title: Activin/Smad2-induced Histone H3 Lys-27 Trimethylation (H3K27me3) Reduction Is Crucial to Initiate Mesendoderm Differentiation of Human Embryonic Stem Cells.
abstract: 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.
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xuanhao
authors.initials: X
authors.lastname: Xu
authors.affiliation: the Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China, and.
authors.forename: Yaqiang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: the Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China, and.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Gaoyang
authors.initials: G
authors.lastname: Zhu
authors.affiliation: the School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Fuyu
authors.initials: F
authors.lastname: Duan
authors.affiliation: the School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Na
authors.affiliation: the Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China, and.
authors.forename: Jing-Dong J
authors.initials: JJ
authors.lastname: Han
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China, ygchen@tsinghua.edu.cn.
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D008745:Methylation; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: H3K27me3; Mesendoderm; PRC2; SMAD transcription factor; Wnt signaling; activin; chromatin modification; embryonic stem cell