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The splicing‐regulatory lncRNA NTRAS sustains vascular integrity
Author(s) -
Fouani Youssef,
Kirchhof Luisa,
Stanicek Laura,
Luxán Guillermo,
Heumüller Andreas W,
Knau Andrea,
Fischer Ariane,
Devraj Kavi,
John David,
Neumann Philipp,
Bindereif Albrecht,
Boon Reinier A,
Liebner Stefan,
Wittig Ilka,
Mogler Carolin,
Karimova Madina,
Dimmeler Stefanie,
Jaé Nicolas
Publication year - 2022
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202154157
Subject(s) - german , library science , conceptualization , art history , philosophy , art , computer science , artificial intelligence , linguistics
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.