Inhibiting DNA methylation switches adipogenesis to osteoblastogenesis by activating Wnt10a.
Inhibiting DNA methylation switches adipogenesis to osteoblastogenesis by activating Wnt10a.
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DOI：
10.1038/srep25283
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发表时间：
2016-05-03
影响因子：
4.6
通讯作者：
Xue B
中科院分区：
文献类型：
--
作者：
Chen YS;Wu R;Yang X;Kou S;MacDougald OA;Yu L;Shi H;Xue B
脂肪细胞和成骨细胞都具有来源于间充质干细胞的中胚层谱系。大多数研究脂肪或成骨细胞发育调控的机制都集中在转录途径上，对这一过程中的表观遗传机制知之甚少。因此，我们确定了5-氮杂-2 ′-脱氧胞苷（5-Aza-dC），一种DNA甲基化抑制剂，在脂肪生成和成骨细胞生成之间的谱系决定中的作用。通过5-Aza-dC抑制3 T3-L1前脂肪细胞中的DNA甲基化显著抑制脂肪生成，而促进成骨细胞生成。5-Aza-dC的这种双重作用与Wnt 10a的上调有关，Wnt 10a是决定间充质谱系向成骨细胞的命运的关键因素。与此同时，Wnt蛋白抑制剂IWP-2可阻断5-Aza-dC对3 T3-L1前脂肪细胞的成脂作用，并阻断5-Aza-dC对ST 2间充质干细胞的成骨作用。最后，Wnt 10a 5′-区域富含CpG位点，其甲基化水平被5-Aza-dC显著降低。因此，我们得出结论，5-Aza-dC抑制DNA甲基化互斥调节脂肪和成骨细胞的谱系决定通过去甲基化Wnt 10a基因和上调其表达。我们的研究将DNA甲基化定义为脂肪细胞和骨细胞发育的一种新机制。
Both adipocytes and osteoblasts share the mesodermal lineage that derives from mesenchymal stem cells. Most studies investigating the mechanisms underlying the regulation of adipogenic or osteoblastogenic development focus on transcriptional pathways; little is known about the epigenetic mechanisms in this process. We thus determined the role of 5-aza-2′-deoxycytidine (5-Aza-dC), an inhibitor of DNA methylation, in the lineage determination between adipogenesis and osteoblastogenesis. Inhibiting DNA methylation in 3T3-L1 preadipocytes by 5-Aza-dC significantly inhibited adipogenesis whereas promoted osteoblastogenesis. This dual effect of 5-Aza-dC was associated with up-regulation of Wnt10a, a key factor determining the fate of the mesenchymal lineage towards osteoblasts. Consistently, IWP-2, an inhibitor of Wnt proteins, was found to prevent the anti-adipogenic effect of 5-Aza-dC in 3T3-L1 preadipocytes and block the osteoblastogenic effect of 5-Aza-dC in ST2 mesenchymal stem cell line. Finally, the Wnt10a 5′-region is enriched with CpG sites, whose methylation levels were markedly reduced by 5-Aza-dC. Thus we conclude that inhibiting DNA methylation by 5-Aza-dC mutual-exclusively regulates the lineage determination of adipogenesis and osteoblastogenesis by demethylating Wnt10a gene and upregulating its expression. Our study defines DNA methylation as a novel mechanism underlying adipocyte and bone cell development.