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 initiati...

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Bibliographic Details
Published in:The Journal of biological chemistry 2017-01, Vol.292 (4), p.1339-1350
Main Authors: Wang, Lu, Xu, Xuanhao, Cao, Yaqiang, Li, Zhongwei, Cheng, Hao, Zhu, Gaoyang, Duan, Fuyu, Na, Jie, Han, Jing-Dong J., Chen, Ye-Guang
Format: Article
Language:English
Subjects:
activin
Cell Differentiation
Cell Line
chromatin modification
Developmental Biology
embryonic stem cell
Enhancer of Zeste Homolog 2 Protein - genetics
Enhancer of Zeste Homolog 2 Protein - metabolism
Epigenesis, Genetic
H3K27me3
Histones - genetics
Histones - metabolism
Human Embryonic Stem Cells - cytology
Human Embryonic Stem Cells - metabolism
Humans
Mesendoderm
Mesoderm - cytology
Mesoderm - metabolism
Methylation
PRC2
SMAD transcription factor
Smad2 Protein - genetics
Smad2 Protein - metabolism
Wnt signaling
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.766949