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Ezh2 encodes a core catalytic component of the Polycomb repressive complex responsible for addition of methyl marks to Histone H3 as a mechanism of repressing target genes. The role of Ezh2 in orofacial clefts remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>To investigate the epithelial role of Ezh2\u2010dependent methylation in secondary palatogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used conditional gene\u2010targeting methods to ablate Ezh2 in the surface ectoderm\u2010derived oral epithelium of mouse embryos. We then performed single\u2010cell RNA sequencing combined with immunofluorescence and RT\u2010qPCR to investigate gene expression in conditional mutant palate. We also employed double knockout analyses of Ezh1 and Ezh2 to address if they have synergistic roles in palatogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that conditional inactivation of Ezh2 in oral epithelia results in partially penetrant cleft palate. Double knockout analyses revealed that another family member Ezh1 is dispensable in orofacial development, and it does not have synergistic roles with Ezh2 in palatogenesis. Histochemistry and single\u2010cell RNA\u2010seq analyses revealed dysregulation of cell cycle regulators in the palatal epithelia of Ezh2 mutant mouse embryos disrupts palatogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Ezh2\u2010dependent histone H3K27 methylation represses expression of cell cycle regulator Cdkn1a and promotes proliferation in the epithelium of the developing palatal shelves. Loss of this regulation may perturb movement of the palatal shelves, causing a delay in palate elevation which may result in failure of the secondary palate to close altogether.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.2216","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T10:41:48Z","timestamp":1689158508000},"page":"1851-1865","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ezh2\u2010dependent methylation in oral epithelia promotes secondary palatogenesis"],"prefix":"10.1002","volume":"115","author":[{"given":"Bo","family":"Sun","sequence":"first","affiliation":[{"name":"Institute for Pediatric Regenerative Medicine of Shriners Hospital for Children\u2014Northern California &amp; Department of Biochemistry and Molecular Medicine School of Medicine, University of California at Davis  Sacramento California 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