RNA-binding proteins regulate post-transcriptional responses to TGF-β to coordinate function and mesenchymal activation of murine endothelial cells
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 p...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
31 Aug 2023
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| In: |
Arteriosclerosis, thrombosis, and vascular biology
Year: 2023, Volume: 43, Issue: 10, Pages: 1967-1989 |
| ISSN: | 1524-4636 |
| DOI: | 10.1161/ATVBAHA.123.319925 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1161/ATVBAHA.123.319925 Verlag, kostenfrei, Volltext: https://www.ahajournals.org/doi/10.1161/ATVBAHA.123.319925 
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| Author Notes: | Rhys Wardman, Merve Keles, Ihor Pachkiv, Shruthi Hemanna, Steve Grein, Jennifer Schwarz, Frank Stein, Roxana Ola, Gergana Dobreva, Matthias W. Hentze, and Joerg Heineke |
| Summary: | 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. |
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| Item Description: | Gesehen am 27.11.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1524-4636 |
| DOI: | 10.1161/ATVBAHA.123.319925 |