Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis

Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown(1,2). The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive marks during development that persist into adulthood(3–9), but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and prevents cardiac pathology by repressing the homeodomain transcription factor Six1, which functions in cardiac progenitors but is stably silenced upon cardiac differentiation(10). Ezh2 deletion in cardiac progenitors caused postnatal myocardial pathology and destabilized cardiac gene expression with activation of Six1-dependent skeletal muscle genes. Six1 induced cardiomyocyte hypertrophy and skeletal muscle gene expression. Furthermore, genetically reducing Six1 levels rescued the pathology of Ezh2-deficient hearts. Thus, Ezh2-mediated repression of Six1 in differentiating cardiac progenitors is essential for stable postnatal heart gene expression and homeostasis. Our results suggest that epigenetic dysregulation in embryonic progenitor cells predisposes to adult disease and dysregulated stress responses.