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September 17, 2026Stem Cell Research & TherapyOpen Access

METTL3 suppresses cardiac differentiation via the PRC2/SMARCA2 Axis

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Authors

XLXuan LiYWYukang WuCHChengcheng Hu

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Overview

Preclinical study reveals that METTL3 inhibits human stem cell cardiac differentiation via PRC2 and SMARCA2, indicating that targeted METTL3 degradation could enhance regenerative cell therapies.

Key Points

  • To investigate the role and molecular mechanisms of the RNA methyltransferase METTL3 in human embryonic stem cell cardiac differentiation and therapeutic cardiac repair.
  • Induced monolayer cardiac differentiation in human embryonic stem cells engineered for doxycycline-inducible METTL3 overexpression or SMASh-tag-mediated degradation.
  • Profiled m6A modification, H3K27me3 chromatin distribution, and protein interactions using MeRIP-seq, ChIP-seq, ChIP-qPCR, polysome profiling, and ubiquitination assays.
  • Assessed cardiac repair following transplantation of early-stage METTL3-degraded cardiomyocytes into a mouse model of myocardial infarction.
  • METTL3 expression naturally declined during cardiac differentiation; overexpression suppressed differentiation, while degradation markedly enhanced cardiomyocyte yield independently of m6A catalytic activity.
  • METTL3 physically bound EED and EZH2, protecting them from ubiquitin-mediated proteasomal degradation and maintaining repressive H3K27me3 marks at cardiac lineage genes in a SMARCA2-dependent manner.
  • Human embryonic stem cell-derived cardiomyocytes generated via early-stage METTL3 degradation preserved therapeutic efficacy and improved myocardial repair in post-infarction mice.

Cite This Study

Li et al. (2026) studied this question.

synapsesocial.com/papers/6aabb7b85f706d05830e6f7dhttps://doi.org/10.1186/s13287-026-05292-y
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Also Consider

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

  1. 1Abstract Thu094: Cardiac METTL3/METTL14 Complex Mediated m6A Modification is Required for Heart Development2025
  2. 2The role of METTL3 in transposable elements regulation and 2C-like program induction in mouse embryonic stem cell2025
  3. 3Abstract Wed081: Cardiomyocyte METTL3 Protects Against Heart Failure with Preserved Ejection Fraction2025
  4. 426-OR: METTL3 Is Essential for Exercise-Induced Cardiac Benefits in Diabetic Cardiomyopathy2024 · 1 citations
  5. 5METTL3-mediated pre-miR-665/DLX3 m6A methylation facilitates the committed differentiation of stem cells from apical papilla2024 · 12 citations