Alcohol-induced suppression of KDM6B dysregulates the mineralization potential in dental pulp stem cells.
Alcohol-induced suppression of KDM6B dysregulates the mineralization potential in dental pulp stem cells.
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DOI：
10.1016/j.scr.2016.05.021
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发表时间：
2016-07
影响因子：
1.2
通讯作者：
Kim, Yong
中科院分区：
文献类型：
--
作者：
Hoang, Michael;Kim, Jeffrey J.;Kim, Yiyoung;Tong, Elizabeth;Trammell, Benjamin;Liu, Yao;Shi, Songtao;Lee, Chang-Ryul;Hong, Christine;Wang, Cun-Yu;Kim, Yong
关键词：
表观遗传变化，如DNA甲基化模式的改变，已被提出作为酒精对成体干细胞维持作用的分子机制。我们已经进行了全基因组基因表达微阵列和DNA甲基化组分析，以确定通过DNA甲基化的变化与人类牙髓干细胞（DPSC）暴露于乙醇（EtOH）的分子改变。通过基因表达和DNA甲基化的联合分析，我们发现了大量的基因可能受到EtOH诱导的DNA甲基化的调控。作为一种集中的方法，我们还进行了以途径为中心的RT-PCR阵列分析，以检查EtOH对DPSC中表观遗传染色质修饰酶、成纤维细胞标志物以及应激和毒性途径相关基因的潜在分子效应。我们已经鉴定并验证了在EtOH暴露后DPSC中赖氨酸特异性脱甲基酶6 B（KDM 6 B）显著失调。在DPSCs的牙源性/成骨分化过程中，EtOH处理抑制了KDM 6 B的诱导，并改变了分化标志物的表达。敲除KDM 6 B导致体内植入DPSC的矿化显著减少。此外，在EtOH处理的DPSC中KDM 6 B的异位表达恢复了分化相关基因的表达。我们的研究表明，EtOH诱导的KDM 6 B抑制在DPSC模型中牙源性/成骨分化的失调中起作用。这表明大量饮酒的细胞损伤的潜在分子机制，其可导致与牙齿发育异常以及骨质减少/骨质疏松症（胎儿酒精谱系障碍的标志性特征）潜在相关的矿物质沉积减少。
Epigenetic changes, such as alteration of DNA methylation patterns, have been proposed as a molecular mechanism underlying the effect of alcohol on the maintenance of adult stem cells. We have performed genome-wide gene expression microarray and DNA methylome analysis to identify molecular alterations via DNA methylation changes associated with exposure of human dental pulp stem cells (DPSCs) to ethanol (EtOH). By combined analysis of the gene expression and DNA methylation, we have found a significant number of genes that are potentially regulated by EtOH-induced DNA methylation. As a focused approach, we have also performed a pathway-focused RT-PCR array analysis to examine potential molecular effects of EtOH on genes involved in epigenetic chromatin modification enzymes, fibroblastic markers, and stress and toxicity pathways in DPSCs. We have identified and verified that lysine specific demethylase 6B (KDM6B) was significantly dysregulated in DPSCs upon EtOH exposure. EtOH treatment during odontogenic/osteogenic differentiation of DPSCs suppressed the induction of KDM6B with alterations in the expression of differentiation markers. Knockdown of KDM6B resulted in a marked decrease in mineralization from implanted DPSCs in vivo. Furthermore, an ectopic expression of KDM6B in EtOH-treated DPSCs restored the expression of differentiation-related genes. Our study has demonstrated that EtOH-induced inhibition of KDM6B plays a role in the dysregulation of odontogenic/osteogenic differentiation in the DPSC model. This suggests a potential molecular mechanism for cellular insults of heavy alcohol consumption that can lead to decreased mineral deposition potentially associated with abnormalities in dental development and also osteopenia/osteoporosis, hallmark features of fetal alcohol spectrum disorders.
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影响因子：
--
作者：
Khalid, Omar;Kim, Jeffrey J;Duan, Lewei;Hoang, Michael;Elashoff, David;Kim, Yong
通讯作者：
Kim, Yong
影响因子：
1.2
作者：
Khalid, Omar;Kim, Jeffrey J.;Kim, Hyun-Sung;Hoang, Michael;Tu, Thanh G.;Elie, Omid;Lee, Connie;Vu, Catherine;Horvath, Steve;Spigelman, Igor;Kim, Yong
通讯作者：
Kim, Yong
DOI：
10.1002/bdra.20113
发表时间：
2005-02-01
影响因子：
--
作者：
Jiménez-Farfán, D;Guevara, J;Hernández-Guerrero, JC
通讯作者：
Hernández-Guerrero, JC
影响因子：
4.3
作者：
Furtado Amaral, Cristine da Silva;Luiz, Ronir Raggio;Thome Leao, Anna Thereza
通讯作者：
Thome Leao, Anna Thereza
影响因子：
3.8
作者：
George, Joseph;Kuboki, Yoshinori;Miyata, Teruo
通讯作者：
Miyata, Teruo