Polycomb Repressive Complex 2 Regulates Normal Development of the Mouse Heart

Author:

He Aibin1,Ma Qing1,Cao Jingjing1,von Gise Alexander1,Zhou Pingzhu1,Xie Huafeng1,Zhang Bing1,Hsing Michael1,Christodoulou Danos C.1,Cahan Patrick1,Daley George Q.1,Kong Sek Won1,Orkin Stuart H.1,Seidman Christine E.1,Seidman Jonathan G.1,Pu William T.1

Affiliation:

1. From the Department of Cardiology (A.H., Q.M., J.C., A.v.G., P.Z., B.Z., M.H., S.W.K., W.T.P.), Children's Hospital Boston and Harvard Medical School, Boston, MA; Department of Pediatric Oncology (H.X., S.H.O.), Dana-Farber Cancer Institute, Children's Hospital Boston, and Harvard Medical School, Boston, MA; Children's Hospital Informatics Program at Harvard-MIT (S.W.K.), Division of Health Sciences and Technology, Department of Medicine, Children's Hospital Boston, Boston, MA; Department of...

Abstract

Rationale: 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. Methods and 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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