Intronic splicing enhancers, cognate splicing factors and context-dependent regulation rules

Nat Struct Mol Biol. 2012 Oct;19(10):1044-52. doi: 10.1038/nsmb.2377. Epub 2012 Sep 16.


Most human genes produce multiple splicing isoforms with distinct functions. To systematically understand splicing regulation, we conducted an unbiased screen and identified >100 intronic splicing enhancers (ISEs), clustered by sequence similarity. All ISEs functioned in multiple cell types and in heterologous introns, and patterns of distribution and conservation across pre-mRNA regions were similar to those of exonic splicing silencers. Consistently, all ISEs inhibited use of splice sites from exons. Putative trans-factors of each ISE group were identified and validated. Five distinct groups were recognized by hnRNP H and hnRNP F, whose C-terminal domains were sufficient to render context-dependent activities of ISEs. The sixth group was controlled by factors that either activate or suppress splicing. We provide a comprehensive picture of general ISE activities and suggest new models of how single elements can function oppositely, depending on locations and binding factors.

Publication types

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

MeSH terms

  • Cell Line
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H / metabolism
  • Humans
  • Introns
  • Nucleotide Motifs
  • Protein Structure, Tertiary
  • RNA Precursors / genetics
  • RNA Splicing*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Reproducibility of Results


  • DAZAP1 protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H
  • RBM4 protein, human
  • RNA Precursors
  • RNA-Binding Proteins