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October 9, 2025Circulation Research

Abstract Thu094: Cardiac METTL3/METTL14 Complex Mediated m6A Modification is Required for Heart Development

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Key result

Cardiomyocyte METTL3 or METTL14 knockout causes fetal dilated cardiomyopathy and neonatal death via impaired sarcomere maturation.

Population

Mice with conditional knockout of METTL3 or METTL14 in cardiomyocytes, and human pluripotent stem…

Comparison

Conditional knockout of METTL3 or METTL14 and… vs Control mice and control hPSCs

Design

Preclinical

Authors

SBStuart BurkeUniversity of Wisconsin HealthSHSophie HandNationwide Children's HospitalDLDonna LiNationwide Children's Hospital

Discussion

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Implication

The METTL3/METTL14 methyltransferase complex is essential for heart development and sarcomere maturation via m6A post-transcriptional regulation of sarcomere transcripts.

Key Points

  • Neonatal lethality is observed in mice lacking either METTL3 or METTL14, suggesting their vital roles in heart development.
  • Transcriptomic analysis shows reduced sarcomere-related gene transcripts in METTL3 and METTL14 knockout hearts, indicating disruption in maturation.
  • Knockdown of METTL3 in human pluripotent stem cells impairs cardiomyocyte maturation and downregulates crucial sarcomere transcripts.
  • This study uncovers a unique mechanism of m6A modification by the METTL3/METTL14 complex in the regulation of heart development and disease.

Structured PICO

P
Population
Mice with conditional knockout of METTL3 (MT3cKO) or METTL14 (MT14cKO) in cardiomyocytes, and human pluripotent stem cell-derived cardiomyocytes (hPSCs)
I
Intervention
Conditional knockout of METTL3 or METTL14 (in mice) and knockdown of METTL3 using shRNA adenovirus (in hPSCs)
C
Comparator
Control mice and control hPSCs
O
Outcome
Heart development phenotypes (neonatal lethality, fetal dilated cardiomyopathy phenotypes) and sarcomere maturation/gene expressionsurrogate

The METTL3/METTL14 methyltransferase complex is essential for heart development and sarcomere maturation via m6A post-transcriptional regulation of sarcomere transcripts.

Cite This Study

Burke et al. (2025) studied Heart development and fetal dilated cardiomyopathy. Conditional knockout of METTL3 or METTL14 vs. Controls was evaluated on Heart development and sarcomere maturation. Conditional knockout of METTL3 or METTL14 in mouse cardiomyocytes resulted in neonatal lethality and fetal dilated cardiomyopathy due to impaired sarcomere maturation.

synapsesocial.com/papers/68e80eb363e2e2f707877ddbhttps://doi.org/10.1161/res.137.suppl_1.thu094
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Abstract Wed081: Cardiomyocyte METTL3 Protects Against Heart Failure with Preserved Ejection Fraction2025
  2. 2Abstract NBT101: m6A mRNA Modifications Regulate Metabolic Transition During Cardiogenesis2025
  3. 3METTL3 suppresses cardiac differentiation via the PRC2/SMARCA2 Axis2026
  4. 426-OR: METTL3 Is Essential for Exercise-Induced Cardiac Benefits in Diabetic Cardiomyopathy2024 · 1 citations
  5. 5Abstract Thu097: METTL3 inhibition reduces myofibroblast activation and adverse remodeling following MI.2025