Trdn-as directs m6A-dependent transcriptional termination for accurate triadin isoform switching, preventing aberrant dyads and cardiomyopathy
Heart failure is a leading cause of mortality, and impaired cardiac excitation-contraction coupling represents a potentially fatal trigger for myocardial dysfunction. Long non-coding RNAs (lncRNAs) can contribute to cardiomyopathy, but comprehensive mechanistic insights remain elusive. We demonstrate that reduction of the lncRNA TRDN-AS in human cardiomyopathy or abrogating it in human iPSC-derived cardiomyocytes and mice causes a switch of cardiac TRDN/TRISK32 to skeletal muscle TRDN/TRISK95. Transcription of Trdn-as in cis is essential for stalling RNA Pol II at the 3' end of the cardiac Trdn transcript, promoting the formation of the cardiac TRDN/TRISK32 isoform. The m6A-methyltransferase METTL3 is crucial for RNA Pol II stalling, enforcing transcriptional termination and proximal polyadenylation of the Trdn transcript. Here, we establish that the switch of TRDN isoforms results in a significantly altered interactome of the cardiac calcium release complex, aberrant calcium handling, altered dyad structure, QT prolongation, and dilated cardiomyopathy in mice and humans.
Authors
- Bio Maria Ghéo Idrissou (ORCID: https://orcid.org/0000-0002-4650-2511)
- Christian Waechter (ORCID: https://orcid.org/0000-0003-1558-0696)
- Theresa Hofmann (ORCID: https://orcid.org/0009-0007-0049-0192)
- Sabine Pankuweit (ORCID: https://orcid.org/0009-0003-5210-5496)
- Salma Hachim (ORCID: https://orcid.org/0009-0002-0133-1867)
- Isabelle Marty (ORCID: https://orcid.org/0000-0003-3625-913X)
- Thomas Braun (ORCID: https://orcid.org/0000-0002-6165-4804)
- Laia Cañes (ORCID: https://orcid.org/0000-0002-9579-1321)
- Thomas Boettger (ORCID: https://orcid.org/0000-0003-4280-8449)
- Hendrik Milting (ORCID: https://orcid.org/0000-0001-9722-0007)
- Stefan Engelhardt (ORCID: https://orcid.org/0000-0001-5378-8661)
- Mario Looso (ORCID: https://orcid.org/0000-0003-1495-9530)
- Sara Hettrich
- Silke Kreher (ORCID: https://orcid.org/0009-0001-0890-2979)
- M Weiss
- Maximilian Staps
Institutions
- Inserm (FR)
- Philipps University of Marburg (DE)
- Heart and Diabetes Center North Rhine-Westphalia (DE)
- Centre Hospitalier Universitaire de Grenoble (FR)
- Max Planck Institute for Heart and Lung Research (DE)
- University Hospital Münster (DE)
- German Centre for Cardiovascular Research (DE)
- Universities of Giessen and Marburg Lung Center (DE)
- Grenoble Institute of Neurosciences (FR)
- Technical University of Munich (DE)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-25
- DOI
- https://doi.org/10.1038/s41467-026-75985-8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsches Zentrum für Herz-Kreislaufforschung
- Deutsche Forschungsgemeinschaft
- Max-Planck-Gesellschaft