NTRAS hnRNPL RNA sequencing in HUVECs

In the current project with aim to unequivocally characterize a novel splicing-regulatory network that proves to be a central mediator of endothelial barrier function and vascular integrity. At the core of this network is the endothelial enriched lncRNA NTRAS (annotated as RP11-354k1.1) is shown to control alternative splicing decisions in HUVECs through interplaying with splicing factor hnRNPL. Specifically, in the project we show that NTRAS sequesters the splicing factor hnRNPL through a CA dinucleotide motif, to enhance TJP1 exon 20 usage, thereby TJP1a+ isoform. In turn disrupting TJP1a+ isoform expression impaired endothelial barrier function. Collectively, this splicing-regulatory network might prove fundamental in unlocking new interventions strategic to prevent or reverse vascular leakage.

本研究旨在明确解析一个全新的剪接调控网络——该网络被证实为内皮屏障功能与血管完整性的核心介导因子。该网络的核心成分为内皮细胞富集的长链非编码RNA（long non-coding RNA, lncRNA）NTRAS（注释编号为RP11-354k1.1），研究证实其可通过与剪接因子异质性细胞核核糖核蛋白L（heterogeneous nuclear ribonucleoprotein L, hnRNPL）相互作用，调控人脐静脉内皮细胞（Human Umbilical Vein Endothelial Cells, HUVEC）中的可变剪接事件。具体而言，本研究发现NTRAS可通过CA二核苷酸基序隔离剪接因子hnRNPL，以增强紧密连接蛋白1（Tight Junction Protein 1, TJP1）第20外显子的剪接包含率，进而促进TJP1a+剪接亚型的生成。反之，干扰TJP1a+亚型的表达会损伤内皮屏障功能。综上，该剪接调控网络有望成为开发预防或逆转血管渗漏新型干预策略的关键基础。