Department of Cell and Molecular Biology, Tulane University, New Orleans, United States.
Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States.
Elife. 2019 Feb 11;8:e40470. doi: 10.7554/eLife.40470.
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, , located in the opposite strand of the 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.
为了鉴定人类血管内皮细胞（EC）高丰度的长链非编码 RNA（lncRNA），我们发现约 500 个 lncRNA 在原代人类 EC 中高度受限。其中，位于 基因的反义链上的 lncEGFL7OS，通过 EC 中的双向启动子被 ETS 因子调控。它在富含血管的人类组织中富集，并在扩张型心肌病患者的心脏中上调。lncEGFL7OS 沉默通过 EC/成纤维细胞共培养、体外/体内和离体人脉络丛发芽血管生成测定显示，损害血管生成，而过表达 lncEGFL7OS 则具有相反的功能。从机制上讲，lncEGFL7OS 通过调节 EGFL7/miR-126 的表达，来调控 MAPK 和 AKT 通路的激活。MAX 蛋白被鉴定为 lncEGFL7OS 的互作蛋白，其功能是调节 EGFL7/miR-126 启动子/增强子中的组蛋白乙酰化。CRISPR 介导的 EGLF7/miR-126/lncEGFL7OS 基因座靶向抑制血管生成，激发了针对该基因座的治疗潜力。我们的研究确立了 lncEGFL7OS 作为人类/灵长类动物特异性 EC 限制的 lncRNA，对于人类血管生成至关重要。
