Trdn-as directs m6A-dependent transcriptional termination for accurate triadin isoform switching, preventing aberrant dyads and cardiomyopathy.
A regulatory RNA preserves heart muscle function; its loss causes dilated cardiomyopathy, revealing a new therapeutic target for heart disease.
This Nature Communications study reveals a novel mechanism by which the lncRNA TRDN-AS maintains cardiac function by stalling RNA Pol II at the cardiac triadin transcript 3' end through METTL3-mediated m6A methylation, ensuring cardiac-specific TRDN/TRISK32 isoform expression. Loss of TRDN-AS causes switch to skeletal muscle isoform TRISK95, disrupting the cardiac calcium release complex, impairing dyad structure, prolonging QT interval, and causing dilated cardiomyopathy validated in both mouse models and human iPSC-cardiomyocytes from cardiomyopathy patients.
What the study was
- Study design
- Mechanistic preclinical (KO mice + human iPSC-cardiomyocytes)
- Population
- Cardiomyocyte-specific Mll4 KO mice; human iPSC-derived cardiomyocytes; human cardiomyopathy tissue samples
- Category
- Genomics/Precision Medicine
- Maturity
- Exploratory
- Journal
- Nature Communications
Why it surfaced
High-novelty mechanism (lncRNA + m6A crosstalk → cardiac isoform switching) in Nature Communications; cardiomyopathy is T7-adjacent; mechanistic insight may inform future therapeutic targets for inherited cardiac arrhythmia/cardiomyopathy.
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