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

Definitive endoderm differentiation is crucial for generating respiratory andgastrointestinal organs including pancreas and liver. However, whether epigeneticregulation contributes to this process is unknown. Here, we show that the H3K27me3demethylases KDM6A and KDM6B play an important role in endoderm differentiation from humanESCs. Knockdown of KDM6A or KDM6B impairs endoderm differentiation, which can be rescuedby sequential treatment with WNT agonist and antagonist. KDM6A and KDM6B contribute to theactivation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 arerequired for mesendoderm and definitive endoderm differentiation, respectively. Our studynot only uncovers an important role of the H3K27me3 demethylases in definitive endodermdifferentiation, but also reveals that they achieve this through modulating the WNTsignaling pathway.