GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency.
GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency.
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DOI：
10.1073/pnas.1708341114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Drukker M
中科院分区：
文献类型：
--
作者：
Krendl C;Shaposhnikov D;Rishko V;Ori C;Ziegenhain C;Sass S;Simon L;Müller NS;Straub T;Brooks KE;Chavez SL;Enard W;Theis FJ;Drukker M
这项研究提供了一个机制解释滋养层细胞从人类多能干细胞的分化，一个依赖于BMP形态发生蛋白的过程。我们发现转录因子GATA2、GATA3、TFAP 2A和TFAP 2C的网络通过激活胎盘基因和抑制多能性基因OCT 4来调节早期滋养层祖细胞特化，从而将滋养层特化与退出多能性相结合。为了证明我们的研究结果在体内的相关性，我们表明，下调GATA 3在灵长类动物胚胎防止滋养外胚层规格。此外，我们提出了一个全基因组的活性和非活性染色质在滋养层祖细胞规范的分析。这些结果为指导人类滋养外胚层发育的研究提供了依据。为了阐明BMP 4诱导的人多能干细胞（PSC）向具有滋养外胚层特征的后代分化的分子基础，我们制作了滋养层祖细胞的转录组、表观基因组H3K4me3、H3K27me3和CpG甲基化图谱，使用表面标记阿帕纯化。我们将它们与前祖细胞期和单个阿帕+细胞的时间分辨转录组相结合。这揭示了二价TFAP 2A、TFAP 2C、GATA 2和GATA 3转录因子的回路，统称为“滋养外胚层四”（TEtra），其也存在于体内的人滋养外胚层中。在分化开始时，TETRA因子在表观遗传学上无活性的胎盘基因和OCT 4中占据多个位点。GATA 3和TFAP 2A的功能操作表明，它们直接将滋养层特异性基因诱导与多能性抑制偶联。因此，在灵长类动物胚胎中敲低GATA 3导致滋养外胚层形成失败。TETRA回路的发现表明滋养外胚层定型在人类胚胎发生中是如何调节的。
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.
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影响因子：
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影响因子：
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作者：
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通讯作者：
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