Human postnatal dental stem cells such as dental pulp stem cells (DPSCs) and stem cells from root apical papilla (SCAPs) are unique precursor populations isolated from dental tissues based on the primary characteristics of bone marrow mesenchymal stem cells (MSCs). Like bone marrow MSCs, dental stem cells are self-renewing, multipotent, and clonogenic. They can be induced to differentiate into odontoblast- or osteoblast-like cells and form mineralized nodules in vitro. When implanted into immunodeficient mice, dental stem cells can form dentin- or cementum-like mineralized tissues or related craniofacial structures. Hence dental stem cells may present promising prospects for tooth regeneration and tissue repair. However, currently, the molecular regulation of their differentiation is poorly understood. Histone demethylases are newly-identified enzymes for removing histone methyl markers associated with gene activation or silencing. While they have been implicated in developmental processes and human diseases, it is largely unknown whether and how histone demethylases play a critical role in regulating dental stem cell differentiation. By studying oculofacialcardiodental syndrome (OFCD), a rare human genetic disorder characterized by teeth with extremely long roots (radiculomegaly), we unexpectedly discovered that the transcription co-repressor BCOR (Bcl-6 co-repressor) epigenetically regulates dental stem cell function and differentiation via histone demethylases. In this competing renewal, we hypothesize that histone epigenetic modification plays an important role in the regulation of dental stem cell function and differentiation. To test our hypothesis, we propose three specific aims.
In Aim 1, we will explore whether and how BCOR epigenetically represses dental stem cell differentiation by histone modification.
In Aim 2, we will determine whether and how BCOR mutation epigenetically de-represses gene transcription and thereby promotes dental stem cell differentiation. These two aims will augment our current work and further define how BCOR mutation promotes dental stem cell differentiation in a pathological condition.
In Aim 3, we will explore whether and how a newly identified histone demethylase JMJD3 (JmjC domain-containing 3) promotes gene expression and controls dental stem cell differentiation in healthy conditions. By studying both normal and abnormal dental stem cells, our results may provide new insights into the molecular biology of human dental stem cells. Moreover, as demethylases, being enzymes, can be readily targeted by small molecule inhibitors, our work may help to develop novel strategies for promoting dental and craniofacial tissue regeneration and repair.
Human postnatal dental stem cells are unique precursor populations which are isolated tooth. These cells are capable of differentiating into dentin/bone-like forming cells. When implanted into immunodeficient mice, dental stem cells can form dentin- or cement-like mineralized tissues. Although dental stem cells may present promising application prospects in tooth regeneration and repair, currently, molecular regulation of their fate is poorly understood. Histone demethylases are newly-identified enzymes that remove histone methyl marks associated with gene activation or repression. While they have been implicated in developmental processes and human diseases, it is largely unknown whether and how histone demethylases play a critical role in dental stem cell function. In this application, we propose to examine how chromatin modification by histone demethylases regulates gene expression and dental stem cell differentiation using molecular and genetic approaches. Our results may provide new insights into the molecular biology of human dental stem cells. Moreover, because demethylases, being enzymes, can be readily targeted by small molecule inhibitors, our work may help to develop novel strategies for improving dental and craniofacial tissue regeneration and repair.
|Cheng, Yingduan; Yuan, Quan; Vergnes, Laurent et al. (2018) KDM4B protects against obesity and metabolic dysfunction. Proc Natl Acad Sci U S A 115:E5566-E5575|
|Hong, Christine; Song, Dayoung; Lee, Dong-Keun et al. (2017) Reducing posttreatment relapse in cleft lip palatal expansion using an injectable estrogen-nanodiamond hydrogel. Proc Natl Acad Sci U S A 114:E7218-E7225|
|Hoang, Michael; Kim, Jeffrey J; Kim, Yiyoung et al. (2016) Alcohol-induced suppression of KDM6B dysregulates the mineralization potential in dental pulp stem cells. Stem Cell Res 17:111-21|
|Fan, Jiabing; Im, Choong Sung; Guo, Mian et al. (2016) Enhanced Osteogenesis of Adipose-Derived Stem Cells by Regulating Bone Morphogenetic Protein Signaling Antagonists and Agonists. Stem Cells Transl Med 5:539-51|
|Hu, Youjin; Huang, Kevin; An, Qin et al. (2016) Simultaneous profiling of transcriptome and DNA methylome from a single cell. Genome Biol 17:88|
|Deng, Peng; Zhou, Chenchen; Alvarez, Ruth et al. (2016) Inhibition of IKK/NF-?B Signaling Enhances Differentiation of Mesenchymal Stromal Cells from Human Embryonic Stem Cells. Stem Cell Reports 6:456-465|
|Lee, Hye-Lim; Yu, Bo; Deng, Peng et al. (2016) Transforming Growth Factor-?-Induced KDM4B Promotes Chondrogenic Differentiation of Human Mesenchymal Stem Cells. Stem Cells 34:711-9|
|Yu, Bo; Wang, Cun-Yu (2016) Osteoporosis: The Result of an 'Aged' Bone Microenvironment. Trends Mol Med 22:641-644|
|Deng, Peng; Chen, Qian-Ming; Hong, Christine et al. (2015) Histone methyltransferases and demethylases: regulators in balancing osteogenic and adipogenic differentiation of mesenchymal stem cells. Int J Oral Sci 7:197-204|
|Alvarez, Ruth; Lee, Hye-Lim; Hong, Christine et al. (2015) Single CD271 marker isolates mesenchymal stem cells from human dental pulp. Int J Oral Sci 7:205-12|
Showing the most recent 10 out of 27 publications