Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation

Megan P. Hall, Roland J. Nagel, W. Samuel Fagg, Lily Shiue, Melissa S. Cline, Rhonda J. Perriman, John Paul Donohue, Manuel Ares

Research output: Contribution to journalArticlepeer-review

Abstract

Alternative splicing contributes to muscle development, but a complete set of muscle-splicing factors and their combinatorial interactions are unknown. Previous work identified ACUAA (-gSTAR-h motif) as an enriched intron sequence near musclespecific alternative exons such as Capzb exon 9. Mass spectrometry of myoblast proteins selected by the Capzb exon 9 intron via RNA affinity chromatography identifies Quaking (QK), a protein known to regulate mRNA function through ACUAA motifs in 3-ΠUTRs. We find that QK promotes inclusion of Capzb exon 9 in opposition to repression by polypyrimidine tract-binding protein (PTB). QK depletion alters inclusion of 406 cassette exons whose adjacent intron sequences are also enriched in ACUAA motifs. During differentiation of myoblasts to myotubes, QK levels increase two-to threefold, suggesting a mechanism for QK-responsive exon regulation. Combined analysis of the PTB-and QK-splicing regulatory networks during myogenesis suggests that 39% of regulated exons are under the control of one or both of these splicing factors. This work provides the first evidence that QK is a global regulator of splicing during muscle development in vertebrates and shows how overlapping splicing regulatory networks contribute to gene expression programs during differentiation.

Original languageEnglish (US)
Pages (from-to)627-638
Number of pages12
JournalRNA
Volume19
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

Keywords

  • Alternative splicing
  • Myogenesis
  • Splicing enhancer
  • Splicing silencer

ASJC Scopus subject areas

  • Molecular Biology

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