Zfp281 shapes the transcriptome of trophoblast stem cells and is essential for placental development

Placental development is a key event in mammalian reproduction and embryogenesis. However, the molecular basis underlying extraembryonic lineage specification and subsequent placental development is not fully understood. Through a genetic screen, we identified Zfp281 as a key factor for extraembryonic development. Disruption of Zfp281 in mice caused severe defects in extraembryonic as well as embryonic tissues. Importantly, Zfp281 was preferentially expressed in the trophoblast stem cell population in an FGF-dependent manner and ensured the expression of genes necessary for placental development. Through the analysis of transcriptome and epigenome, we identified Zfp281 as an important factor to shape the transcriptome of mammalian trophoblast stem cells. To study the role of Zfp281 in transcriptional regulation, we performed RNA-seq using mouse and human TS cells. Furthermore, we performed H3K4me3 ChIP-seq and ATAC-seq to reveal the roles of Zfp281 in chromatin regulation.胎盘发育是哺乳动物生殖与胚胎发生过程中的核心事件。然而，胚外线谱系特化及后续胎盘发育的分子基础尚未完全阐明。本研究通过遗传筛选，鉴定出Zfp281是胚外发育的关键调控因子。在小鼠体内敲除Zfp281，会导致胚外组织与胚胎组织均出现严重发育缺陷。值得注意的是，Zfp281以成纤维细胞生长因子（fibroblast growth factor, FGF）依赖的方式，优先在滋养层干细胞（trophoblast stem cell, TSC）群体中表达，并保障胎盘发育所需基因的正常转录。通过转录组与表观基因组分析，我们证实Zfp281是塑造哺乳动物滋养层干细胞转录组特征的重要调控因子。为探究Zfp281在转录调控中的功能，我们分别利用小鼠与人类TS细胞开展了RNA测序（RNA-seq）实验。此外，我们还通过H3K4me3染色质免疫共沉淀测序（chromatin immunoprecipitation sequencing, ChIP-seq）与转座酶可及性测序（assay for transposase-accessible chromatin sequencing, ATAC-seq），解析了Zfp281在染色质调控中的作用。