Trdn-as directs m6A-dependent transcriptional termination for accurate triadin isoform switching, preventing aberrant dyads and cardiomyopathy.

Abstract

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.