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

Christian Krendl, Dmitry Shaposhnikov, Valentyna Rishko, Chaido Ori, Christoph Ziegenhain, Steffen Sass, Lukas Simon, Nikola S. Müller, Tobias Straub, Kelsey E. Brooks, Shawn L. Chavez, Wolfgang Enard, Fabian J. Theis, Micha Drukker

    Research output: Contribution to journalArticle

    19 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)E9579-E9588
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume114
    Issue number45
    DOIs
    StatePublished - Nov 7 2017

    Keywords

    • BMP4
    • Differentiation
    • Trophectoderm
    • Trophoblast
    • hESC

    ASJC Scopus subject areas

    • General

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  • Cite this

    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. (2017). GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency. Proceedings of the National Academy of Sciences of the United States of America, 114(45), E9579-E9588. https://doi.org/10.1073/pnas.1708341114