RNA-binding proteins regulate post-transcriptional responses to TGF-β to coordinate function and mesenchymal activation of murine endothelial cells

• Verfasst von: Wardman, Rhys [VerfasserIn]
• Verfasst von: Keles, Merve [VerfasserIn]
• Verfasst von: Pachkiv, Ihor [VerfasserIn]
• Verfasst von: Hemanna, Shruthi [VerfasserIn]
• Verfasst von: Grein, Steve [VerfasserIn]
• Verfasst von: Schwarz, Jennifer [VerfasserIn]
• Verfasst von: Stein, Frank [VerfasserIn]
• Verfasst von: Ola, Roxana [VerfasserIn]
• Verfasst von: Dobreva, Gergana [VerfasserIn]
• Verfasst von: Hentze, Matthias W. [VerfasserIn]
• Verfasst von: Heineke, Jörg [VerfasserIn]
• Titel: RNA-binding proteins regulate post-transcriptional responses to TGF-β to coordinate function and mesenchymal activation of murine endothelial cells
• Verf.angabe: Rhys Wardman, Merve Keles, Ihor Pachkiv, Shruthi Hemanna, Steve Grein, Jennifer Schwarz, Frank Stein, Roxana Ola, Gergana Dobreva, Matthias W. Hentze, and Joerg Heineke
• E-Jahr: 2023
• Jahr: 31 Aug 2023
• Umfang: 23 S.
• Fussnoten: Gesehen am 27.11.2023
• Titel Quelle: Enthalten in: Arteriosclerosis, thrombosis, and vascular biology
• Ort Quelle: Philadelphia, Pa. : Lippincott, Williams & Wilkins, 1981
• Jahr Quelle: 2023
• Band/Heft Quelle: 43(2023), 10 vom: Okt., Seite 1967-1989
• ISSN Quelle: 1524-4636
• ISSN Quelle: 2330-9180
• ISSN Quelle: 2330-9199
• DOI: doi:10.1161/ATVBAHA.123.319925
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: endothelial cells
• Sach-SW: heterogeneous nuclear ribonucleoprotein
• Sach-SW: phenotype
• Sach-SW: RNA-binding proteins
• Sach-SW: transforming growth factors
• K10plus-PPN: 1871282748

Abstract

BACKGROUND: - - Endothelial cells (ECs) are primed to respond to various signaling cues. For example, TGF (transforming growth factor)-β has major effects on EC function and phenotype by driving ECs towards a more mesenchymal state (ie, triggering endothelial to mesenchymal activation), a dynamic process associated with cardiovascular diseases. Although transcriptional regulation triggered by TGF-β in ECs is well characterized, post-transcriptional regulatory mechanisms induced by TGF-β remain largely unknown. - - METHODS: - - Using RNA interactome capture, we identified global TGF-β driven changes in RNA-binding proteins in ECs. We investigated specific changes in the RNA-binding patterns of hnRNP H1 (heterogeneous nuclear ribonucleoprotein H1) and Csde1 (cold shock domain containing E1) using RNA immunoprecipitation and overlapped this with RNA-sequencing data after knockdown of either protein for functional insight. Using a modified proximity ligation assay, we visualized the specific interactions between hnRNP H1 and Csde1 and target RNAs in situ both in vitro and in mouse heart sections. - - RESULTS: - - Characterization of TGF-β-regulated RBPs (RNA-binding proteins) revealed hnRNP H1 and Csde1 as key regulators of the cellular response to TGF-β at the post-transcriptional level, with loss of either protein-promoting mesenchymal activation in ECs. We found that TGF-β drives an increase in binding of hnRNP H1 to its target RNAs, offsetting mesenchymal activation, but a decrease in Csde1 RNA-binding, facilitating this process. Both, hnRNP H1 and Csde1, dynamically bind and regulate specific subsets of mRNAs related to mesenchymal activation and endothelial function. - - CONCLUSIONS: - - Together, we show that RBPs play a key role in the endothelial response to TGF-β stimulation at the post-transcriptional level and that the RBPs hnRNP H1 and Csde1 serve to maintain EC function and counteract mesenchymal activation. We propose that TGF-β profoundly modifies RNA-protein interaction entailing feedback and feed-forward control at the post-transcriptional level, to fine-tune mesenchymal activation in ECs.