RBM24 Is a Major Regulator of Muscle-Specific Alternative Splicing

• RBM24 is a muscle-specific splicing factor required for organ development
• We identify 68 RBM24 splicing targets by RNA-seq
• RBM24 is sufficient to mediate muscle-specific exon inclusion
• RBM24 prevents PTB- and hnRNP A1/A2-mediated suppression of exon inclusion

SummaryCell-type-specific splicing generates numerous alternatively spliced transcripts playing important roles for organ development and homeostasis, but only a few tissue-specific splicing factors have been identified. We found that RBM24 governs a large number of muscle-specific splicing events that are critically involved in cardiac and skeletal muscle development and disease. Targeted inactivation of RBM24 in mice disrupted cardiac development and impaired sarcomerogenesis in striated muscles. In vitro splicing assays revealed that recombinant RBM24 is sufficient to promote muscle-specific exon inclusion in nuclear extracts of nonmuscle cells. Furthermore, we demonstrate that binding of RBM24 to an intronic splicing enhancer (ISE) is essential and sufficient to overcome repression of exon inclusion by an exonic splicing silencer (ESS) containing PTB and hnRNP A1/A2 binding sites. Introduction of ESS and ISE converted a constitutive exon into an RMB24-dependent alternative exon. We reason that RBM24 is a major regulator of alternative splicing in striated muscles.

Graphical AbstractFigure optionsDownload high-quality image (348 K)Download as PowerPoint slide