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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.

Original publication




Journal article


Genome Res

Publication Date





1 - 13


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