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

ABSTRACT: 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 gene Six1, which functions in cardiac progenitor cells but is stably silenced upon cardiac differentiation. Deletion of Ezh2 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 gene expression and homeostasis in the postnatal heart. Our results suggest that epigenetic dysregulation in embryonic progenitor cells is a predisposing factor for adult disease and dysregulated stress responses.

SUBMITTER: Delgado-Olguin P

PROVIDER: S-EPMC3288669 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Delgado-Olguín Paul P Huang Yu Y Li Xue X Christodoulou Danos D Seidman Christine E CE Seidman J G JG Tarakhovsky Alexander A Bruneau Benoit G BG

Nature genetics 20120122 3

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 gene Six1, which functions in cardiac progenit ...[more]

PMID: 22267199

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Project description:Cardiovascular disease, until now, is still the leading cause of death in the United States. Due to the limited regenerative capacity of adult hearts, the damage caused by heart injury cannot be reversed and eventually progress into heart failure. In need of cardiovascular disease treatment, many therapies aimed at either cell transplantation or cell regeneration have been proposed. Direct reprogramming of somatic cells into induced cardiomyocytes (iCMs) is considered to be a promising strategy for regenerative medicine. The induction of cardiomyocytes from non-myocytes can be achieved efficiently via ectopic expression of reprogramming factors both in vitro and in vivo in the mouse model, however, the generation of human induced cardiomyocyte-like cells (hiCMs) remains challenging. The inefficiency of hiCMs production called for the identification of the additional epigenetic memories in non-myocytes which might be damping the hiCM reprogramming. Here, we conducted an unbiased loss-of-function screening focusing on epigenetic regulators and identified enhancer of zeste homolog 2 (EZH2) as an important epigenetic barrier during hiCM reprogramming. We found that the removal of EZH2 via genetic knockdown or treatment of EZH2 selective degrader significantly increased the hiCM reprogramming efficiency and led to profound activation of cardiac genes and repression of collagen and extracellular matrix genes. Furthermore, EZH2 inhibitors targeting its catalytic activity also promotes hiCM reprogramming, suggesting that EZH2 may restrain cardiac conversion through H3K27me3-mediated gene repression. Indeed, genomic profiling of H3K27me3 revealed a subset of cardiac genes that remain repressed with high levels of H3K27me3 despite of the delivery of the reprogramming factors. Inhibition of EZH2, however, leads to reduced H3K27me3 occupancy and robust activation of these cardiac genes. Taken together, our data suggested that EZH2 inhibition facilitates the activation of cardiac genes in fibroblasts and eases the production of hiCMs.

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

Publications

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

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