upregulated in HUVEC induced by RA-FLS. The overexpression of LncRNA HOTAIR significantly increased the expression of vascular endothelial growth factor, basic fibroblast growth factor, CD34, and CD105 in HUVEC, promoting their proliferation, migration, and lumen formation. At the same time, the overexpression of LncRNA HOTAIR inhibited the expression of miR-126-3p, promoted the expression of PIK3R2, activated the PI3K/AKT pathway, and promoted the expression of PI3K, AKT and phosphorylated-AKT, while the silence of LncRNA HOTAIR reversed these expressions. Bioinformatics and double luciferase reporter gene experiments confirmed the targeting relationship among LncRNA HOTAIR, miR-126-3p, and PIK3R2. Finally, the rescue experiments showed that PI3K agonists could reverse the inhibitory effect of silent LncRNA HOTAIR on HUVEC.ConclusionLncRNA HOTAIR has the potential to activate the PI3K/AKT pathway, likely through the regulatory axis involving miR-126-3p/PIK3R2, consequently contributing to synovial angiogenesis in RA.

Dataset Information

LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus.

Publications

LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus.

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