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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Cell Differentiation
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Cell Line
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism*
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Endoderm / cytology*
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Endoderm / metabolism
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Histone Demethylases / antagonists & inhibitors
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Histone Demethylases / genetics
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Histone Demethylases / metabolism*
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Histones / genetics
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Histones / metabolism
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism*
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Methylation
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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RNA Interference
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RNA, Small Interfering / metabolism
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Up-Regulation
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Wnt Signaling Pathway
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Wnt3 Protein / agonists
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Wnt3 Protein / antagonists & inhibitors
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Wnt3 Protein / metabolism*
Substances
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DKK1 protein, human
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Histones
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Intercellular Signaling Peptides and Proteins
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Nuclear Proteins
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RNA, Small Interfering
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Wnt3 Protein
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Histone Demethylases
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Jumonji Domain-Containing Histone Demethylases
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KDM6A protein, human
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KDM6B protein, human