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: Shiying Liu, Norihisa Higashihori, Kohei Yahiro, Keiji Moriyama
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 458 Issue 3 Pg. 525-530 (Mar 13 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25677622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Histones
• RNA, Messenger
• Tretinoin
• Histone-Lysine N-Methyltransferase
• WHSC1 protein, mouse

Topics

• Animals
• Cell Line
• Cleft Palate (chemically induced, genetics, metabolism)
• Down-Regulation (drug effects)
• Drug Overdose (complications)
• Female
• Histone-Lysine N-Methyltransferase (analysis, antagonists & inhibitors, genetics, metabolism)
• Histones (metabolism)
• Methylation (drug effects)
• Mice
• Mice, Inbred C57BL
• Palate (abnormalities, embryology)
• RNA, Messenger (genetics)
• Tretinoin (adverse effects)