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  Locus-Conserved Circular RNA cZNF292 Controls Endothelial Cell Flow Responses

Heumueller, A. W., Jones, A. N., Mourao, A., Klangwart, M., Shi, C., Wittig, I., et al. (2022). Locus-Conserved Circular RNA cZNF292 Controls Endothelial Cell Flow Responses. CIRCULATION RESEARCH, 130(1), 67-79. doi:10.1161/CIRCRESAHA.121.320029.

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 Creators:
Heumueller, Andreas W., Author
Jones, Alisha N., Author
Mourao, Andre, Author
Klangwart, Marius, Author
Shi, Chenyue1, Author              
Wittig, Ilka, Author
Fischer, Ariane, Author
Muhly-Reinholz, Marion, Author
Buchmann, Giulia K., Author
Dieterich, Christoph, Author
Potente, Michael1, Author              
Braun, Thomas2, Author              
Grote, Phillip, Author
Jae, Nicolas, Author
Sattler, Michael, Author
Dimmeler, Stefanie, Author
Affiliations:
1Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591701              
2Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591695              

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 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 and Results: Combining published endothelial RNA-sequencing data sets 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 localization and focal adhesion organization. Mechanistically, we identified the protein SDOS (syndesmos) 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 reorganization thereby recapitulating cZfp292 knockout phenotypes. Conclusions: Together, our data reveal a hitherto unknown role of cZNF292/cZfp292 in endothelial flow responses, which influences endothelial shape.

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 Dates: 2021-11-182022-01-07
 Publication Status: Published in print
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Title: CIRCULATION RESEARCH
Source Genre: Journal
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Pages: - Volume / Issue: 130 (1) Sequence Number: - Start / End Page: 67 - 79 Identifier: ISSN: 0009-7330