Ezh2 knockout in mesenchymal cells causes enamel hyper-mineralization

Kobayashi, Yoshifumi; Quispe-Salcedo, Ángela; Bodas, Sanika; Matsumura, Satoko; Li, Erhao; Johnson, Richard S.; Choudhury, Minati; Fine, Daniel H.; Nadimpalli, Siva; Duncan, Henry F.; Dudakovic, Amel; Wijnen, André J. van; Shimizu, Emi

doi:10.1016/j.bbrc.2021.06.003

Cited by 11 publications

(8 citation statements)

References 34 publications

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“…Enhancer of zeste homolog 2 (Ezh2), histone lysine methyltransferase (HKMT), is a sub‐unit of Poly‐comb histone (PCG), which mainly mediates the trimethylation of H3K27. Conditional knockout of Ezh2 in the uncommitted mesenchymal cells reduced the formation of the enamel matrix and increases the activity of enamel protease, resulting in overmineralization of enamel, which was characterized by denser enamel and higher hardness (Kobayashi et al, 2021). Bisphenol A, an environmental endocrine disruptor (EDC), is widely used in plastic products as a raw material of synthetic resin.…”

Section: Resultsmentioning

confidence: 99%

Epigenetics in developmental defects of enamel: A scoping review

Zhang

Cui

et al. 2023

Oral Diseases

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ObjectivesThe significant role of epigenetics has been revealed in normal enamel formation process and occurrence of developmental defects. This presented literature is aiming at summarizing the regulatory function of epigenetics in physiological amelogenesis process and reviewing the epigenetic mechanisms in occurrence of developmental defects of enamel (DDE), so as to provide biological foundation evidence to support early predication and clinical management of DDE.MethodAn extensive literature review was conducted using electronic databases MEDLINE (through PubMed), Web of Science and EMBASE up to November 30, 2022. Studies about epigenetic effects on enamel tissue or cells associated with amelogenesis, including in vivo studies using human or animal models, and in vitro studies, are selected.ResultsA total of 22 studies were included. Epigenetic factors or effects specifically activate or silence certain genes, which may regulate related biological activities including cell proliferation, cell differentiation, enamel secretion, and mineralization during the process of amelogenesis. Once the status of epigenetic modification is altered, the quantity and quality of enamel may both be disturbed, which can finally result in DDE.ConclusionEpigenetics plays a noteworthy role of regulating the amelogenesis process and DDE potentially by altering the expression levels of genes related to enamel formation, providing a new perspective of early predication and clinical management of DDE.

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Section: Resultsmentioning

confidence: 99%

Epigenetics in developmental defects of enamel: A scoping review

Zhang

Cui

et al. 2023

Oral Diseases

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“…Recent research works revealed that genome‐wide H3K27me3 changed dynamically in response to altered oxygen tension via EZH2/KDM6 (Prickaerts et al, 2016). The periodontal neural crest lineage differentiation is characterized by repressive H3K27me3 marks on typical dentinogenesis‐related genes (Francis et al, 2020), and H3K27me3 alternation affected the enamel mineralization (Kobayashi et al, 2021) and osteogenic differentiation of osteoblast (Galvan et al, 2021), periodontal ligament stem cells (PDLCs) (Jiang & Jia, 2021) and DFSCs (Deng et al, 2018). With ChIP‐seq, we found that HOTAIRM1 altered the enrichment of H3K27me3 in promoter region of ALP, M‐CSF, Wnt‐3a, Wnt‐5a, Wnt‐7a, and β‐catenin and promote their transcription.…”

Section: Discussionmentioning

confidence: 99%

LncRNA HOTAIRM1 promotes dental follicle stem cell‐mediated bone regeneration by regulating HIF‐1α/KDM6/EZH2/H3K27me3 axis

Chen

Gan

Chen

et al. 2023

Journal Cellular Physiology

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Large bone defect reconstruction undergoes hypoxia and remains a major practical challenge. Bone tissue engineering with a more promising stem cell source facilitates the development of better therapeutic outcomes. Human dental follicle stem cells (hDFSCs) with superior multipotency, osteogenic capacity, and accessibility have been proven a promising cell source for bone regeneration. We previously identified a novel long noncoding RNA (lncRNA), HOTAIRM1, to be highly expressed in hDFSCs. Here we found that HOTAIRM1 overexpressed hDFSCs promoted bone regeneration in rat critical‐size calvarial defect model. Mechanically, HOTAIRM1 was induced in hDFSCs under hypoxic conditions and activated HIF‐1α. RNA‐sequencing analysis indicated that HOTAIRM1 upregulated oxygen‐sensing histone demethylases KDM6A/B and suppressed methyltransferase EZH2 via targeting HIF‐1α. The osteogenic differentiation of hDFSCs was accompanied with demethylation of H3K27, and HOTAIRM1 overexpression decreased the distribution of H3K27me3 in osteogenic genes, including ALP, M‐CSF, Wnt‐3a, Wnt‐5a, Wnt‐7a, and β‐catenin, thus promoted their transcription. Our study provided evidence that HOTAIRM1 upregulated KDM6A/B and inhibited EZH2 in a HIF‐1α dependent manner to enhance the osteogenesis of hDFSCs. HOTAIRM1‐mediated hDFSCs may serve as a promising therapeutic approach to promote bone regeneration in clinical practice.

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“…This finding is consistent with previous data showing that the deposition of H3K27me3 by methyltransferase Ezh2, the catalytic unit of the polycomb repressive unit 2 (PRC2), regulates MSC commitment to osteogenic and adipogenic lineages [ 16 , 21 – 27 ]. Accordingly, downregulation of Ezh2 by pharmacological inhibition, RNA interference or knockout permits transcription of osteoblastic genes, enhances osteoblast differentiation in vitro and bone formation in vivo [ 25 , 26 , 28 – 33 ] as well as promotes mineralization of dental tissues [ 34 ], while not affecting on tendon differentiation [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Lysine-Specific Demethylase 1 (LSD1) epigenetically controls osteoblast differentiation

et al. 2022

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Epigenetic mechanisms regulate osteogenic lineage differentiation of mesenchymal stromal cells. Histone methylation is controlled by multiple lysine demethylases and is an important step in controlling local chromatin structure and gene expression. Here, we show that the lysine-specific histone demethylase Kdm1A/Lsd1 is abundantly expressed in osteoblasts and that its suppression impairs osteoblast differentiation and bone nodule formation in vitro. Although Lsd1 knockdown did not affect global H3K4 methylation levels, genome-wide ChIP-Seq analysis revealed high levels of Lsd1 at gene promoters and its binding was associated with di- and tri-methylation of histone 3 at lysine 4 (H3K4me2 and H3K4me3). Lsd1 binding sites in osteoblastic cells were enriched for the Runx2 consensus motif suggesting a functional link between the two proteins. Importantly, inhibition of Lsd1 activity decreased osteoblast activity in vivo. In support, mesenchymal-targeted knockdown of Lsd1 led to decreased osteoblast activity and disrupted primary spongiosa ossification and reorganization in vivo. Together, our studies demonstrate that Lsd1 occupies Runx2-binding cites at H3K4me2 and H3K4me3 and its activity is required for proper bone formation.

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Ezh2 knockout in mesenchymal cells causes enamel hyper-mineralization

Cited by 11 publications

References 34 publications

Epigenetics in developmental defects of enamel: A scoping review

Epigenetics in developmental defects of enamel: A scoping review

LncRNA HOTAIRM1 promotes dental follicle stem cell‐mediated bone regeneration by regulating HIF‐1α/KDM6/EZH2/H3K27me3 axis

Lysine-Specific Demethylase 1 (LSD1) epigenetically controls osteoblast differentiation

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