A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature

Nat Struct Mol Biol. 2015 May;22(5):370-6. doi: 10.1038/nsmb.3005. Epub 2015 Apr 6.

Abstract

Alternative pre-mRNA splicing is a highly cell type-specific process essential to generating protein diversity. However, the mechanisms responsible for the establishment and maintenance of heritable cell-specific alternative-splicing programs are poorly understood. Recent observations point to a role of histone modifications in the regulation of alternative splicing. Here we report a new mechanism of chromatin-mediated splicing control involving a long noncoding RNA (lncRNA). We have identified an evolutionarily conserved nuclear antisense lncRNA, generated from within the human FGFR2 locus, that promotes epithelial-specific alternative splicing of FGFR2. The lncRNA acts through recruitment of Polycomb-group proteins and the histone demethylase KDM2a to create a chromatin environment that impairs binding of a repressive chromatin-splicing adaptor complex important for mesenchymal-specific splicing. Our results uncover a new function for lncRNAs in the establishment and maintenance of cell-specific alternative splicing via modulation of chromatin signatures.

Publication types

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

MeSH terms

  • Alternative Splicing / genetics*
  • Argonaute Proteins / genetics
  • Cell Cycle Proteins / genetics
  • Cell Line
  • Chromatin / genetics*
  • DEAD-box RNA Helicases / genetics
  • Enhancer of Zeste Homolog 2 Protein
  • Epithelial Cells
  • Eukaryotic Initiation Factors / genetics
  • F-Box Proteins / metabolism
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • MCF-7 Cells
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism
  • Polycomb-Group Proteins / metabolism
  • Polypyrimidine Tract-Binding Protein / genetics
  • RNA Interference
  • RNA Precursors / genetics*
  • RNA, Long Noncoding / genetics*
  • RNA, Small Interfering
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*
  • Ribonuclease III / genetics

Substances

  • AGO1 protein, human
  • AGO2 protein, human
  • Argonaute Proteins
  • Cell Cycle Proteins
  • Chromatin
  • Eukaryotic Initiation Factors
  • F-Box Proteins
  • Histones
  • Polycomb-Group Proteins
  • RNA Precursors
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • SUZ12 protein, human
  • Polypyrimidine Tract-Binding Protein
  • Jumonji Domain-Containing Histone Demethylases
  • KDM2A protein, human
  • EZH1 protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2
  • DICER1 protein, human
  • Ribonuclease III
  • DEAD-box RNA Helicases