title: Polycomb repressive complex 2 regulates normal development of the mouse heart.
abstract: BACKGROUND
  Epigenetic marks are crucial for organogenesis, but their role in heart development is poorly understood. Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27, which establishes H3K27me3 repressive epigenetic marks that promote tissue-specific differentiation by silencing ectopic gene programs.
  
  
  OBJECTIVE
  We studied the function of PRC2 in murine heart development using a tissue-restricted conditional inactivation strategy.
  
  
  RESULTS
  Inactivation of the PRC2 subunit Ezh2 by Nkx2-5(Cre) (Ezh2(NK)) caused lethal congenital heart malformations, namely, compact myocardial hypoplasia, hypertrabeculation, and ventricular septal defect. Candidate and genome-wide RNA expression profiling and chromatin immunoprecipitation analyses of Ezh2(NK) heart identified genes directly repressed by EZH2. Among these were the potent cell cycle inhibitors Ink4a/b (inhibitors of cyclin-dependent kinase 4 A and B), the upregulation of which was associated with decreased cardiomyocyte proliferation in Ezh2(NK). EZH2-repressed genes were enriched for transcriptional regulators of noncardiomyocyte expression programs such as Pax6, Isl1, and Six1. EZH2 was also required for proper spatiotemporal regulation of cardiac gene expression, because Hcn4, Mlc2a, and Bmp10 were inappropriately upregulated in ventricular RNA. PRC2 was also required later in heart development, as indicated by cardiomyocyte-restricted TNT-Cre inactivation of the PRC2 subunit Eed. However, Ezh2 inactivation by TNT-Cre did not cause an overt phenotype, likely because of functional redundancy with Ezh1. Thus, early Ezh2 inactivation by Nk2-5(Cre) caused later disruption of cardiomyocyte gene expression and heart development.
  
  
  CONCLUSIONS
  Our study reveals a previously undescribed role of EZH2 in regulating heart formation and shows that perturbation of the epigenetic landscape early in cardiogenesis has sustained disruptive effects at later developmental stages.
authors.affiliation: Department of Cardiology, Children's Hospital Boston, MA, USA.
authors.forename: Aibin
authors.initials: A
authors.lastname: He
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Jingjing
authors.initials: J
authors.lastname: Cao
authors.forename: Alexander
authors.initials: A
authors.lastname: von Gise
authors.forename: Pingzhu
authors.initials: P
authors.lastname: Zhou
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xie
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Hsing
authors.forename: Danos C
authors.initials: DC
authors.lastname: Christodoulou
authors.forename: Patrick
authors.initials: P
authors.lastname: Cahan
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Sek Won
authors.initials: SW
authors.lastname: Kong
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D055106:Genome-Wide Association Study; D006321:Heart / Q000196:embryology* / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000502:physiology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D063146:Polycomb-Group Proteins; D021122:Protein Subunits; D012097:Repressor Proteins; D014157:Transcription Factors; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2