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Locus-conserved circular RNA cZNF292 controls endothelial cell flow responses

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Item Type:Article
Title:Locus-conserved circular RNA cZNF292 controls endothelial cell flow responses
Creators Name:Heumüller, A.W. and Jones, A. N. and Mourão, A. and Klangwart, M. and Shi, C. and Wittig, I. and Fischer, A. and Muhly Reinholz, M. and Buchmann, G.K. and Dieterich, C. and Potente, M. and Braun, T. and Grote, P. and Jaé, N. and Sattler, M. and Dimmeler, S.
Abstract: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.
Keywords:Blood Circulation, Circular RNA, DNA-Binding Proteins, Endothelial Cells, Inbred C57BL Mice, Intracellular Signaling Peptides and Proteins, Protein Binding, Syndecan-4, Transcription Factors, Vascular Endothelium, Animals, Mice
Source:Circulation Research
Publisher:American Heart Association
Page Range:67-79
Date:7 January 2022
Official Publication:https://doi.org/10.1161/CIRCRESAHA.121.320029
PubMed:View item in PubMed

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