Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway

• Published in: Cell research Vol. 23; no. 1; pp. 122 - 130
• Main Authors: Jiang, Wei, Wang, Jinzhao, Zhang, Yi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2013; Nature Publishing Group
• Subjects: 631/136/142; 631/208/200; 631/80/86; Biomedical and Life Sciences; Cell Biology; Cell Differentiation; Cell Line; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Endoderm - cytology; Endoderm - metabolism; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histones - genetics; Histones - metabolism; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Life Sciences; Methylation; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; original-article; RNA Interference; RNA, Small Interfering - metabolism; Up-Regulation; WNT; Wnt Signaling Pathway; Wnt3 Protein - agonists; Wnt3 Protein - antagonists & inhibitors; Wnt3 Protein - metabolism; 人类胚胎干细胞; 信号转导通路; 分化阶段; 受体激动剂; 组蛋白; 胚层; 调制; KDM6A/KDM6B; WNT pathway regulation; definitive endoderm differentiation
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2012.119

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 en- doderm 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.