MicroRNA-93-5p regulates odontogenic differentiation and dentin formation via KDM6B.

BACKGROUND: Epigenetic factors influence the odontogenic differentiation of dental pulp stem cells and play indispensable roles during tooth development. Some microRNAs can epigenetically regulate other epigenetic factors like DNA methyltransferases and histone modification enzymes, functioning as epigenetic-microRNAs. In our previous study, microarray analysis suggested microRNA-93-5p (miR-93-5p) was differentially expressed during the bell stage in human tooth germ. Prediction tools indicated that miR-93-5p may target lysine-specific demethylase 6B (KDM6B). Therefore, we explored the role of miR-93-5p as an epi-miRNA in tooth development and further investigated the underlying mechanisms of miR-93-5p in regulating odontogenic differentiation and dentin formation. METHODS: The expression pattern of miR-93-5p and KDM6B of dental pulp stem cells (DPSCs) was examined during tooth development and odontogenic differentiation. Dual luciferase reporter and ChIP-qPCR assay were used to validate the target and downstream regulatory genes of miR-93-5p in human DPSCs (hDPSCs). Histological analyses and qPCR assays were conducted for investigating the effects of miR-93-5p mimic and inhibitor on odontogenic differentiation of hDPSCs. A pulpotomy rat model was further established, microCT and histological analyses were performed to explore the effects of KDM6B-overexpression and miR-93-5p inhibition on the formation of tertiary dentin. RESULTS: The expression level of miR-93-5p decreased as odontoblast differentiated, in parallel with elevated expression of histone demethylase KDM6B. In hDPSCs, miR-93-5p overexpression inhibited the odontogenic differentiation and vice versa. MiR-93-5p targeted 3' untranslated region (UTR) of KDM6B, thereby inhibiting its protein translation. Furthermore, KDM6B bound the promoter region of BMP2 to demethylate H3K27me3 marks and thus upregulated BMP2 transcription. In the rat pulpotomy model, KDM6B-overexpression or miR-93-5p inhibition suppressed H3K27me3 level in DPSCs and consequently promoted the formation of tertiary dentin. CONCLUSIONS: MiR-93-5p targets epigenetic regulator KDM6B and regulates H3K27me3 marks on BMP2 promoters, thus modulating the odontogenic differentiation of DPSCs and dentin formation.

METTL3 enhances dentinogenesis differentiation of dental pulp stem cells via increasing GDF6 and STC1 mRNA stability.

BACKGROUND: The dentinogenesis differentiation of dental pulp stem cells (DPSCs) is controlled by the spatio-temporal expression of differentiation related genes. RNA N6-methyladenosine (m6A) methylation, one of the most abundant internal epigenetic modification in mRNA, influences various events in RNA processing, stem cell pluripotency and differentiation. Methyltransferase like 3 (METTL3), one of the essential regulators, involves in the process of dentin formation and root development, while mechanism of METTL3-mediated RNA m6A methylation in DPSC dentinogenesis differentiation is still unclear. METHODS: Immunofluorescence staining and MeRIP-seq were performed to establish m6A modification profile in dentinogenesis differentiation. Lentivirus were used to knockdown or overexpression of METTL3. The dentinogenesis differentiation was analyzed by alkaline phosphatase, alizarin red staining and real time RT-PCR. RNA stability assay was determined by actinomycin D. A direct pulp capping model was established with rat molars to reveal the role of METTL3 in tertiary dentin formation. RESULTS: Dynamic characteristics of RNA m6A methylation in dentinogenesis differentiation were demonstrated by MeRIP-seq. Methyltransferases (METTL3 and METTL14) and demethylases (FTO and ALKBH5) were gradually up-regulated during dentinogenesis process. Methyltransferase METTL3 was selected for further study. Knockdown of METTL3 impaired the DPSCs dentinogenesis differentiation, and overexpression of METTL3 promoted the differentiation. METTL3-mediated m6A regulated the mRNA stabiliy of GDF6 and STC1. Furthermore, overexpression of METTL3 promoted tertiary dentin formation in direct pulp capping model. CONCLUSION: The modification of m6A showed dynamic characteristics during DPSCs dentinogenesis differentiation. METTL3-mediated m6A regulated in dentinogenesis differentiation through affecting the mRNA stability of GDF6 and STC1. METTL3 overexpression promoted tertiary dentin formation in vitro, suggesting its promising application in vital pulp therapy (VPT).

Epigenetics in developmental defects of enamel: A scoping review.

OBJECTIVES: The 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. METHOD: An 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. RESULTS: A 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. CONCLUSION: Epigenetics 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.

Epigenetic regulation of dental-derived stem cells and their application in pulp and periodontal regeneration.

Dental-derived stem cells have excellent proliferation ability and multi-directional differentiation potential, making them an important research target in tissue engineering. An increasing number of dental-derived stem cells have been discovered recently, including dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHEDs), stem cells from apical papilla (SCAPs), dental follicle precursor cells (DFPCs), and periodontal ligament stem cells (PDLSCs). These stem cells have significant application prospects in tissue regeneration because they are found in an abundance of sources, and they have good biocompatibility and are highly effective. The biological functions of dental-derived stem cells are regulated in many ways. Epigenetic regulation means changing the expression level and function of a gene without changing its sequence. Epigenetic regulation is involved in many biological processes, such as embryonic development, bone homeostasis, and the fate of stem cells. Existing studies have shown that dental-derived stem cells are also regulated by epigenetic modifications. Pulp and periodontal regeneration refers to the practice of replacing damaged pulp and periodontal tissue and restoring the tissue structure and function under normal physiological conditions. This treatment has better therapeutic effects than traditional treatments. This article reviews the recent research on the mechanism of epigenetic regulation of dental-derived stem cells, and the core issues surrounding the practical application and future use of pulp and periodontal regeneration.

Metabolic-epigenetic nexus in regulation of stem cell fate.

Stem cell fate determination is one of the central questions in stem cell biology, and although its regulation has been studied at genomic and proteomic levels, a variety of biological activities in cells occur at the metabolic level. Metabolomics studies have established the metabolome during stem cell differentiation and have revealed the role of metabolites in stem cell fate determination. While metabolism is considered to play a biological regulatory role as an energy source, recent studies have suggested the nexus between metabolism and epigenetics because several metabolites function as cofactors and substrates in epigenetic mechanisms, including histone modification, DNA methylation, and microRNAs. Additionally, the epigenetic modification is sensitive to the dynamic metabolites and consequently leads to changes in transcription. The nexus between metabolism and epigenetics proposes a novel stem cell-based therapeutic strategy through manipulating metabolites. In the present review, we summarize the possible nexus between metabolic and epigenetic regulation in stem cell fate determination, and discuss the potential preventive and therapeutic strategies via targeting metabolites.

Deletion of ApoE Leads to Intervertebral Disc Degeneration via Aberrant Activation of Adipokines.

STUDY DESIGN: Animal experiment: a mouse model of intervertebral disc (IVD) degeneration induced by deletion of apolipoprotein E (apoE). OBJECTIVE: The aim of this study was to investigate the role and mechanism of apoE on the process of IVD degeneration. SUMMARY OF BACKGROUND DATA: Abnormal lipid metabolism has been demonstrated to be closely related to IVD degeneration, a common chronic degenerative joint disease. ApoE, a component of apolipoproteins, plays a crucial role in lipid transportation and metabolic balance. But the relationship between apoE and IVD degeneration remains largely unknown. METHODS: ApoE knockout (KO) mouse was employed to investigate the progressive disc degeneration. The changes of vertebral bone and intervertebral disc space were measured by micro-computed tomography (micro-CT). The histo-morphological changes of cartilage endplate (CEP) and underlying signals were tested using immunohistochemistry and immunofluorescence staining. RESULTS: The deletion of apoE gene accelerated the lumbar spine degeneration. Compared with WT mice, apoE KO mice showed reduced IVD space and increased vertebral bone mass. The progressive CEP degeneration was further found with cartilage degradation and endplate sclerosis in apoE KO mice. The deletion of apoE stimulated abnormal CEP bone remodeling and activation of adipokines signals. CONCLUSION: The deletion of apoE gene induced abnormal activation of adipokines signals, thus contribute to the CEP degeneration. LEVEL OF EVIDENCE: N/A.

Epigenetic regulation of dental pulp stem cells and its potential in regenerative endodontics.

Regenerative endodontics (RE) therapy means physiologically replacing damaged pulp tissue and regaining functional dentin-pulp complex. Current clinical RE procedures recruit endogenous stem cells from the apical papilla, periodontal tissue, bone marrow and peripheral blood, with or without application of scaffolds and growth factors in the root canal space, resulting in cementum-like and bone-like tissue formation. Without the involvement of dental pulp stem cells (DPSCs), it is unlikely that functional pulp regeneration can be achieved, even though acceptable repair can be acquired. DPSCs, due to their specific odontogenic potential, high proliferation, neurovascular property, and easy accessibility, are considered as the most eligible cell source for dentin-pulp regeneration. The regenerative potential of DPSCs has been demonstrated by recent clinical progress. DPSC transplantation following pulpectomy has successfully reconstructed neurovascularized pulp that simulates the physiological structure of natural pulp. The self-renewal, proliferation, and odontogenic differentiation of DPSCs are under the control of a cascade of transcription factors. Over recent decades, epigenetic modulations implicating histone modifications, DNA methylation, and noncoding (nc)RNAs have manifested as a new layer of gene regulation. These modulations exhibit a profound effect on the cellular activities of DPSCs. In this review, we offer an overview about epigenetic regulation of the fate of DPSCs; in particular, on the proliferation, odontogenic differentiation, angiogenesis, and neurogenesis. We emphasize recent discoveries of epigenetic molecules that can alter DPSC status and promote pulp regeneration through manipulation over epigenetic profiles.

Roles of Dental Mesenchymal Stem Cells in the Management of Immature Necrotic Permanent Teeth.

Dental caries and trauma always lead to pulp necrosis and subsequent root development arrest of young permanent teeth. The traditional treatment, apexification, with the absence of further root formation, results in abnormal root morphology and compromises long-term prognosis. Regeneration endodontics procedures (REPs) have been developed and considered as an alternative strategy for management of immature permanent teeth with pulpal necrosis, including cell-free and cell-based REPs. Cell-free REPs, including revascularization and cell homing with molecules recruiting endogenous mesenchymal stem cells (MSCs), have been widely applied in clinical treatment, showing optimistic periapical lesion healing and continued root development. However, the regenerated pulp-dentin complex is still absent in these cases. Dental MSCs, as one of the essentials of tissue engineering, are vital seed cells in regenerative medicine. Dental MSC-based REPs have presented promising potential with pulp-dentin regeneration in large animal studies and clinical trials via cell transplantation. In the present review, we summarize current understanding of the biological basis of clinical treatments for immature necrotic permanent teeth and the roles of dental MSCs during this process and update the progress of MSC-based REPs in the administration of immature necrotic permanent teeth.

New insight into dental epithelial stem cells: Identification, regulation, and function in tooth homeostasis and repair.

Tooth enamel, a highly mineralized tissue covering the outermost area of teeth, is always damaged by dental caries or trauma. Tooth enamel rarely repairs or renews itself, due to the loss of ameloblasts and dental epithelial stem cells (DESCs) once the tooth erupts. Unlike human teeth, mouse incisors grow continuously due to the presence of DESCs that generate enamel-producing ameloblasts and other supporting dental epithelial lineages. The ready accessibility of mouse DESCs and wide availability of related transgenic mouse lines make mouse incisors an excellent model to examine the identity and heterogeneity of dental epithelial stem/progenitor cells; explore the regulatory mechanisms underlying enamel formation; and help answer the open question regarding the therapeutic development of enamel engineering. In the present review, we update the current understanding about the identification of DESCs in mouse incisors and summarize the regulatory mechanisms of enamel formation driven by DESCs. The roles of DESCs during homeostasis and repair are also discussed, which should improve our knowledge regarding enamel tissue engineering.

Epigenetic Regulation of Dental Pulp Stem Cell Fate.

Epigenetic regulation, mainly involving DNA methylation, histone modification, and noncoding RNAs, affects gene expression without modifying the primary DNA sequence and modulates cell fate. Mesenchymal stem cells derived from dental pulp, also called dental pulp stem cells (DPSCs), exhibit multipotent differentiation capacity and can promote various biological processes, including odontogenesis, osteogenesis, angiogenesis, myogenesis, and chondrogenesis. Over the past decades, increased attention has been attracted by the use of DPSCs in the field of regenerative medicine. According to a series of studies, epigenetic regulation is essential for DPSCs to differentiate into specialized cells. In this review, we summarize the mechanisms involved in the epigenetic regulation of the fate of DPSCs.

Dental Tissue-Derived Human Mesenchymal Stem Cells and Their Potential in Therapeutic Application.

Human mesenchymal stem cells (hMSCs) are multipotent cells, which exhibit plastic adherence, express specific cell surface marker spectrum, and have multi-lineage differentiation potential. These cells can be obtained from multiple tissues. Dental tissue-derived hMSCs (dental MSCs) possess the ability to give rise to mesodermal lineage (osteocytes, adipocytes, and chondrocytes), ectodermal lineage (neurocytes), and endodermal lineages (hepatocytes). Dental MSCs were first isolated from dental pulp of the extracted third molar and till now they have been purified from various dental tissues, including pulp tissue of permanent teeth and exfoliated deciduous teeth, apical papilla, periodontal ligament, gingiva, dental follicle, tooth germ, and alveolar bone. Dental MSCs are not only easily accessible but are also expandable in vitro with relative genomic stability for a long period of time. Moreover, dental MSCs have exhibited immunomodulatory properties by secreting cytokines. Easy accessibility, multi-lineage differentiation potential, and immunomodulatory effects make dental MSCs distinct from the other hMSCs and an effective tool in stem cell-based therapy. Several preclinical studies and clinical trials have been performed using dental MSCs in the treatment of multiple ailments, ranging from dental diseases to nondental diseases. The present review has summarized dental MSC sources, multi-lineage differentiation capacities, immunomodulatory features, its potential in the treatment of diseases, and its application in both preclinical studies and clinical trials. The regenerative therapeutic strategies in dental medicine have also been discussed.

Dental Follicle Cells: Roles in Development and Beyond.

Dental follicle cells (DFCs) are a group of mesenchymal progenitor cells surrounding the tooth germ, responsible for cementum, periodontal ligament, and alveolar bone formation in tooth development. Cascades of signaling pathways and transcriptional factors in DFCs are involved in directing tooth eruption and tooth root morphogenesis. Substantial researches have been made to decipher multiple aspects of DFCs, including multilineage differentiation, senescence, and immunomodulatory ability. DFCs were proved to be multipotent progenitors with decent amplification, immunosuppressed and acquisition ability. They are able to differentiate into osteoblasts/cementoblasts, adipocytes, neuron-like cells, and so forth. The excellent properties of DFCs facilitated clinical application, as exemplified by bone tissue engineering, tooth root regeneration, and periodontium regeneration. Except for the oral and maxillofacial regeneration, DFCs were also expected to be applied in other tissues such as spinal cord defects (SCD), cardiomyocyte destruction. This article reviewed roles of DFCs in tooth development, their properties, and clinical application potentials, thus providing a novel guidance for tissue engineering.

A large pool of actively cycling progenitors orchestrates self-renewal and injury repair of an ectodermal appendage.

The classical model of tissue renewal posits that small numbers of quiescent stem cells (SCs) give rise to proliferating transit-amplifying cells before terminal differentiation. However, many organs house pools of SCs with proliferative and differentiation potentials that diverge from this template. Resolving SC identity and organization is therefore central to understanding tissue renewal. Here, using a combination of single-cell RNA sequencing (scRNA-seq), mouse genetics and tissue injury approaches, we uncover cellular hierarchies and mechanisms that underlie the maintenance and repair of the continuously growing mouse incisor. Our results reveal that, during homeostasis, a group of actively cycling epithelial progenitors generates enamel-producing ameloblasts and adjacent layers of non-ameloblast cells. After injury, tissue repair was achieved through transient increases in progenitor-cell proliferation and through direct conversion of Notch1-expressing cells to ameloblasts. We elucidate epithelial SC identity, position and function, providing a mechanistic basis for the homeostasis and repair of a fast-turnover ectodermal appendage.

Epiregulin enhances odontoblastic differentiation of dental pulp stem cells via activating MAPK signalling pathway.

OBJECTIVES: The odontoblastic differentiation of dental pulp stem cells (DPSCs) contributes to tertiary dentin formation. Our previous study indicated that epiregulin (EREG) enhanced odontogenesis potential of dental pulp. Here, we explored the effects of EREG during DPSC odontoblastic differentiation. METHODS: The changes in EREG were detected during tertiary dentin formation. DPSCs were treated with recombinant human EREG (rhEREG), EREG receptor inhibitor gefitinib and short hairpin RNAs. The odontoblastic differentiation was assessed with ALP staining, ALP activity assay, alizarin red S staining and real-time RT-PCR of DSPP, OCN, RUNX2 and OSX. Western blot was conducted to examine the levels of p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (Erk1/2). The expression of EREG and odontoblastic differentiation-related markers was investigated in human dental pulp from teeth with deep caries and healthy teeth. RESULTS: Epiregulin was upregulated during tertiary dentin formation. rhEREG enhanced the odontoblastic differentiation of DPSCs following upregulated p38 MAPK and Erk1/2 phosphorylation, but not JNK, whereas depletion of EREG suppressed DPSC differentiation. Gefitinib decreased odontoblastic differentiation with decreased phosphorylation of p38 MAPK and Erk1/2. And suppression of p38 MAPK and Erk1/2 pathways attenuated DPSC differentiation. In human dental pulp tissue, EREG upregulation in deep caries correlates with odontoblastic differentiation enhancement. CONCLUSION: Epiregulin is released during tertiary dentin formation. And EREG enhanced DPSC odontoblastic differentiation via MAPK pathways.

Disturbed bone remodelling activity varies in different stages of experimental, gradually progressive apical periodontitis in rats.

Bone remodelling keeps going through the lifespan of human by bone formation and bone resorption. In the craniofacial region, mandibles act as the main force for biting and chewing, and also become susceptible to a common bone-loss disease, namely, apical periodontitis, once infected dental pulp is not treated timely, during which bone resorption occurs from the apical foramen to the apical bone area. Although conventional root canal treatment (RCT) can remove the most of the infection, chronical apical periodontitis due to incomplete removal of dental pulp and subsequent microleakage will become refractory and more challenging, and this process has scarcely been specifically studied as a bone remodelling issue in rat models. Therefore, to study chronical and refractory apical periodontitis owing to incomplete cleaning of infected dental pulp and microleackage in vivo, we establish a modified rat model of gradually progressive apical periodontitis by sealing residual necrotic dental pulp and introducing limited saliva, which simulates gradually progressive apical periodontitis, as observed in the clinical treatment of chronical and refractory apical periodontitis. We show that bone-loss is inevitable and progressive in this case of apical periodontitis, which confirms again that complete and sound root canal treatment is crucial to halt the progression of chronical and refractory apical periodontitis and promote bone formation. Interestingly, bone remodelling was enhanced at the initial stage of apical periodontitis in this model while reduced with a high osteoblast number afterwards, as shown by the time course study of the modified model. Suggesting that the pathological apical microenvironment reserve its hard tissue formation ability to some degree but in a disturbed manner. Hopefully, our findings can provide insights for future bone regenerative treatment for apical periodontitis-associated bone loss.

One-Carbon Metabolism Links Nutrition Intake to Embryonic Development via Epigenetic Mechanisms.

Beyond energy production, nutrient metabolism plays a crucial role in stem cell lineage determination. Changes in metabolism based on nutrient availability and dietary habits impact stem cell identity. Evidence suggests a strong link between metabolism and epigenetic mechanisms occurring during embryonic development and later life of offspring. Metabolism regulates epigenetic mechanisms such as modifications of DNA, histones, and microRNAs. In turn, these epigenetic mechanisms regulate metabolic pathways to modify the metabolome. One-carbon metabolism (OCM) is a crucial metabolic process involving transfer of the methyl groups leading to regulation of multiple cellular activities. OCM cycles and its related micronutrients are ubiquitously present in stem cells and feed into the epigenetic mechanisms. In this review, we briefly introduce the OCM process and involved micronutrients and discuss OCM-associated epigenetic modifications, including DNA methylation, histone modification, and microRNAs. We further consider the underlying OCM-mediated link between nutrition and epigenetic modifications in embryonic development.

Evaluation of Chitosan Hydrogel for Sustained Delivery of VEGF for Odontogenic Differentiation of Dental Pulp Stem Cells.

The pulpotomy with pulp capping is aimed at retaining vital pulp with reparative dentin formation. Vascular endothelial growth factor (VEGF) plays a crucial role in dentin regeneration; however, its constant administrations in the human body is still problematic. Chitosan was widely studied as an effective carrier to deliver bioactive molecules in regenerative medicine. In this study, we conducted a chitosan/ß-glycerophosphate (CS/ß-GP) hydrogel as a VEGF-sustained release system and explored its effects on dental pulp stem cells (DPSCs). CS/ß-GP hydrogel was manufactured using a sol-gel method. SEM assay showed the spongy and porous microstructure of the lyophilized hydrogels. DPSCs cultured in the CS/ß-GP hydrogel kept adhesion and vitality. CCK-8 assay tested the promoted proliferation activity of DPSCs on the hydrogel. Besides, the added VEGF protein could continually release from VEGF/CS/ß-GP hydrogel. The VEGF/CS/ß-GP hydrogel could promote the odontogenic differentiation of DPSCs better than VEGF treatment without hydrogel. Our results suggested that CS/ß-GP hydrogel could continually release VEGF and contribute to odontogenic differentiation of DPSCs, thus may become a potential carrier of bioactive molecules in pulp capping therapy.

The Origin and Identification of Mesenchymal Stem Cells in Teeth: from Odontogenic to Non-odontogenic.

BACKGROUND: Mesenchymal stem cells (MSCs) in teeth have been exploited as vital seed cells for stem cell-based dental medicine. To date, several mesenchymal stem cell populations originated from odontogenic tissue have been isolated and characterized by their expression of MSC surface markers and capacity of multi-lineage differentiation, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), stem cells from apical papilla (SCAP) and so on. However, their identity in vivo remains elusive, which hinders further understanding of their application in stem cell-based tooth regeneration. Label retaining and lineage tracing analyses, which serve as gold standards for identification of stem cells in vivo, provide feasibility for identifying MSCs in teeth. OBJECTIVES: In this review, we will discuss the issues of MSCs, including the origin and identification of both odontogenic and non-odontogenic MSCs, and address the role of nerve-derived Sonic hedgehog (Shh) in the regulation of MSCs in the neurovascular bundle (NVB). CONCLUSION: Based on label retaining and lineage tracing analyses, latest studies have found new populations of non-odontogenic MSCs in teeth, periarterial-derived and glial-derived, regulated by the Shh derived from nerves in the NVB, which provides a new hope for tooth regeneration.

Bivalent Histone Modifications and Development.

BACKGROUND: Development is an epigenetic regulation dependent event. As one pretranscriptional regulator, bivalent histone modifications were observed to be involved in development recently. It is believed that histone methylation potentially takes charge of cell fate determination and differentiation. The synchronous existence of functionally opposite histone marks at transcript start sequence (TSS) is defined as "Bivalency", which mainly mark development related genes. H3K4me3 and H3K27me3, the prominent histone methylations of bivalency, are implicated in transcriptional activation and transcriptional repression respectively. The delicate balance between H3K4me3 and H3K27me3 produces diverse chromatin architectures, resulting in different transcription states of downstream genes: "poised", "activated" or "repressed". OBJECTIVE: In order to explore the developmental role of bivalent histone modification and the underlying mechanism, we did systematic review and rigorous assessment about relative literatures. RESULT: Bivalent histone modifications are considered to set up genes for activation during lineage commitment by H3K4me3 and repress lineage control genes to maintain pluripotency by H3K27me3. Summarily, bivalency in stem cells keeps stemness via poising differentiation relevant genes. After receiving developmental signals, the balance between "gene activation" and "gene repression" is broken, which turns genes transcription state from "poised" effect to switch on or switch off effect, thus initiates irreversible and spontaneous differentiation procedures. CONCLUSION: Bivalent histone modifications and the associated histone-modifying complexes safeguard proper and robust differentiation of stem cells, thus playing an essential role in development.

Insights into the Regulation of Yap/Taz from Cellular Systems and Mouse Models.

BACKGROUND: The Hippo signaling pathway serves as a main regulator of tissue growth and organ size through the moderation of cell cycle dynamics across many different species. In mammals, the two downstream transcriptional regulators of this pathway are Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ). Recent studies found in addition to the core Hippo signaling pathway, other signaling pathways can also regulate YAP/TAZ activity, either directly or through crosstalk with the Hippo pathway. OBJECTIVE: In this review, we discuss what is known about the regulation of YAP/TAZ from studies conducted using both cell line and mouse models. CONCLUSION: To add to the complexity of YAP/TAZ regulation, the activity of YAP/TAZ is also controlled by mechanical and cytoskeletal cues and by multiple extracellular factors.