Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Cell Rep. 2019 May 7;27(6):1742-1754.e6. doi: 10.1016/j.celrep.2019.04.028.
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.
胎盘发育是哺乳动物生殖和胚胎发生中的一个关键事件。然而，胎盘发育的分子基础还不完全清楚。在这里，我们进行了正向遗传筛选，以鉴定胚胎外发育的调节剂，并鉴定 Zfp281 为关键因子。在小鼠胚胎干细胞中过表达 Zfp281 有助于诱导滋养层干细胞样细胞。Zfp281 以 FGF 依赖性方式优先表达于未分化的滋养层干细胞群体中，并且小鼠中 Zfp281 的破坏导致早期胎盘发育严重缺陷。一致地，Zfp281 耗尽的滋养层干细胞在维持转录组和分化能力方面表现出缺陷。在机制上，Zfp281 与 MLL 或 COMPASS 亚基相互作用，并占据其靶基因的启动子。重要的是，该因子的人同源物 ZNF281 对于稳定人滋养层干细胞的未分化状态是必需的。因此，我们将 Zfp281 鉴定为维持滋养层干细胞可塑性的保守因子。
