RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts

Genome Res. 2015 Jan;25(1):1-13. doi: 10.1101/gr.181990.114.


Ninety-four percent of mammalian protein-coding exons exceed 51 nucleotides (nt) in length. The paucity of micro-exons (≤ 51 nt) suggests that their recognition and correct processing by the splicing machinery present greater challenges than for longer exons. Yet, because thousands of human genes harbor processed micro-exons, specialized mechanisms may be in place to promote their splicing. Here, we survey deep genomic data sets to define 13,085 micro-exons and to study their splicing mechanisms and molecular functions. More than 60% of annotated human micro-exons exhibit a high level of sequence conservation, an indicator of functionality. While most human micro-exons require splicing-enhancing genomic features to be processed, the splicing of hundreds of micro-exons is enhanced by the adjacent binding of splice factors in the introns of pre-messenger RNAs. Notably, splicing of a significant number of micro-exons was found to be facilitated by the binding of RBFOX proteins, which promote their inclusion in the brain, muscle, and heart. Our analyses suggest that accurate regulation of micro-exon inclusion by RBFOX proteins and PTBP1 plays an important role in the maintenance of tissue-specific protein-protein interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Brain / metabolism
  • Chromosome Mapping
  • Conserved Sequence
  • Exons*
  • Gene Expression Regulation
  • Genomics
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism*
  • Humans
  • Introns
  • Mice
  • Nucleotides / genetics
  • Polypyrimidine Tract-Binding Protein / genetics
  • Polypyrimidine Tract-Binding Protein / metabolism*
  • Protein Interaction Domains and Motifs
  • RNA Splicing Factors
  • RNA, Messenger
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*


  • Heterogeneous-Nuclear Ribonucleoproteins
  • Nucleotides
  • PTBP1 protein, human
  • RBFOX1 protein, human
  • RNA Splicing Factors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Polypyrimidine Tract-Binding Protein