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    • Based on our findings on genome wide epigenetic effects of

    2018-10-20

    Based on our findings on genome-wide, epigenetic effects of EtOH on DPSCs, we analyzed known epigenetic modifiers to elucidate a potential epigenetic link between alcohol and osteoporosis. Consistent with our conclusion, KDM6B, a known epigenetic modifier involved in osteogenic and odontogenic differentiation, was found to be significantly dysregulated in response to EtOH. Knockdown of KDM6B resulted in a similar phenotype as EtOH treatment in vitro while concurrently showing similar reductions in the gene KPT-185 profiles of known osteomarkers. Thus, it is suggested that dysregulation of KDM6B by EtOH reduces odontogenic/osteogenic potency of DPSCs, however the molecular pathways behind the interactions of KDM6B and known mineralization-associated markers remain to be discovered. Recent studies show that KDM6B is involved in the control of calcium-induced differentiation (Sen et al., 2008), regulates osteoblast differentiation (Yang et al., 2013), and contributes to neuronal survival and differentiation (Wijayatunge et al., 2014), odontogenic differentiation of DPSCs (Xu et al., 2013), and osteogenic differentiation of human BMSCs (Ye et al., 2012). It has been reported that calcium-induced differentiation leads to increased binding of KDM6B and erasure of repressive marks such as H3K27me3 (Sen et al., 2008). It has been demonstrated that BMP4/7-mediated activation of SMAD1/4 may induce the expression of KDM6B and trigger the osteogenic pathway (Ye et al., 2012). Mechanistically, KDM6B is recruited to bone morphogenic protein 2 (BMP2) and HOX (homeotic genes) promoters and activate the odontogenic differentiation-related gene expression (Ye et al., 2012). KDM6B removes epigenetic marks such as H3K27me3, from the promoter of osteogenic genes to promote osteogenic commitment (Ye et al., 2012). In addition, a recent study has demonstrated the facilitating role of KDM6B on odontogenic differentiation (Xu et al., 2013). It needs to be experimentally demonstrated if EtOH triggers dysregulation of KDM6B via altered regulation of differentiation signal-induced activation of the SMAD1/4 pathway and the control of the H3K27me3 mark as demonstrated in BMSCs (Ye et al., 2012). In conclusion, our findings confirmed that EtOH has a significant impact on the dysregulation of KDM6B and provides a potential epigenetic effect of heavy alcohol exposure in DPSCs. These findings will be helpful in identifying molecular mechanisms associated with alcohol induced osteoporosis in a proper model, as it suggests a potential mechanism of EtOH-induced suppression of mineralization. Further study is needed to evaluate the significance of our findings in fetal development where maternal alcohol consumption results in craniofacial and dental abnormalities, which are hallmark features of fetal alcohol spectrum disorders (FASD). The following are the supplementary data related to this article.
    Acknowledgment This work was supported by a research grant award from NIH/NIAAA (R01AA21301), a UCLA School of Dentistry Faculty Seed Grant Award to Y.K., and a CIRM CSUN-UCLA Bridges to Stem Cell Research Award to B.T. (TB1-01183).
    Introduction Podocytes are terminally differentiated epithelial cells that have limited capacity to proliferate. This feature makes them vulnerable to critical levels of cell stress leading to detachment and progressive cell loss, a central mediator of glomerular sclerosis. Over the last decade, investigators have attempted to understand why podocyte depletion per se is sufficient to cause glomerulosclerosis, and to identify the mediators responsible for local propagation of podocyte injury. In this context, the possibility of having podocyte cultures would be a valuable tool for clarifying the molecular mechanisms underlying specific podocytopathies with a view to developing targeted therapy. First attempts to derive primary podocytes from isolated glomeruli failed largely because podocytes cultured under standard conditions dedifferentiate rapidly, with a loss of foot processes and expression of synaptopodin, a key marker of differentiated podocytes. Changes in culture conditions resulted in cells with the characteristic arborized phenotype and rapid growth arrest, and the latter closely reflected in vivo podocyte behaviour, but limited cell culture abilities for in vitro experiments (Shankland et al., 2007). The establishment of conditionally immortalized cell lines circumvented the detrimental cell growth arrest, generating highly proliferative cells under permissive conditions, which stopped growing in non-permissive conditions. However, despite their widespread use for studying podocyte biology, these cell lines show dramatic differences in the expression of podocyte markers, response to toxins, and motility, not only between podocytes of different species but even between similarly-derived cell lines (Chittiprol et al., 2011).