A complex network of factors with overlapping affinities represses splicing through intronic elements

Nat Struct Mol Biol. 2013 Jan;20(1):36-45. doi: 10.1038/nsmb.2459. Epub 2012 Dec 16.


To better understand splicing regulation, we used a cell-based screen to identify ten diverse motifs that inhibit splicing from introns. Motifs were validated in another human cell type and gene context, and their presence correlated with in vivo splicing changes. All motifs exhibited exonic splicing enhancer or silencer activity, and grouping these motifs according to their distributions yielded clusters with distinct patterns of context-dependent activity. Candidate regulatory factors associated with each motif were identified, to recover 24 known and new splicing regulators. Specific domains in selected factors were sufficient to confer intronic-splicing-silencer activity. Many factors bound multiple distinct motifs with similar affinity, and all motifs were recognized by multiple factors, which revealed a complex overlapping network of protein-RNA interactions. This arrangement enables individual cis elements to function differently in distinct cellular contexts, depending on the spectrum of regulatory factors present.

Publication types

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

MeSH terms

  • Base Composition
  • Cell Line
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Introns*
  • RNA Interference
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA Splicing*
  • RNA, Small Interfering
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism


  • RNA Precursors
  • RNA, Small Interfering
  • RNA-Binding Proteins