Epigenetics, Chromatin and microRNAs

CP27 In the Nucleus

Epigenetics encompasses all the mechanisms by which the organism controls gene expression without changing the DNA sequence. The major mechanisms involved in epigenetic control include changes to chromatin and chromatin packaging, changes in DNA methylation and histone methylation and acetylation, as well as the effects of small RNAs on the inhibition of gene expression, which are sometimes considered a field on its own. Two decades ago, we cloned and sequenced the SRCAP chromatin complex member cp27 in our laboratory (Diekwisch et al. 1999). This factor turned out to have essential roles in embryonic development and cell division (Diekwisch and Luan 2002, Luan and Diekwisch 2002).  We then characterized the cp27 promoter and identified the CCAAT box binding transcription factor NF-Y as one of its key regulators (Luan et al. 2010, Ito et al. 2011).  Currently, we are defining the role of this factor in chromatin segregation and heterochromatin.

The essential function of chromatin in early development prompted us to ask how epigenetic factors contribute to the differentiation of dental tissues. Here we focused on histone modifications as early marks in tissue differentiation (Gopinathan et al. 2023). Our studies identified a switch from active to repressive histone marks during periodontal differentiation (Dangaria et al. 2011). We also reported that dentin-related genes such as DSPP and DMP are repressed in dental follicle progenitors while they are active in dental pulp lineage (Gopinathan et al. 2013).  In support of an epigenetic mechanism responsible for the inhibition of mineralization gene expression in the periodontal ligament, we used the histone methylation inhibitors DZNep and Chaetocin to reactivate RUNX2 and OSX expression and narrow the periodontal ligament space (Gopinathan et al. 2023).

Contributions to Journals

• Gopinathan, G., Zhang, X., Luan, X., and Diekwisch, T.G.H. (2023).  Changes in Hox Gene Chromatin Organization during Odontogenic Lineage Specification.  Genes 2023, 14(1), 198; https://doi.org/10.3390/genes14010198.
• Gopinathan, G., Luan, X., and Diekwisch, T.G.H. (2023).  Epigenetic repression of RUNX2 and OSX promoters controls the nonmineralized state of the periodontal ligament.  Genes 2023, 14, 201. https://doi.org/10.3390/genes14010201.
• Francis, M., Gopinathan, G., Salapatas, A., Nares, S., Gonzalez, M., Diekwisch, T.G.H., and Luan, X. (2020).  SETD1 and NF-κB regulate periodontal inflammation through H3K4 trimethylation.  J. Dent. Res. 99, 1486-1493. 
• Francis, M., Gopinathan, G., Foyle, D., Fallah, P., Gonzalez, M., Luan, X., and Diekwisch, T.G.H. (2020).  Histone methylation: achilles heel and powerful mediator of periodontal homeostasis.  J. Dent. Res. 99, 1332-1340. 
• Gopinathan, G., Foyle, D., Luan, X., Diekwisch, T.G.H. (2019). The Wnt Antagonist SFRP1: A Key Regulator of Periodontal Mineral Homeostasis. Stem Cells Dev.
• Francis, M., Pandya, M., Gopinathan, G., Lyu, H., Ma, W., Foyle, D., Nares, S., Luan, X. (2019). Histone methylation mechanisms modulate the inflammatory response of periodontal ligament progenitors. Stem Cells Dev. 28, 1015–1025.
• Luan, X., Zhou, X., Naqvi, A., Francis, M., Foyle, D., Nares, S., Diekwisch, T.G.H. (2018). MicroRNAs and immunity in periodontal health and disease.  International J. Oral Sci. 10, 24. doi: 10.1038/s41368-018-0025-y.
• Luan, X., Zhou, X., Trombetta-eSilva, J., Francis, M., Gaharwar, A.K., Atsawasuwan, P., and Diekwisch, T.G.H. (2017). MicroRNAs and periodontal homeostasis. J. Dent. Res. 96, 491-500.
• Zhou, X.*, Luan, X.*, Chen, Z., Francis, M., Gopinathan, G., Li, W., Lu, X., Li, S., Wu, C., and Diekwisch, T.G.H. (2016). MicroRNA-138 inhibits periodontal progenitor differentiation under inflammatory conditions. J. Dent. Res. 95, 230-237.
• Diekwisch, T.G.H. (2016). Novel approaches toward managing the micromanagers: ‘non-toxic’ but effective. Gene Therapy 23, 697–698.
• Chen, Y., Evans C.A., Zhou X., Luan X., Diekwisch, T.G.H., and Atsawasuwan, P. (2015). Cyclic stretch and compression forces alter microRNA-29 expression of human periodontal ligament cells. Gene 566, 13-17.
• Gopinathan G., Kolokythas, A., Luan, X., and Diekwisch, T.G.H. (2013). Epigenetic marks define the lineage and differentiation potential of two distinct neural crest-derived odontogenic progenitors. Stem Cells Dev. 22, 1763-1778.
• Dangaria, S., Ito, Y., Luan, X., and Diekwisch, T.G.H. (2011). Differentiation of neural crest-derived intermediate pluripotent progenitors into committed periodontal population involves unique molecular signature changes, cohort shifts, and epigenetic modifications. Stem Cells and Development 20, 39-52.
• Ito, Y., Zhang, Y., Dangaria, S., Luan, X., and Diekwisch, T.G.H. (2011). NF-Y and USF1 transcription factor binding to CCAAT box and E-box elements activates the CP27 promoter. Gene 473, 92-99.
• Luan, X., Ito, Y., Zhang, Y., and Diekwisch, T.G.H. (2010). Characterization of the mouse CP27 promoter and NF-Y mediated gene regulation. Gene 460, 8-19.
• Diekwisch, T.G.H., Luan, X., and McIntosh, J.E. (2002). CP27 localization in the dental lamina basement membrane and in the stellate reticulum of developing teeth. J. Histochem. Cytochem 50, 583-585.
• Luan, X., and Diekwisch, T.G.H. (2002). CP27 affects viability, proliferation, attachment, and gene expression in embryonic fibroblasts. Cell Proliferation 35, 207-219.
• Diekwisch, T.G.H. and Luan, X. (2002). CP27 function is necessary for cell survival and differentiation during tooth morphogenesis in organ culture. Gene 287, 141-147.
• Diekwisch, T.G.H., Marches, F., Williams, A., and Luan, X. (1999). Cloning, gene expression, and characterization of CP27, a novel gene in mouse embryogenesis. Gene 235, 19-30.