Abstract
Lysine methyltransferase 2D (KMT2D), as one of the key histone methyltransferases responsible for histone 3 lysine 4 methylation (H3K4me), has been proved to be the main pathogenic gene of Kabuki syndrome disease. Kabuki patients with KMT2D mutation frequently present various dental abnormalities, including abnormal tooth number and crown morphology. However, the exact function of KMT2D in tooth development remains unclear. In this report, we systematically elucidate the expression pattern of KMT2D in early tooth development and outline the molecular mechanism of KMT2D in dental epithelial cell line. KMT2D and H3K4me mainly expressed in enamel organ and Kmt2d knockdown led to the reduction in cell proliferation activity and cell cycling activity in dental epithelial cell line (LS8). RNA-sequencing (RNA-seq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis screened out several important pathways affected by Kmt2d knockdown including Wnt signaling. Consistently, Top/Fop assay confirmed the reduction in Wnt signaling activity in Kmt2d knockdown cells. Nuclear translocation of β-catenin was significantly reduced by Kmt2d knockdown, while lithium chloride (LiCl) partially reversed this phenomenon. Moreover, LiCl partially reversed the decrease in cell proliferation activity and G1 arrest, and the down-regulation of Wnt-related genes in Kmt2d knockdown cells. In summary, the present study uncovered a pivotal role of histone methyltransferase KMT2D in dental epithelium proliferation and cell cycle homeostasis partially through regulating Wnt/β-catenin signaling. The findings are important for understanding the role of KMT2D and histone methylation in tooth development.
Highlights
Tooth development starts from the formation of dental lamina, after which dental epithelial cells proliferate downward to form a tooth bud and the enamel organ [1]
The results showed that during the bud stage (Embryo Day 12.5, E12.5, Fig. 1A1) and cap stage (Embryo Day 14.5, E14.5, Fig. 1A2) of mouse tooth germs, KMT2D was expressed mainly in dental epithelium, whereas few signals were observed in the mesenchyme
At the early bell stage (Embryo Day 16.5, E16.5, Fig. 1A3), KMT2D was distributed in the inner enamel epithelium, with no signal observed in the dental papilla
Summary
Tooth development starts from the formation of dental lamina, after which dental epithelial cells proliferate downward to form a tooth bud and the enamel organ [1]. The stable control of dental epithelium proliferation is essential for the formation of the enamel knot, which determines the morphology of the enamel organ and tooth crown. Studies on the mechanisms underlying dental epithelial cell proliferation are crucial for understanding tooth development, which would help to lay a foundation for tooth regeneration. Classical signaling pathways have been widely found to take part in dental epithelium proliferation and tooth development[2,3,4]. :QWȕ-catenin signaling is considered to play crucial roles at different stages of tooth formation[5, 6]. The importance of epigenetic regulation has been gradually emphasized in embryonic development, since that the possibly reversible ability of epigenetic messages such as histone modification showed great therapeutic
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