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Heumüller, A.W.* ; Jones, A. ; Mourao, A. ; Klangwart, M.* ; Shi, C.* ; Wittig, I.* ; Fischer, A.* ; Muhly Reinholz, M.* ; Buchmann, G.K.* ; Dieterich, C.* ; Potente, M.* ; Braun, T.* ; Grote, P.* ; Jaé, N.* ; Sattler, M. ; Dimmeler, S.*

Locus-conserved circular RNA cZNF292 controls endothelial cell flow responses.

Circ. Res. 130, 67-79 (2022)
Postprint DOI PMC
Open Access Hybrid
Background: Circular RNAs (circRNAs) are generated by back-splicing of mostly mRNAs and are gaining increasing attention as a novel class of regulatory RNAs that control various cellular functions. However, their physiological roles and functional conservation in vivo are rarely addressed, given the inherent challenges of their genetic inactivation. Here we aimed to identify locus conserved circRNAs in mice and humans, which can be genetically deleted due to retained intronic elements not contained in the mRNA host gene to eventually address functional conservation. Methods: Mechanistically, we identified the protein syndesmos (SDOS) to specifically interact with cZNF292 in endothelial cells by RNA affinity purification and subsequent mass spectrometry analysis. Silencing of SDOS or its protein binding partner Syndecan-4, or mutation of the SDOS-cZNF292 binding site, prevented laminar flow-induced cytoskeletal reorganisation thereby recapitulating cZfp292 phenotypes. Results: Combining published endothelial RNA sequencing datasets with circRNAs of the circATLAS databank, we identified locus-conserved circRNA retaining intronic elements between mice and humans. CRISPR/Cas9 mediated genetic depletion of the top expressed circRNA cZfp292 resulted in an altered endothelial morphology and aberrant flow alignment in the aorta in vivo. Consistently, depletion of cZNF292 in endothelial cells in vitro abolished laminar flow-induced alterations in cell orientation, paxillin localisation and focal adhesion organisation. Conclusion: Together, our data reveal a hitherto unknown role of cZNF292/cZfp292 in endothelial flow responses, which influences endothelial shape.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cytoskeleton ; Endothelial Cells ; Humans ; Mice ; Rna ; Circular ; Rna ; Non-coding; Cytoplasmic Domain; Syndecan-4; Syndesmos; Identification; Protein
Sprache englisch
Veröffentlichungsjahr 2022
Prepublished im Jahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 0009-7330
e-ISSN 1524-4571
Zeitschrift Circulation Research
Quellenangaben Band: 130, Heft: 1, Seiten: 67-79 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503000-001
Förderungen Foundation Leducq Transatlantic Network
ERC (Consolidator Grant EMERGE)
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
ERC
DOI 10.1161/CIRCRESAHA.121.320029
WOS ID WOS:000739927500009
Scopus ID 85123218551
PubMed ID 34789007
Erfassungsdatum 2021-12-10
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