Zfp281 Shapes the Transcriptome of Trophoblast Stem Cells and Is Essential for Placental Development
Zfp281 Shapes the Transcriptome of Trophoblast Stem Cells and Is Essential for Placental Development
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DOI：
10.1016/j.celrep.2019.04.028
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发表时间：
2019-05-07
期刊：
影响因子：
8.8
通讯作者：
Sasaki, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ishiuchi, Takashi;Ohishi, Hiroaki;Sasaki, Hiroyuki
胎盘发育是哺乳动物生殖和胚胎发生的关键事件。然而，胎盘发育的分子基础还不完全清楚。在这里，我们进行正向基因筛查，以确定胚胎外发育的调节因子，并确定Zfp281是一个关键因素。Zfp281在小鼠胚胎干细胞中的过表达有助于滋养层干细胞的诱导。Zfp281以成纤维细胞生长因子依赖的方式在未分化的滋养层干细胞群体中优先表达，而Zfp281在小鼠体内的破坏会导致早期胎盘发育的严重缺陷。一直以来，Zfp281缺失的滋养层干细胞在维持转录组和分化能力方面存在缺陷。在机制上，Zfp281与MLL或COMPASS亚基相互作用，占据其靶基因的启动子。重要的是，该因子的人类同源基因ZNF281是稳定人类滋养层干细胞未分化状态所必需的。因此，我们认为Zfp281是维持滋养层干细胞可塑性的一个保守因子。
Placental development is a key event in mammalian reproduction and embryogenesis. However, the molecular basis underlying placental development is not fully understood. Here, we conduct a forward genetic screen to identify regulators for extraembryonic development and identify Zfp281 as a key factor. Zfp281 overexpression in mouse embryonic stem cells facilitates the induction of trophoblast stem-like cells. Zfp281 is preferentially expressed in the undifferentiated trophoblast stem cell population in an FGF-dependent manner, and disruption of Zfp281 in mice causes severe defects in early placental development. Consistently, Zfp281-depleted trophoblast stem cells exhibit defects in maintaining the transcriptome and differentiation capacity. Mechanistically, Zfp281 interacts with MLL or COMPASS subunits and occupies the promoters of its target genes. Importantly, ZNF281, the human ortholog of this factor, is required to stabilize the undifferentiated status of human trophoblast stem cells. Thus, we identify Zfp281 as a conserved factor for the maintenance of trophoblast stem cell plasticity.