Transcriptional Regulation of Dental Epithelial Cell Fate

Yoshizaki, Keigo; Fukumoto, Satoshi; Bikle, Daniel; Oda, Yuko

doi:10.3390/ijms21238952

Cited by 12 publications

(22 citation statements)

References 87 publications

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“…During tooth development, various genes are involved in the differentiation of dental cells and cell fate determination (Thesleff 2003; Yoshizaki et al 2020). To date, numerous studies have sought to identify the genes involved in tooth development.…”

Section: Discussionmentioning

confidence: 99%

Integration of Single-Cell RNA- and CAGE-seq Reveals Tooth-Enriched Genes

et al. 2021

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Organ development is dictated by the regulation of genes preferentially expressed in tissues or cell types. Gene expression profiling and identification of specific genes in organs can provide insights into organogenesis. Therefore, genome-wide analysis is a powerful tool for clarifying the mechanisms of development during organogenesis as well as tooth development. Single-cell RNA sequencing (scRNA-seq) is a suitable tool for unraveling the gene expression profile of dental cells. Using scRNA-seq, we can obtain a large pool of information on gene expression; however, identification of functional genes, which are key molecules for tooth development, via this approach remains challenging. In the present study, we performed cap analysis of gene expression sequence (CAGE-seq) using mouse tooth germ to identify the genes preferentially expressed in teeth. The CAGE-seq counts short reads at the 5′-end of transcripts; therefore, this method can quantify the amount of transcripts without bias related to the transcript length. We hypothesized that this CAGE data set would be of great help for further understanding a gene expression profile through scRNA-seq. We aimed to identify the important genes involved in tooth development via bioinformatics analyses, using a combination of scRNA-seq and CAGE-seq. We obtained the scRNA-seq data set of 12,212 cells from postnatal day 1 mouse molars and the CAGE-seq data set from postnatal day 1 molars. scRNA-seq analysis revealed the spatiotemporal expression of cell type–specific genes, and CAGE-seq helped determine whether these genes are preferentially expressed in tooth or ubiquitously. Furthermore, we identified candidate genes as novel tooth-enriched and dental cell type–specific markers. Our results show that the integration of scRNA-seq and CAGE-seq highlights the genes important for tooth development among numerous gene expression profiles. These findings should contribute to resolving the mechanism of tooth development and establishing the basis for tooth regeneration in the future.

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Section: Discussionmentioning

confidence: 99%

Integration of Single-Cell RNA- and CAGE-seq Reveals Tooth-Enriched Genes

et al. 2021

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“…Various transcription factors have been reported to regulate ameloblast differentiation during tooth development (Yoshizaki et al, 2020). Epiprofin ( Epfn/Sp6 ) is one of the transcription factors essential for amelogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Differentiated ameloblasts produce enamel matrix proteins, such as ameloblastin (AMBN), for enamel formation. Various transcription factors are involved in this ameloblast lineage development (Yoshizaki et al, 2020). By performing gene expression screening of developing teeth, we recently identified Sox21 and AmeloD/Ascl5 as key transcription factors in ameloblast development (He et al, 2018; Saito et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

The tooth‐specific basic helix‐loop‐helix factor AmeloD promotes differentiation of ameloblasts

Jia

Chiba

Saito

et al. 2021

Journal Cellular Physiology

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Tissue-specific basic helix-loop-helix (bHLH) transcription factors play an important role in cellular differentiation. We recently identified AmeloD as a tooth-specific bHLH transcription factor. However, the role of AmeloD in cellular differentiation has not been investigated. The aim of this study was to elucidate the role of AmeloD in dental epithelial cell differentiation. We found that AmeloD-knockout (AmeloD-KO) mice developed an abnormal structure and altered ion composition of enamel in molars, suggesting that AmeloD-KO mice developed enamel hypoplasia.In molars of AmeloD-KO mice, the transcription factor Sox21 encoding SRY-Box transcription factor 21 and ameloblast differentiation marker genes were significantly downregulated. Furthermore, overexpression of AmeloD in the dental epithelial cell line M3H1 upregulated Sox21 and ameloblast differentiation marker genes, indicating that AmeloD is critical for ameloblast differentiation. Our study demonstrated that AmeloD is an important transcription factor in amelogenesis for promoting ameloblast differentiation. This study provides new insights into the mechanisms of amelogenesis.

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“…The activity of signal molecules is mediated by transcription factors, which activate a battery of genes and eventually determine ameloblast differentiation ( Balic and Thesleff, 2015 ; Yoshizaki et al, 2020 ). Epiprofin (Epfn), a zinc-finger transcription factor from the Sp/KLF family, is specifically expressed in the dental epithelial lineage ( Nakamura et al, 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Epiprofin Transcriptional Activation Promotes Ameloblast Induction From Mouse Induced Pluripotent Stem Cells via the BMP-Smad Signaling Axis

Miao

Niibe

et al. 2022

Front. Bioeng. Biotechnol.

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The transcriptional regulation of induced pluripotent stem cells (iPSCs) holds promise for their directed differentiation into ameloblasts, which are usually lost after tooth eruption. Ameloblast differentiation is regulated by multiple signaling molecules, including bone morphogenetic proteins (BMPs). Epiprofin (Epfn), a transcription factor, is expressed in the dental epithelium, and epithelial Epfn overexpression results in ectopic ameloblast differentiation and enamel formation in mouse incisor, a striking phenotype resembling that of mice with deletion of follistatin (a BMP inhibitor). However, it remains unknown whether and how Epfn transcriptional activation promotes ameloblast induction from mouse iPSCs. Here, we generated doxycycline-inducible Epfn-expressing mouse iPSCs (Epfn-iPSCs). Ameloblasts, which are characterized by positive staining for keratin 14 and amelogenin and alizarin red S staining, were successfully derived from Epfn-iPSCs based on a stage-specific induction protocol, which involved the induction of the surface ectoderm, dental epithelial cells, and ameloblasts at stages 1, 2, and 3, respectively. Epfn activation by doxycycline at stages 2 and/or 3 decreased cell proliferation and promoted ameloblast differentiation, along with the upregulation of p-Smad1/5/8, a key regulator of the BMP-Smad signaling pathway. Gene analysis of the BMP-Smad signaling pathway-associated molecules revealed that Epfn activation decreased follistatin expression at stage 2, but increased BMP2/4/7 expression at stage 3. Perturbations in the ameloblast differentiation process were observed when the BMP-Smad signaling pathway was inhibited by a BMP receptor inhibitor (LDN-193189). Simultaneous LDN-193189 treatment and Epfn activation largely reversed the perturbations in ameloblast induction, with partial recovery of p-Smad1/5/8 expression, suggesting that Epfn activation promotes ameloblast induction from mouse iPSCs partially by upregulating BMP-Smad activity. These results reveal the potential regulatory networks between Epfn and the BMP-Smad pathway and suggest that Epfn is a promising target for inducing the differentiation of ameloblasts, which can be used in enamel and tooth regeneration.

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Transcriptional Regulation of Dental Epithelial Cell Fate

Cited by 12 publications

References 87 publications

Integration of Single-Cell RNA- and CAGE-seq Reveals Tooth-Enriched Genes

Integration of Single-Cell RNA- and CAGE-seq Reveals Tooth-Enriched Genes

The tooth‐specific basic helix‐loop‐helix factor AmeloD promotes differentiation of ameloblasts

Epiprofin Transcriptional Activation Promotes Ameloblast Induction From Mouse Induced Pluripotent Stem Cells via the BMP-Smad Signaling Axis

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