Zfp281 Shapes the Transcriptome of Trophoblast Stem Cells and Is Essential for Placental Development

• Published in: Cell reports (Cambridge) 2019-05, Vol.27 (6), p.1742-1754.e6
• Main Authors: Ishiuchi, Takashi, Ohishi, Hiroaki, Sato, Tetsuya, Kamimura, Satoshi, Yorino, Masayoshi, Abe, Shusaku, Suzuki, Atsushi, Wakayama, Teruhiko, Suyama, Mikita, Sasaki, Hiroyuki
• Format: Article
• Language: English
• Subjects: MLL-COMPASS; placental development; trophoblast stem cell; Zfp281
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •A forward genetic screen identifies Zfp281 as a factor for ES-to-TS-like conversion•Zfp281 shapes the transcriptome of TS cells and regulates early placental development•Zfp281 interacts with MLL or COMPASS subunits and binds to the promoters of target genes•ZNF281 stabilizes the transcriptome in undifferentiated human TS cells Ishiuchi et al. demonstrate that Zfp281 regulates gene expression through the interaction with MLL or COMPASS in trophoblast stem (TS) cells. Depletion of Zfp281 impairs TS cell plasticity in vitro and in vivo. Knockdown of ZNF281 downregulates a set of genes enriched in undifferentiated human TS cells, including ELF5 and LIN28A.