组蛋白 H3K27me3 去甲基酶 KDM6A 和 KDM6B 通过调节 WNT 信号通路调节人 ESC 向终末内胚层的分化。
Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway.
机构信息
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.
出版信息
Cell Res. 2013 Jan;23(1):122-30. doi: 10.1038/cr.2012.119. Epub 2012 Aug 21.
Abstract
Definitive endoderm differentiation is crucial for generating respiratory and gastrointestinal organs including pancreas and liver. However, whether epigenetic regulation contributes to this process is unknown. Here, we show that the H3K27me3 demethylases KDM6A and KDM6B play an important role in endoderm differentiation from human ESCs. Knockdown of KDM6A or KDM6B impairs endoderm differentiation, which can be rescued by sequential treatment with WNT agonist and antagonist. KDM6A and KDM6B contribute to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive endoderm differentiation, respectively. Our study not only uncovers an important role of the H3K27me3 demethylases in definitive endoderm differentiation, but also reveals that they achieve this through modulating the WNT signaling pathway.
摘要
确定内胚层分化对于产生包括胰腺和肝脏在内的呼吸和胃肠道器官至关重要。然而，表观遗传调控是否对此过程有贡献尚不清楚。在这里，我们表明 H3K27me3 去甲基化酶 KDM6A 和 KDM6B 在人 ESC 的内胚层分化中发挥重要作用。KDM6A 或 KDM6B 的敲低会损害内胚层分化，而用 WNT 激动剂和拮抗剂进行顺序处理可以挽救这种情况。当 WNT3 和 DKK1 分别需要中胚层和确定内胚层分化时，KDM6A 和 KDM6B 在不同的分化阶段有助于 WNT3 和 DKK1 的激活。我们的研究不仅揭示了 H3K27me3 去甲基化酶在确定内胚层分化中的重要作用，还表明它们通过调节 WNT 信号通路来实现这一作用。
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