Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway
Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway
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DOI：
10.1038/cr.2012.119
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发表时间：
2013-01-01
期刊：
影响因子：
44.1
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Wang, Jinzhao;Zhang, Yi
明确的内胚层分化对包括胰腺和肝脏在内的呼吸和胃肠道器官的产生至关重要。然而，表观遗传调控是否有助于这一过程尚不清楚。在这里，我们证明了H3K27me3去甲基酶KDM6A和KDM6B在人胚胎干细胞内胚层分化过程中起着重要作用。KDM6A或KDM6B基因敲除会损害内胚层分化，用WNT激动剂和拮抗剂序贯治疗可以挽救内胚层分化。KDM6A和KDM6B在不同的分化阶段参与了WNT3和Dkk1的激活，而WNT3和Dkk1分别是中胚层分化和最终内胚层分化所必需的。我们的研究不仅揭示了H3K27me3去甲基酶在最终内胚层分化中的重要作用，而且揭示了它们通过调节WNT信号通路来实现这一点。
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.