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.
Highlights
Angiogenesis plays a critical role in tissue development and homeostasis
Hierarchical cluster analysis of the array results validated the clustering of endothelial cell (EC) lines, which clearly separates from the human dermal fibroblast cell (HDF) and retinal pigment epithelial (RPE) cell lines based on long noncoding RNAs (lncRNAs) and mRNA expression (Figure 1A)
LncRNAs appeared to be a stronger classifier to distinguish between EC and non-ECs than mRNAs. 498 lncRNAs are enriched in all three EC lines for more than two folds compared to the non-ECs
Summary
Aberrant angiogenesis has been associated with numerous diseases, including heart disease, tumor growth, metastasis and age-related macular degeneration (AMD) (Carmeliet, 2003). Usually associated with compensatory angiogenesis and vasculogenesis, has been observed in human dilated cardiomyopathy (DCM) patients (Roura et al, 2007; Gavin et al, 1998; De Boer et al, 2003). Anti-angiogenic therapy, such as antibodies to vascular endothelial growth factors (VEGF), has shown efficacy clinically in treating wet AMD, the leading blinding disease in the elderly (Brown et al, 2006; Rosenfeld et al, 2006; Zampros et al, 2012; Hurwitz et al, 2004). Anti-angiogenic therapies have shown efficacy in certain cancers when used alone or combined with chemotherapy
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