Dynamics Regulation Of H3K27me3 During The Onset Of Mesendoderm Differentiation Of Human Embryonic Stem Cells

Various extrinsic signals have been shown to be important in directing mesendoderm(ME)differentiation of human embryonic stem cells(hESCs),and the epigenetic and transcriptional regulation of ME marker genes are also reasonably appreciated.However,of these signals,what are the essential ones to govern ME differentiation and how they control the important epigenetic modifications in this process remain elusive.In this study,we provide various evidence that Activin and Wnt signaling are necessary and sufficient to drive ME differentiation of hESCs.Using large-scale ChIP-seq,we found that Activin,but not Wnt signaling,reduces H3K27me3 modification in ME signature genes at the begining of ME specification,and this priming step is essential for efficient ME differentiation.Mechanistically,Activin signaling,via Smad2,recruits the E3 ubiquitin ligase Smurf2 to ubiquitinate and degrade EZH2 protein,the key component of the polycomb repressor complex 2(PRC2)that sustains the H3K27me3 mark.Smad2 also competes with SUZ12 to bind to EZH2,leading in the disruption of the PRC2 complex.As such,Activin signaling decreases PRC2 complex activity and reduces H3K27me3 level at the initiating of ME differentiation,which then ensures the following differentiation by collaborative effects of Activin and Wnt signaling at the transcriptional level.Taken together,these results reveal a two-step process of firstly epigenetic priming and secondly transcription activation in the early stage of ME differentiation.Our findings arise new views into the understanding of mesendoderm specification and early development of vertebrate embryos,and also unravel a direct interaction between extrinsic signals and epigenetic modifications in cell fate determination.