The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy
| Autor: | Caines, Rachel, Cochrane, Amy, Kelaini, Sophia, Gonzalez, Marta Vila, Yang, Chunbo, Eleftheriadou, Magdalini, Moez, Arya, Stitt, Alan W, Zeng, Lingfang, Grieve, David J, Margariti, Andriana |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Caines, R, Cochrane, A, Kelaini, S, Gonzalez, M V, Yang, C, Eleftheriadou, M, Moez, A, Stitt, A W, Zeng, L, Grieve, D J & Margariti, A 2019, ' The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy ', Journal of Cell Science . https://doi.org/10.1242/jcs.230276 |
| DOI: | 10.1242/jcs.230276 |
| Popis: | Rationale: Endothelial Cell (ECs) and Vascular Smooth Muscle Cell (VSMCs) dysfunction is central to Cardiovascular Disease pathology. Stem cell therapy holds great promise, but greater understanding of mechanisms underpinning vascular cell differentiation from pluripotent precursors is required.Objective: RNA Binding Proteins (RBPs) are novel post-transcriptional regulators of alternative splicing and we have previously shown that Quaking (QKI) is critical for EC differentiation. This study elucidates the role of alternative splicing isoform Quaking 6 (QKI-6) in VSMC differentiation from induced pluripotent stem cells(iPSCs).Results: PDGF-BB stimulation of differentiating iPSC-VSMCs upregulated QKI-6 which bound HDAC7 intron 1, promoting HDAC7 splicing and differentiation of iPS-VSMCs. QKI-6 transcriptionally activated VSMC marker SM22 and promoted cell contractility while QKI knockdown diminished differentiation capability. When QKI-6 VSMCs were combined with iPS-ECs-overexpressing QKI-5, the cells exhibited greater angiogenic potential in in vivo Matrigel Plugs.Conclusions: This study demonstrates that QKI-6 is critical for modulation of HDAC7 splicing, regulating phenotypically and functionally robust iPS-VSMCs. These findings highlight that RNA Binding Protein QKI isoforms hold key roles in alternative splicing and facilitate a model for vascular therapies. |
| Databáze: | OpenAIRE |
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