@article{97ba9c9d076747e68847c08d7c5c18ae,
title = "The splicing-regulatory lncRNA NTRAS sustains vascular integrity",
abstract = "Vascular integrity is essential for organ homeostasis to prevent edema formation and infiltration of inflammatory cells. Long non-coding RNAs (lncRNAs) are important regulators of gene expression and often expressed in a cell type-specific manner. By screening for endothelial-enriched lncRNAs, we identified the undescribed lncRNA NTRAS to control endothelial cell functions. Silencing of NTRAS induces endothelial cell dysfunction in vitro and increases vascular permeability and lethality in mice. Biochemical analysis revealed that NTRAS, through its CA-dinucleotide repeat motif, sequesters the splicing regulator hnRNPL to control alternative splicing of tight junction protein 1 (TJP1; also named zona occludens 1, ZO-1) pre-mRNA. Deletion of the hnRNPL binding motif in mice (Ntras∆CA/∆CA) significantly repressed TJP1 exon 20 usage, favoring expression of the TJP1α- isoform, which augments permeability of the endothelial monolayer. Ntras∆CA/∆CA mice further showed reduced retinal vessel growth and increased vascular permeability and myocarditis. In summary, this study demonstrates that NTRAS is an essential gatekeeper of vascular integrity.",
keywords = "alternative splicing, long non-coding RNA, tight junctions, vascular integrity",
author = "Youssef Fouani and Luisa Kirchhof and Laura Stanicek and Guillermo Lux{\'a}n and Heum{\"u}ller, {Andreas W.} and Andrea Knau and Ariane Fischer and Kavi Devraj and David John and Philipp Neumann and Albrecht Bindereif and Boon, {Reinier A.} and Stefan Liebner and Ilka Wittig and Carolin Mogler and Madina Karimova and Stefanie Dimmeler and Nicolas Ja{\'e}",
note = "Funding Information: We thank Aditi Patel for assistance in generating the NtrasΔCA/ΔCA mice, Silke Schreiner for support with the in vitro splicing assays, Marion Muhly-Reinholz for help with microscopy, and Jana Meisterknecht for assistance in sample preparation for mass spectrometry. This study was supported by the ERC (Advanced Grant Angiolnc to S.D.), the DFG (TRR 267 to S.D., N.J., and I.W.; SFB1366 to C.M. and S.D.; FOR2325 to S.L.), the CPI (390649896 to S.L), the EU HORIZON 2020 ITN (BtRAIN 675619 to S.L.), the DZHK (81X2200133 to S.L.), and the State of Hesse with a LOEWE-Grant to the CePTER-Consortium (www.uni-frankfurt.de/67689811; to S.L.). Open Access funding enabled and organized by Projekt DEAL. Funding Information: We thank Aditi Patel for assistance in generating the Ntras mice, Silke Schreiner for support with the splicing assays, Marion Muhly‐Reinholz for help with microscopy, and Jana Meisterknecht for assistance in sample preparation for mass spectrometry. This study was supported by the ERC (Advanced Grant Angiolnc to S.D.), the DFG (TRR 267 to S.D., N.J., and I.W.; SFB1366 to C.M. and S.D.; FOR2325 to S.L.), the CPI (390649896 to S.L), the EU HORIZON 2020 ITN (BtRAIN 675619 to S.L.), the DZHK (81X2200133 to S.L.), and the State of Hesse with a LOEWE‐Grant to the CePTER‐Consortium ( www.uni‐frankfurt.de/67689811 ; to S.L.). Open Access funding enabled and organized by Projekt DEAL. ΔCA/ΔCA in vitro Publisher Copyright: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2022",
month = jun,
day = "7",
doi = "https://doi.org/10.15252/embr.202154157",
language = "English",
volume = "23",
journal = "EMBO reports",
issn = "1469-221X",
publisher = "Wiley-Blackwell",
number = "6",
}