Author:
Krendl Christian,Shaposhnikov Dmitry,Rishko Valentyna,Ori Chaido,Ziegenhain Christoph,Sass Steffen,Simon Lukas,Müller Nikola S.,Straub Tobias,Brooks Kelsey E.,Chavez Shawn L.,Enard Wolfgang,Theis Fabian J.,Drukker Micha
Abstract
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.
Funder
Helmholtz-Gemeinschaft
Bundesministerium für Bildung und Forschung
HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development
Ludwig-Maximilians-Universität München
Deutsche Forschungsgemeinschaft
Publisher
Proceedings of the National Academy of Sciences
Cited by
126 articles.
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