The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy

Rachel Caines, Amy Cochrane, Sophia Kelaini, Marta Vila-Gonzalez, Chunbo Yang, Magdalini Eleftheriadou, Arya Moez, Alan W. Stitt, Lingfang Zeng, David J. Grieve, Andriana Margariti

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Dysfunction of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) leads to ischaemia, the central pathology of cardiovascular disease. Stem cell technology will revolutionise regenerative medicine, but a need remains to understand key mechanisms of vascular differentiation. RNA-binding proteins have emerged as novel post-transcriptional regulators of alternative splicing and we have previously shown that the RNA-binding protein Quaking (QKI) plays roles in EC differentiation. In this study, we decipher the role of the alternative splicing isoform Quaking 6 (QKI-6) to induce VSMC differentiation from induced pluripotent stem cells (iPSCs). PDGF-BB stimulation induced QKI-6, which bound to HDAC7 intron 1 via the QKI-binding motif, promoting HDAC7 splicing and iPS-VSMC differentiation. Overexpression of QKI-6 transcriptionally activated SM22 (also known as TAGLN), while QKI-6 knockdown diminished differentiation capability. VSMCs overexpressing QKI-6 demonstrated greater contractile ability, and upon combination with iPS-ECs-overexpressing the alternative splicing isoform Quaking 5 (QKI-5), exhibited higher angiogenic potential in vivo than control cells alone. This study demonstrates that QKI-6 is critical for modulation of HDAC7 splicing, regulating phenotypically and functionally robust iPS-VSMCs. These findings also highlight that the QKI isoforms hold key roles in alternative splicing, giving rise to cells which can be used in vascular therapy or for disease modelling.This article has an associated First Person interview with the first author of the paper.

Original languageEnglish
JournalJournal of cell science
Volume132
Issue number16
DOIs
Publication statusPublished - 15 Aug 2019

Keywords

  • Cell signalling
  • Cellular reprogramming
  • Revascularisation
  • Stem cells
  • Vascular smooth muscle cell

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