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RBM20 isoform regulation by independent transcription start sites adapts alternative splicing in development and disease

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 gener...

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Autori principali: Radke, Michael (Autore) , Badillo Lisakowski, Victor (Autore) , Meinke, Stefan (Autore) , Britto-Borges, Thiago (Autore) , Schneider-Lunitz, Valentin (Autore) , Hummel, Oliver (Autore) , van Heesch, Sebastiaan (Autore) , Ruiz Orera, Jorge (Autore) , Hubner, Norbert (Autore) , Granzier, Henk L. (Autore) , Dieterich, Christoph (Autore) , Gotthardt, Michael (Autore)
Natura: Article (Journal)
Lingua:inglese
Pubblicazione: 23 May 2026
In: Nature Communications
Year: 2026, Volume: 17, Pages: 1-16
ISSN:2041-1723
DOI:10.1038/s41467-026-73230-w
Accesso online:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-026-73230-w
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-026-73230-w
Testo
Note sull'autore:Michael H. Radke, Victor Badillo Lisakowski, Stefan Meinke, Thiago Britto-Borges, Valentin Schneider-Lunitz, Oliver Hummel, Sebastiaan van Heesch, Jorge Ruiz Orera, Norbert Hubner, Henk Granzier, Christoph Dieterich & Michael Gotthardt
Descrizione
Riassunto: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.
Descrizione del documento:Gesehen am 09.07.2026
Descrizione fisica:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-026-73230-w

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