Activin/Smad2-induced H3K27me3 reduction is crucial to initiate mesendoderm differentiation of ES Cells

Mesendoderm (ME) differentiation of human embryonic stem cells (hESCs) is directed by various extrinsic signals together with intrinsic epigenetic modifications. However, the dynamics of epigenetic modifications and their regulation to initiate ME differentiation remain elusive. In this study, we report that H3K27me3 is decreased during ME initiation, which is essential for the subsequent differentiation by collaborative effects of Activin and Wnt signaling. Mechanistically, Activin decreases the H3K27me3 level via disruption of the SUZ12-EZH2 interaction and EZH2 degradation mediated by Smad2. Our data suggest a two-step process of ME initiation: firstly H3K27me3-marked epigenetic priming and secondly transcription activation. Our findings unravel a critical role of H3K27me3 priming and a direct interaction between extrinsic signals and epigenetic modifications during ME initiation. Overall design: mRNA profile of H1-hESC and treated with Activin A, Wnt3a separately or together for 6h and 24h. Together with H3K27me3 and H3K4me3 profiles of H1-hESC and treated with Activin A, wnt3a seperately or together for 2h and 6h.