TY - JOUR
T1 - GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency
AU - Krendl, Christian
AU - Shaposhnikov, Dmitry
AU - Rishko, Valentyna
AU - Ori, Chaido
AU - Ziegenhain, Christoph
AU - Sass, Steffen
AU - Simon, Lukas
AU - Müller, Nikola S.
AU - Straub, Tobias
AU - Brooks, Kelsey E.
AU - Chavez, Shawn L.
AU - Enard, Wolfgang
AU - Theis, Fabian J.
AU - Drukker, Micha
N1 - Funding Information:
ACKNOWLEDGMENTS. For prolific scientific discussions and critical reading of the manuscript, we thank Tal Raveh. We also acknowledge Deutsche Forschungsgemeinschaft Grant DR1008/1-1 (to M.D.).
Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
PY - 2017/11/7
Y1 - 2017/11/7
N2 - 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.
AB - 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.
KW - BMP4
KW - Differentiation
KW - Trophectoderm
KW - Trophoblast
KW - hESC
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U2 - 10.1073/pnas.1708341114
DO - 10.1073/pnas.1708341114
M3 - Article
C2 - 29078328
AN - SCOPUS:85033451046
SN - 0027-8424
VL - 114
SP - E9579-E9588
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -