TY  - JOUR
A1  - Fouani, Youssef
A1  - Kirchhof, Luisa
A1  - Stanicek, Laura
A1  - Luxán, Guillermo
A1  - Heumüller, Andreas
A1  - Knau, Andrea
A1  - Fischer, Ariane
A1  - Devraj, Kavi
A1  - John, David
A1  - Neumann, Philipp
A1  - Bindereif, Albrecht
A1  - Boon, Reinier
A1  - Liebner, Stefan
A1  - Wittig, Ilka
A1  - Mogler, Carolin
A1  - Karimova, Madina
A1  - Dimmeler, Stefanie
A1  - Jaé, Nicolas Christopher
T1  - The splicing-regulatory lncRNA NTRAS sustains vascular integrity
T2  - EMBO reports
N2  - 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.
KW  - alternative splicing
KW  - long non-coding RNA
KW  - tight junctions
KW  - vascular integrity
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/79181
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-791819
SN  - 1469-3178
N1  - 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.
N1  - RNA deep sequencing data were deposited at the ArrayExpress database under the accession number E-MTAB-11311 (http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-11311/). The proteomics data are uploaded to the ProteomeXchange Consortium and can be accessed via the accession number PXD030620 (https://www.ebi.ac.uk/pride/archive/projects/PXD030620).
VL  - 23
IS  - 6, art. e54157
SP  - 1
EP  - 13
PB  - EMBO Press ; Wiley
CY  - Heidelberg ; Hoboken, NJ [u.a.]
ER  -