title: RBM4 down-regulates PTB and antagonizes its activity in muscle cell-specific alternative splicing.
abstract: Alternative splicing contributes largely to cell differentiation and functional specification. We previously reported that the RNA-binding protein RBM4 antagonizes the activity of splicing factor PTB to modulate muscle cell-specific exon selection of α-tropomyosin. Here we show that down-regulation of PTB and its neuronal analogue nPTB during muscle cell differentiation may involve alternative splicing-coupled nonsense-mediated mRNA decay. RBM4 regulates PTB/nPTB expression by activating exon skipping of their transcripts during myogenesis. Moreover, RBM4 and PTB target a common set of transcripts that undergo muscle cell-specific alternative splicing. Overexpression of RBM4 invariably promoted expression of muscle cell-specific isoforms, which recapitulated in vivo alternative splicing changes during muscle differentiation, whereas PTB acted oppositely to RBM4 in expression of mRNA isoforms specific for late-stage differentiation. Therefore, RBM4 may synergize its effect on muscle cell-specific alternative splicing by down-regulating PTB expression and antagonizing the activity of PTB in exon selection, which highlights a hierarchical role for RBM4 in a splicing cascade that regulates myogenesis.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 11529, Taiwan.
authors.forename: Jung-Chun
authors.initials: JC
authors.lastname: Lin
authors.forename: Woan-Yuh
authors.initials: WY
authors.lastname: Tarn
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D024510:Muscle Development; D009132:Muscles / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis*
chemical_list: D020033:Protein Isoforms; C473692:RBM4 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D038941:Polypyrimidine Tract-Binding Protein