{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:59:36Z","timestamp":1791305976087,"version":"4.3.1"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2012,2,3]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>We studied the function of PRC2 in murine heart development using a tissue-restricted conditional inactivation strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Inactivation of the PRC2 subunit\n                      <jats:italic>Ezh2<\/jats:italic>\n                      by Nkx2\u20135\n                      <jats:sup>Cre<\/jats:sup>\n                      (Ezh2\n                      <jats:sup>NK<\/jats:sup>\n                      ) 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\n                      <jats:sup>NK<\/jats:sup>\n                      heart identified genes directly repressed by EZH2. Among these were the potent cell cycle inhibitors\n                      <jats:italic>Ink4a\/b<\/jats:italic>\n                      (inhibitors of cyclin-dependent kinase 4 A and B), the upregulation of which was associated with decreased cardiomyocyte proliferation in Ezh2\n                      <jats:sup>NK<\/jats:sup>\n                      . EZH2-repressed genes were enriched for transcriptional regulators of noncardiomyocyte expression programs such as\n                      <jats:italic>Pax6<\/jats:italic>\n                      ,\n                      <jats:italic>Isl1<\/jats:italic>\n                      , and\n                      <jats:italic>Six1<\/jats:italic>\n                      . EZH2 was also required for proper spatiotemporal regulation of cardiac gene expression, because\n                      <jats:italic>Hcn4<\/jats:italic>\n                      ,\n                      <jats:italic>Mlc2a<\/jats:italic>\n                      , and\n                      <jats:italic>Bmp10<\/jats:italic>\n                      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\n                      <jats:italic>Eed<\/jats:italic>\n                      . However,\n                      <jats:italic>Ezh2<\/jats:italic>\n                      inactivation by TNT-Cre did not cause an overt phenotype, likely because of functional redundancy with\n                      <jats:italic>Ezh1<\/jats:italic>\n                      . Thus, early Ezh2 inactivation by Nk2\u20135\n                      <jats:sup>Cre<\/jats:sup>\n                      caused later disruption of cardiomyocyte gene expression and heart development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.111.252205","type":"journal-article","created":{"date-parts":[[2011,12,9]],"date-time":"2011-12-09T02:14:58Z","timestamp":1323396898000},"page":"406-415","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":214,"title":["Polycomb Repressive Complex 2 Regulates Normal Development of the Mouse Heart"],"prefix":"10.1161","volume":"110","author":[{"given":"Aibin","family":"He","sequence":"first","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Ma","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Cao","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"von Gise","sequence":"additional","affiliation":[{"name":"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 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