title: Retinoic acid inhibits histone methyltransferase Whsc1 during palatogenesis.
abstract: Cleft lip with or without palate (CL/P) is a common congenital anomaly in humans and is thought to be caused by genetic and environmental factors. However, the epigenetic mechanisms underlying orofacial clefts are not fully understood. Here, we investigate how the overdose of retinoic acid (RA), which can induce cleft palate in mice and humans, regulates histone methyltransferase, Wolf-Hirschhorn syndrome candidate 1 (WHSC1) during palatal development in mice. We treated mouse embryonic fibroblasts (MEFs) with 1 μM all-trans RA and discovered that the global level of H3K36me3 was downregulated and that expression of the H3K36 methyltransferase gene, Whsc1, was reduced. The expression level of WHSC1 in embryonic palatal shelves was reduced during palatogenesis, following maternal administration of 100 mg/kg body weight of RA by gastric intubation. Furthermore, the expression of WHSC1 in palatal shelves was observed in epithelial and mesenchymal cells at all stages, suggesting an important role for palatal development. Our results suggest that the pathogenesis of cleft palate observed after excessive RA exposure is likely to be associated with a reduction in the histone methyltransferase, WHSC1.
authors: Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Shiying
authors: S
authors: Liu
authors: Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Electronic address: n-higashihori.mort@tmd.ac.jp.
authors: Norihisa
authors: N
authors: Higashihori
authors: Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Kohei
authors: K
authors: Yahiro
authors: Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Keiji
authors: K
authors: Moriyama
mesh_terms: D000818:Animals; D002460:Cell Line; D002972:Cleft Palate / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D062787:Drug Overdose / Q000150:complications*; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010159:Palate / Q000002:abnormalities / Q000196:embryology*; D012333:RNA, Messenger / Q000235:genetics; D014212:Tretinoin / Q000009:adverse effects*
chemical_list: D006657:Histones; D012333:RNA, Messenger; D014212:Tretinoin; D011495:Histone-Lysine N-Methyltransferase; C543213:WHSC1 protein, mouse
keywords: Cleft palate; Epigenetic; Histone methyltransferase; Retinoic acid; Whsc1