Conditional ablation of Ezh2 in murine hearts reveals its essential roles in endocardial cushion formation, cardiomyocyte proliferation and survival.
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.
Department of Stem Cell Engineering, Basic Research Laboratories, Texas Heart Institute, Houston, Texas, United States of America.
Li
L
Chen
Yanlin
Y
Ma
Eun Young
EY
Kim
Wei
W
Yu
Robert J
RJ
Schwartz
Ling
L
Qian
Jun
J
Wang
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D054338:Cell Transdifferentiation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D054089:Endocardial Cushions / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics; D017353:Gene Deletion; D006367:HeLa Cells; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D063151:Polycomb Repressive Complex 2; D012097:Repressor Proteins / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; C485778:Hey2 protein, mouse; C097348:T-Box Domain Protein 2; C498410:Ezh2 protein, mouse