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Ezh2 knockout in mesenchymal cells causes enamel hyper-mineralization.

ABSTRACT: Enhancer of zeste homolog 2 (EZH2) is the catalytic core of polycomb repressive complex 2 (PRC2), which primarily methylates lysine 27 on histone H3 (H2K27me3), generating transcriptionally suppressed heterochromatin. Since EZH2 suppresses expression of genes involved in dentin formation, we examined the role of EZH2 in tooth development. Intriguingly, microCT analysis of teeth from mice with conditional Ezh2 knockout in uncommitted mesenchymal cells showed hyper-mineralization of enamel, which is produced by the epithelial-lineage cells, ameloblasts. Scanning electron microscopy analysis and nano-indentation of the incisor enamel from knockout mice revealed smaller inter-rod spaces and higher hardness compared to wild type enamel, respectively. Interestingly, expression of the calcium channel subunit gene, Orai2, was decreased compared to its competitor, Orai1, both in knockout mouse incisors and the ex vivo culture of ameloblasts with the surrounding tissues under EZH2 inhibition. Moreover, histological analysis of incisor from knockout mice showed decreased ameloblastin and expedited KLK4 expression in the ameloblasts. These observations suggest that EZH2 depletion in dental mesenchymal cells reduces enamel matrix formation and increases enamel protease activity from ameloblasts, resulting in enamel hyper-mineralization. This study demonstrates the significant role of the suppressive H3K27me3 mark for heterochromatin on enamel formation.

SUBMITTER: Kobayashi Y

PROVIDER: S-EPMC8290883 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Ezh2 knockout in mesenchymal cells causes enamel hyper-mineralization.

Kobayashi Yoshifumi Y Quispe-Salcedo Angela A Bodas Sanika S Matsumura Satoko S Li Erhao E Johnson Richard R Choudhury Marwa M Fine Daniel H DH Nadimpalli Siva S Duncan Henry F HF Dudakovic Amel A van Wijnen Andre J AJ Shimizu Emi E

Biochemical and biophysical research communications 20210616

Enhancer of zeste homolog 2 (EZH2) is the catalytic core of polycomb repressive complex 2 (PRC2), which primarily methylates lysine 27 on histone H3 (H2K27me3), generating transcriptionally suppressed heterochromatin. Since EZH2 suppresses expression of genes involved in dentin formation, we examined the role of EZH2 in tooth development. Intriguingly, microCT analysis of teeth from mice with conditional Ezh2 knockout in uncommitted mesenchymal cells showed hyper-mineralization of enamel, which ...[more]

PMID: 34144503

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Project description:The present study was conducted to investigate the role of proteolysis by matrix metalloproteinase 20 (MMP20) in regulating the initial formation of the enamel mineral structure during the secretory stage of amelogenesis, utilizing Mmp20-null mice that lack this essential protease. Ultrathin sagittal sections of maxillary incisors from 8-wk-old wild-type (WT), Mmp20-null (KO), and heterozygous (HET) littermates were prepared. Secretory-stage enamel ultrastructures from each genotype as a function of development were compared using transmission electron microscopy, selected area electron diffraction, and Raman microspectroscopy. Characteristic rod structures observed in WT enamel exhibited amorphous features in newly deposited enamel, which subsequently transformed into apatite-like crystals in older enamel. Surprisingly, initial mineral formation in KO enamel was found to proceed in the same manner as in the WT. However, soon after a rod structure began to form, large plate-like crystals appeared randomly within the developing KO enamel layer. As development continued, observed plate-like crystals became dominant and obscured the appearance of the enamel rod structure. Upon formation of these plate-like crystals, the KO enamel layer stopped growing in thickness, unlike WT and HET enamel layers that continued to grow at the same rate. Raman results indicated that Mmp20-KO enamel contains a significant portion of octacalcium phosphate, unlike WT enamel. Although normal in all other respects, large, randomly dispersed mineral crystals were observed in secretory HET enamel, although to a lesser extent than that seen in KO enamel, indicating that the level of MMP20 expression has a proportional effect on suppressing aberrant mineral formation. In conclusion, we found that proteolysis of extracellular enamel matrix proteins by MMP20 is not required for the initial development of the enamel rod structure during the early secretory stage of amelogenesis. Proteolysis by MMP20, however, is essential for the prevention of abnormal crystal formation during amelogenesis.

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Ezh2 knockout in mesenchymal cells causes enamel hyper-mineralization.

Publications

Ezh2 knockout in mesenchymal cells causes enamel hyper-mineralization.

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