Activin/Smad2-induced Histone H3 Lys-27 Trimethylation (H3K27me3) Reduction Is Crucial to Initiate Mesendoderm Differentiation of Human Embryonic Stem Cells.
Differentiation of human embryonic stem cells into mesendoderm (ME) is directed by extrinsic signals and intrinsic epigenetic modifications. However, the dynamics of these epigenetic modifications and the mechanisms by which extrinsic signals regulate the epigenetic modifications during the initiation of ME differentiation remain elusive. In this study, we report that levels of histone H3 Lys-27 trimethylation (H3K27me3) decrease during ME initiation, which is essential for subsequent differentiation induced by the combined effects of activin and Wnt signaling. Furthermore, we demonstrate that activin mediates the H3K27me3 decrease via the Smad2-mediated reduction of EZH2 protein level. Our results suggest a two-step process of ME initiation: first, epigenetic priming via removal of H3K27me3 marks and, second, transcription activation. Our findings demonstrate a critical role of H3K27me3 priming and a direct interaction between extrinsic signals and epigenetic modifications during ME initiation.
['Wang|Lu|L|', 'Xu|Xuanhao|X|', 'Cao|Yaqiang|Y|', 'Li|Zhongwei|Z|', 'Cheng|Hao|H|', 'Zhu|Gaoyang|G|', 'Duan|Fuyu|F|', 'Na|Jie|J|', 'Han|Jing-Dong J|JJ|', 'Chen|Ye-Guang|YG|']
D002454:Cell Differentiation D002460:Cell Line D000071221:Enhancer of Zeste Homolog 2 Protein D044127:Epigenesis, Genetic D006657:Histones D000066449:Human Embryonic Stem Cells D006801:Humans D008648:Mesoderm D008745:Methylation D051899:Smad2 Protein
activin H3K27me3 Mesendoderm embryonic stem cell Wnt signaling PRC2 SMAD transcription factor chromatin modification