title: RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts.
abstract: 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.
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom yangili@stanford.edu chris.ponting@dpag.ox.ac.uk.
authors.forename: Yang I
authors.identifier: http://orcid.org/0000-0002-0736-251X
authors.initials: YI
authors.lastname: Li
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Pulido
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Wilfried
authors.initials: W
authors.lastname: Haerty
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom; yangili@stanford.edu chris.ponting@dpag.ox.ac.uk.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000378:metabolism; D002874:Chromosome Mapping; D017124:Conserved Sequence; D005091:Exons; D005786:Gene Expression Regulation; D023281:Genomics; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007438:Introns; D051379:Mice; D009711:Nucleotides / Q000235:genetics; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009711:Nucleotides; C450006:PTBP1 protein, human; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D038941:Polypyrimidine Tract-Binding Protein