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| Item Type: | Article |
|---|---|
| Title: | RBM20 isoform regulation by independent transcription start sites adapts alternative splicing in development and disease |
| Creators Name: | Radke, Michael H., Badillo Lisakowski, Victor, Meinke, Stefan, Britto-Borges, Thiago, Schneider-Lunitz, Valentin, Hummel, Oliver, van Heesch, Sebastiaan, Ruiz Orera, Jorge, Hubner, Norbert, Granzier, Henk, Dieterich, Christoph and Gotthardt, Michael |
| Abstract: | RBM20 is a cardiac splicing regulator whose dysfunction causes severe cardiomyopathies. Here, we uncover an unexpected layer of RBM20 regulation through a previously unrecognized transcription start site located between the canonical exon 1 and exon 2. This alternative transcription start site generates a shorter, functional RBM20 isoform translated from an internal ATG in exon 2—identified as the predominant translation start site by ribosome profiling. Despite lacking exon 1, the isoform maintains splicing activity and is conserved across mouse, rat, and human. Strikingly, isoform ratios are tightly controlled during the perinatal period but are selectively altered in disease: in hypertrophic-, unlike in dilated cardiomyopathy, upregulation of RBM20 is driven largely by the alternative isoform. Our findings reveal disease and isoform-specific regulation as a second axis of RBM20 control, operating alongside phosphorylation-dependent nuclear localization, with broad implications for developmental splicing programs, cardiac remodeling, and targeted therapeutic strategies. |
| Keywords: | Alternative Splicing, Developmental Gene Expression Regulation, Dilated Cardiomyopathy, Exons, Myocardium, Protein Isoforms, RNA-Binding Proteins, Transcription Initiation Site, Animals, Mice, Rats |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 17 |
| Number: | 1 |
| Page Range: | 4607 |
| Date: | 23 May 2026 |
| Official Publication: | https://doi.org/10.1038/s41467-026-73230-w |
| PubMed: | View item in PubMed |
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