Abstract
Ezh2 is a histone trimethyltransferase that silences genes mainly via catalyzing trimethylation of histone 3 lysine 27 (H3K27Me3). The role of Ezh2 as a regulator of gene silencing and cell proliferation in cancer development has been extensively investigated; however, its function in heart development during embryonic cardiogenesis has not been well studied. In the present study, we used a genetically modified mouse system in which Ezh2 was specifically ablated in the mouse heart. We identified a wide spectrum of cardiovascular malformations in the Ezh2 mutant mice, which collectively led to perinatal death. In the Ezh2 mutant heart, the endocardial cushions (ECs) were hypoplastic and the endothelial-to-mesenchymal transition (EMT) process was impaired. The hearts of Ezh2 mutant mice also exhibited decreased cardiomyocyte proliferation and increased apoptosis. We further identified that the Hey2 gene, which is important for cardiomyocyte proliferation and cardiac morphogenesis, is a downstream target of Ezh2. The regulation of Hey2 expression by Ezh2 may be independent of Notch signaling activity. Our work defines an indispensible role of the chromatin remodeling factor Ezh2 in normal cardiovascular development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Cell Proliferation
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Cell Survival / genetics
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Cell Transdifferentiation / genetics
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Down-Regulation / genetics
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Endocardial Cushions / cytology
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Endocardial Cushions / metabolism*
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Endocardial Cushions / pathology
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Enhancer of Zeste Homolog 2 Protein
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Epigenesis, Genetic / genetics
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Gene Deletion*
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HeLa Cells
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Heart Atria / cytology
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Heart Atria / metabolism
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Heart Atria / pathology
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Heart Defects, Congenital / genetics
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Heart Defects, Congenital / metabolism
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Heart Defects, Congenital / pathology
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Heart Ventricles / cytology
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Heart Ventricles / metabolism
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Heart Ventricles / pathology
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Histone-Lysine N-Methyltransferase / deficiency*
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Histone-Lysine N-Methyltransferase / genetics*
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Humans
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Mice
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Myocytes, Cardiac / cytology*
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Myocytes, Cardiac / metabolism*
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Myocytes, Cardiac / pathology
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Polycomb Repressive Complex 2
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Repressor Proteins / genetics
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T-Box Domain Proteins / genetics
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hey2 protein, mouse
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Repressor Proteins
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T-Box Domain Protein 2
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T-Box Domain Proteins
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Enhancer of Zeste Homolog 2 Protein
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Ezh2 protein, mouse
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Histone-Lysine N-Methyltransferase
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Polycomb Repressive Complex 2