TY - JOUR A1 - Li, Yang I. A1 - Sanchez-Pulido, Luis A1 - Haerty, Wilfried A1 - Ponting, Chris P. T1 - RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts Y1 - 2015/01/01 JF - Genome Research JO - Genome Research SP - 1 EP - 13 DO - 10.1101/gr.181990.114 VL - 25 IS - 1 UR - http://genome.cshlp.org/content/25/1/1.abstract N2 - 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. ER -