GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency
| Autor: | Shawn L. Chavez, Fabian J. Theis, Micha Drukker, Chaido Ori, Christoph Ziegenhain, Wolfgang Enard, Kelsey E. Brooks, Steffen Sass, Nikola S. Müller, Lukas M. Simon, Dmitry Shaposhnikov, Christian Krendl, Valentyna Rishko, Tobias Straub |
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| Rok vydání: | 2017 |
| Předmět: |
Pluripotent Stem Cells
0301 basic medicine Placenta Embryonic Development BMP4 Bone Morphogenetic Protein 4 GATA3 Transcription Factor Biology Cell Line Transcriptome 03 medical and health sciences Pregnancy medicine Animals Humans Human embryogenesis Induced pluripotent stem cell Transcription factor Embryonic Stem Cells reproductive and urinary physiology Multidisciplinary GATA2 Trophoblast Cell Differentiation differentiation Epigenome Biological Sciences Macaca mulatta trophoblast Molecular biology Bmp4 Differentiation Hesc Trophectoderm Trophoblasts GATA2 Transcription Factor 030104 developmental biology medicine.anatomical_structure Transcription Factor AP-2 PNAS Plus hESC embryonic structures DNA methylation Female trophectoderm Developmental Biology |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proc. Natl. Acad. Sci. U.S.A. 114, E9579-E9588 (2017) |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance This study provides a mechanistic explanation for the differentiation of trophoblasts from human pluripotent stem cells, a process relying on BMP morphogens. We found that a network of the transcription factors GATA2, GATA3, TFAP2A, and TFAP2C regulates early trophoblast progenitor specification by activating placental genes and inhibiting the pluripotency gene OCT4, thus acting to couple trophoblast specification with exit from pluripotency. To demonstrate the relevance of our findings in vivo, we show that down-regulating GATA3 in primate embryos prevents trophectoderm specification. In addition, we present a genome-wide analysis of active and inactive chromatin during trophoblast progenitor specification. These results provide a basis to guide investigations of human trophectoderm development. 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. |
| Databáze: | OpenAIRE |
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