RNA G-quadruplex secondary structure promotes alternative splicing via the RNA-binding protein hnRNPF

Genes Dev. 2017 Nov 15;31(22):2296-2309. doi: 10.1101/gad.305862.117. Epub 2017 Dec 21.


It is generally thought that splicing factors regulate alternative splicing through binding to RNA consensus sequences. In addition to these linear motifs, RNA secondary structure is emerging as an important layer in splicing regulation. Here we demonstrate that RNA elements with G-quadruplex-forming capacity promote exon inclusion. Destroying G-quadruplex-forming capacity while keeping G tracts intact abrogates exon inclusion. Analysis of RNA-binding protein footprints revealed that G quadruplexes are enriched in heterogeneous nuclear ribonucleoprotein F (hnRNPF)-binding sites and near hnRNPF-regulated alternatively spliced exons in the human transcriptome. Moreover, hnRNPF regulates an epithelial-mesenchymal transition (EMT)-associated CD44 isoform switch in a G-quadruplex-dependent manner, which results in inhibition of EMT. Mining breast cancer TCGA (The Cancer Genome Atlas) data sets, we demonstrate that hnRNPF negatively correlates with an EMT gene signature and positively correlates with patient survival. These data suggest a critical role for RNA G quadruplexes in regulating alternative splicing. Modulation of G-quadruplex structural integrity may control cellular processes important for tumor progression.

Keywords: EMT; RNA G quadruplex; alternative splicing; hnRNPF; splicing factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Cell Line
  • Epithelial-Mesenchymal Transition
  • Exons
  • Female
  • G-Quadruplexes*
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H / metabolism*
  • Humans
  • Hyaluronan Receptors / genetics
  • Neoplasm Invasiveness
  • RNA / chemistry*
  • RNA / metabolism
  • RNA Precursors / chemistry


  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H
  • Hyaluronan Receptors
  • RNA Precursors
  • RNA