Rbm20 regulates titin alternative splicing as a splicing repressor

Nucleic Acids Res. 2013 Feb 1;41(4):2659-72. doi: 10.1093/nar/gks1362. Epub 2013 Jan 9.


Titin, a sarcomeric protein expressed primarily in striated muscles, is responsible for maintaining the structure and biomechanical properties of muscle cells. Cardiac titin undergoes developmental size reduction from 3.7 megadaltons in neonates to primarily 2.97 megadaltons in the adult. This size reduction results from gradually increased exon skipping between exons 50 and 219 of titin mRNA. Our previous study reported that Rbm20 is the splicing factor responsible for this process. In this work, we investigated its molecular mechanism. We demonstrate that Rbm20 mediates exon skipping by binding to titin pre-mRNA to repress the splicing of some regions; the exons/introns in these Rbm20-repressed regions are ultimately skipped. Rbm20 was also found to mediate intron retention and exon shuffling. The two Rbm20 speckles found in nuclei from muscle tissues were identified as aggregates of Rbm20 protein on the partially processed titin pre-mRNAs. Cooperative repression and alternative 3' splice site selection were found to be used by Rbm20 to skip different subsets of titin exons, and the splicing pathway selected depended on the ratio of Rbm20 to other splicing factors that vary with tissue type and developmental age.

Publication types

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

MeSH terms

  • Alternative Splicing*
  • Animals
  • Cell Line
  • Cell Nucleus / chemistry
  • Connectin
  • Exons
  • Heart / growth & development
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Myocytes, Cardiac / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • RNA Splice Sites
  • RNA-Binding Proteins / analysis
  • RNA-Binding Proteins / metabolism*
  • Rats


  • Connectin
  • Muscle Proteins
  • Protein Isoforms
  • RBM20 protein, rat
  • RNA Splice Sites
  • RNA-Binding Proteins
  • TTN protein, human
  • ribonucleic acid binding motif protein 20, human
  • Protein Kinases