Activin/Smad2 and Wnt/β-catenin up-regulate HAS2 and ALDH3A2 to facilitate mesendoderm differentiation of human embryonic stem cells

Activin and Wnt signaling are necessary and sufficient for mesendoderm (ME) differentiation of human embryonic stem cells (ESCs). In this study, we report that during ME differentiation induced by Activin and Wnt, Activin/Smad2 induces a decrease of the repressive histone modification of H3K27me3 by...

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Bibliographic Details
Published in:The Journal of biological chemistry 2018-11, Vol.293 (48), p.18444-18453
Main Authors: Xu, Xuanhao, Wang, Lu, Liu, Bofeng, Xie, Wei, Chen, Ye-Guang
Format: Article
Language:English
Subjects:
Activins - physiology
Aldehyde Oxidoreductases - physiology
beta Catenin - physiology
Cell Biology
Cell Differentiation - physiology
Chromatin - metabolism
Endoderm - cytology
Enhancer of Zeste Homolog 2 Protein - metabolism
Epigenesis, Genetic
Forkhead Transcription Factors - metabolism
Histones - metabolism
Human Embryonic Stem Cells - cytology
Humans
Hyaluronan Synthases - physiology
Mesoderm - cytology
Promoter Regions, Genetic
Proteolysis
Smad2 Protein - physiology
Up-Regulation
Wnt Signaling Pathway
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Summary:Activin and Wnt signaling are necessary and sufficient for mesendoderm (ME) differentiation of human embryonic stem cells (ESCs). In this study, we report that during ME differentiation induced by Activin and Wnt, Activin/Smad2 induces a decrease of the repressive histone modification of H3K27me3 by promoting the proteasome-dependent degradation of enhancer of zeste 2 polycomb (EZH2)-repressive complex 2 subunit. As a result, recruitment of the forkhead protein FOXH1 on open chromatin regions integrates the signals of Activin/Smad2 and Wnt/β-catenin to activate the expression of the ME genes including HAS2 and ALDH3A2. Consistently, H3K27me3 decrease is enriched on open chromatin around regulatory regions. Furthermore, knockdown of HAS2 or ALDH3A2 greatly attenuates ME differentiation. These findings unveil a pathway from extracellular signals to epigenetic modification–mediated gene activation during ME commitment.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA118.003688