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 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.
Authors
- Jorge Ruiz Orera
- Victor Badillo Lisakowski (ORCID: https://orcid.org/0000-0001-5906-2589)
- Christoph Dieterich (ORCID: https://orcid.org/0000-0001-9468-6311)
- Stefan Meinke (ORCID: https://orcid.org/0000-0001-5083-3383)
- Valentin Schneider-Lunitz (ORCID: https://orcid.org/0000-0002-3980-3789)
- Thiago Britto-Borges
- Michael H. Radke
- Sebastiaan van Heesch (ORCID: https://orcid.org/0000-0001-9593-1980)
- Michael Gotthardt (ORCID: https://orcid.org/0000-0003-1788-3172)
- Henk Granzier (ORCID: https://orcid.org/0000-0002-9516-407X)
- Norbert Hubner (ORCID: https://orcid.org/0000-0002-1218-6223)
- Oliver Hummel
Institutions
- Helmholtz Association of German Research Centres (DE)
- University of Arizona (US)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Oncode Institute (NL)
- Princess Máxima Center (NL)
- German Centre for Cardiovascular Research (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Heidelberg University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-23
- DOI
- https://doi.org/10.1038/s41467-026-73230-w
- Primary Topic
- Cardiomyopathy and Myosin Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsches Zentrum für Herz-Kreislaufforschung
- British Heart Foundation
- European Commission
- Deutsche Forschungsgemeinschaft
- Fondation Leducq
- HORIZON EUROPE European Innovation Council