The Transcription Factor DLX3 Regulates the Osteogenic Differentiation of Human Dental Follicle Precursor Cells

Viale-Bouroncle, Sandra; Felthaus, Oliver; Schmalz, Gottfried; Brockhoff, Gero; Reichert, Torsten E.; Morsczeck, Christian

doi:10.1089/scd.2011.0422

Cited by 54 publications

(49 citation statements)

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“…Dlx3 is a member of the distalless homeobox family that interacts with transcription factors specific to mineralized tissue to regulate craniofacial and postnatal skeletal development (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Our results indicate that there is a cellular requirement for miR-665 to fine-tune the expression of Dlx3 within physiologic limits for maturation of progenitors to odontoblasts.…”

Section: Discussionmentioning

confidence: 78%

“…Studies from several research groups have revealed that homeodomain gene Dlx3 (Online Mendelian Inheritance in Man [OMIM] entry 600525) is a highly critical regulator of craniofacial and postnatal skeletal development (28)(29)(30)(31)(32)(33)(34). Mutations in DLX3 in humans have been associated with tricho-dento-osseous syndrome (TDO; OMIM 190320) and amelogenesis imperfecta with taurodontism (AIHHT; OMIM 104510), both of which are conditions characterized by abnormalities in tooth formation (35)(36)(37)(38)(39).…”

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confidence: 99%

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MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

Heair

Kemper

Roy

et al. 2015

Molecular and Cellular Biology

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bStudies of proteins involved in microRNA (miRNA) processing, maturation, and silencing have indicated the importance of miRNAs in skeletogenesis, but the specific miRNAs involved in this process are incompletely defined. Here, we identified miRNA 665 (miR-665) as a potential repressor of odontoblast maturation. Studies with cultured cell lines and primary embryonic cells showed that miR-665 represses the expression of early and late odontoblast marker genes and stage-specific proteases involved in dentin maturation. Notably, miR-665 directly targeted Dlx3 mRNA and decreased Dlx3 expression. Furthermore, RNA-induced silencing complex (RISC) immunoprecipitation and biotin-labeled miR-665 pulldown studies identified Kat6a as another potential target of miR-665. KAT6A interacted physically and functionally with RUNX2, activating tissue-specific promoter activity and prompting odontoblast differentiation. Overexpression of miR-665 reduced the recruitment of KAT6A to Dspp and Dmp1 promoters and prevented KAT6A-induced chromatin remodeling, repressing gene transcription. Taken together, our results provide novel molecular evidence that miR-665 functions in an miRNA-epigenetic regulatory network to control dentinogenesis. D entinogenesis is the process by which dentin, the major mineralized tissue of teeth, is formed through progressive cytodifferentiation of progenitor cells to mature odontoblasts (1). Multiple layers of gene regulation, including those by microRNA (miRNA), orchestrate the physiologic process of dentinogenesis in a stage-specific manner (2). Progenitor cells, including dental papilla cells or dental follicle cells, derived from the ectomesenchyme of the cranial neural crest, differentiate into preodontoblasts and produce predentin. Predentin stimulates further differentiation of the cells it surrounds, giving rise to mature odontoblasts that produce dentin. Odontoblast secretion of dentin extracellular matrix proteins, including dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP1), aids in the process of mineralization that forms primary dentin. However, the mechanisms of odontoblast-specific gene regulation by miRNA during dentinogenesis are not clearly understood.miRNAs are endogenous, noncoding RNAs implicated in posttranscriptional RNA silencing (3-9). The importance of miRNAs in skeletogenesis has been shown in mice by loss-offunction analysis of proteins involved in miRNA processing (Drosha and DGCR8), maturation (Dicer), and silencing (argonaute 2; AGO2), which revealed embryonic lethality and severe developmental defects upon loss of these proteins (10-15). Furthermore, cartilage-specific deletion of Dicer led to accelerated differentiation and subsequent cell death (11), whereas osteoblast-and osteoclast-specific deletion increased bone mass (13,16). Current studies on miRNA regulation of gene expression indicate a key role for this process in tooth development (17)(18)(19)(20) and in controlling cellular signaling (18,(21)(22)(23)(24)(25) and differentiation (2,26). However, ...

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Section: Discussionmentioning

confidence: 78%

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confidence: 99%

MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

Heair

Kemper

Roy

et al. 2015

Molecular and Cellular Biology

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“…[52,53] Dlx3 collaborates with transcription factors unique to mineralized tissue to regulate craniofacial and postnatal skeletal development. [54][55][56] Dlx3 stimulates dentinogenesis. The posttranscriptional regulation of Dlx3 by miR-665 controlled by BMP2 and RUNX2, implies an combined network of signaling and transcription factors that coordinate the stagespecific events of odontoblast differentiation.…”

Section: Dentinogenesismentioning

confidence: 99%

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Juneius

2016

AJP

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Aim: To review the literature on the oral health status of the population, evidence-based understanding of epigenetic mechanisms, and its significant role in diseases occurring in the oral cavity. Background: Epigenetics is the study of heritable changes in gene expression that does not involve changes to the underlying DNA sequence. In other words, it is a change in phenotype without a change in genotype, which in turn affects the way cells read genes. Epigenetic change is a regular and natural occurrence but can also be influenced by several factors including age, the environment/lifestyle, and disease state. The field of epigenetics is quickly growing, and it is believed that both the environment and lifestyle can interact with the genome to influence epigenetic change. These changes may be reflected at various stages throughout a person's life and even in later generations. Conclusion: Epigenetic codes help us understand the biological phenotype that arises from the interaction of the human genome with the environment in health and in disease. Epigenetics is a major turn away from molecular biology. Current epigenetics not only offers new insights into gene regulation and heredity, but also it challenges the way we think about evolution, genetics, and development. Most interestingly, it suggests testable mechanisms whereby environmental factors (ranging from stress to infection) can influence genetic expression.

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“…Using microarray technology, the authors showed that overexpression of DLX3 in DFSCs leads to upregulation of 73 genes ( e.g ., IL8, CXCL10, CXCL11, MMP1, BMP2, NR4A2, HES1 and ATF3) and downregulation of 55 genes ( e.g ., COL3A1, ELN, OMD and PLXNC1). DLX3 regulates osteogenic differentiation and mineralization of DFSCs through BMP2-dependent pathway and feedback control [ 60 ].…”

Section: Genetic Modifi Cation For Modulation Of Cell Phenotype and Omentioning

confidence: 99%

Genetically Engineered Dental Stem Cells for Regenerative Medicine

2016

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The Transcription Factor DLX3 Regulates the Osteogenic Differentiation of Human Dental Follicle Precursor Cells

Cited by 54 publications

References 51 publications

MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

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Genetically Engineered Dental Stem Cells for Regenerative Medicine

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