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Krendl, C. ; Shaposhnikov, D. ; Rishko, V. ; Ori, C. ; Ziegenhain, C.* ; Sass, S. ; Simon, L. ; Müller, N.S. ; Straub, T.* ; Brooks, K.E.* ; Chavez, S.L.* ; Enard, W.* ; Theis, F.J. ; Drukker, M.

GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency.

Proc. Natl. Acad. Sci. U.S.A. 114, E9579-E9588 (2017)
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To elucidate the molecular basis of BMP4-induced differentiation of human pluripotent stem cells (PSCs) toward progeny with trophectoderm characteristics, we produced transcriptome, epigenome H3K4me3, H3K27me3, and CpG methylation maps of trophoblast progenitors, purified using the surface marker APA. We combined them with the temporally resolved transcriptome of the preprogenitor phase and of single APA+ cells. This revealed a circuit of bivalent TFAP2A, TFAP2C, GATA2, and GATA3 transcription factors, coined collectively the "trophectoderm four" (TEtra), which are also present in human trophectoderm in vivo. At the onset of differentiation, the TEtra factors occupy multiple sites in epigenetically inactive placental genes and in OCT4 Functional manipulation of GATA3 and TFAP2A indicated that they directly couple trophoblast-specific gene induction with suppression of pluripotency. In accordance, knocking down GATA3 in primate embryos resulted in a failure to form trophectoderm. The discovery of the TEtra circuit indicates how trophectoderm commitment is regulated in human embryogenesis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Bmp4 ; Differentiation ; Hesc ; Trophectoderm ; Trophoblast; Bone Morphogenetic Protein-4; Gene-expression Data; Trophoblast Differentiation; In-vitro; Mammalian Development; Mesoderm Formation; Factor Ap-2-gamma; Mouse Embryos; Rna-seq; Lineage
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 114, Issue: 45, Pages: E9579-E9588 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Publishing Place Washington
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)
Institute of Computational Biology (ICB)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30205 - Bioengineering and Digital Health
Research field(s) Stem Cell and Neuroscience
Enabling and Novel Technologies
PSP Element(s) G-552400-001
G-503800-001
PubMed ID 29078328
DOI 10.1073/pnas.1708341114
WOS ID WOS:000414631200020
Scopus ID 85033451046
Erfassungsdatum 2017-10-30
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