2025-07-01 バッファロー大学(UB)
Research reveals how targeting gene could help correct oral disorders, prevent craniofacial birth defects
<関連情報>
- https://www.buffalo.edu/news/releases/2025/07/tooth-enamel-gene-study.html
- https://journals.sagepub.com/doi/abs/10.1177/00220345251320922
KMT2Dは歯エナメル質の発達を制御する KMT2D Regulates Tooth Enamel Development
J.-M. Lee, H. Jung, […], and H.-J.E. Kwon
Journal of Dental Research Published:March 18, 2025
DOI:https://doi.org/10.1177/00220345251320922
Abstract
Amelogenesis, the process of enamel formation, is tightly regulated and essential for producing the tooth enamel that protects teeth from decay and wear. Disruptions in amelogenesis can result in amelogenesis imperfecta, a group of genetic conditions characterized by defective enamel, including enamel hypoplasia, marked by thin or underdeveloped enamel. Mutations in the KMT2D (MLL4) gene, which encodes histone H3 lysine 4 methyltransferase, are associated with Kabuki syndrome, a developmental disorder that can involve dental anomalies such as enamel hypoplasia. However, the specific role of KMT2D in amelogenesis remains poorly understood. To address this gap, we generated a conditional knockout (cKO) mouse model with ectoderm-specific deletion of Kmt2d (Krt14-Cre;Kmt2dfl/fl, or Kmt2d-cKO) and characterized the resulting enamel defects using gross, radiographic, histologic, cellular, and molecular analyses. Micro–computed tomography and scanning electron microscopy revealed that adult Kmt2d-cKO mice exhibited 100% penetrant amelogenesis imperfecta, characterized by hypoplastic and hypomineralized enamel, partially phenocopying human Kabuki syndrome. Additionally, Kmt2d-cKO neonates developed molar tooth germs with subtle cusp shape alterations and mild delays in ameloblast differentiation at birth. RNA sequencing analysis of the first molar tooth germ at birth revealed that 33.7% of known amelogenesis-related genes were significantly downregulated in the Kmt2d-cKO teeth. Integration with KMT2D CUT&RUN sequencing results identified 8 overlapping genes directly targeted by KMT2D. Reanalysis of a single-cell RNA sequencing data set in the developing mouse incisors revealed distinct roles for these genes in KMT2D-regulated differentiation across various cell subtypes within the dental epithelium. Among these genes, Satb1 and Sp6 are likely direct targets involved in the differentiation of preameloblasts into ameloblasts. Taken together, we propose that KMT2D plays a crucial role in amelogenesis by directly activating key genes involved in ameloblast differentiation, offering insights into the molecular basis of enamel development and related dental pathologies.
