Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation.
Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation.
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DOI：
10.1038/srep25112
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发表时间：
2016-04-28
影响因子：
4.6
通讯作者：
Hemberger M
中科院分区：
文献类型：
--
作者：
Murray A;Sienerth AR;Hemberger M
在胚胎干细胞(ESCs)中高甲基化并抑制，但在滋养细胞(TSCs)干细胞中低甲基化并表达的基因位点非常罕见，可能在早期发育细胞命运决定中具有特别重要的作用，就像先前对ELF5所显示的那样。在这里，我们评估了这个小基因组中的另一个成员，胎盘表达转录本1(Plet1)，以确定滋养层细胞的谱系特征和调节滋养层细胞分化的功能。我们发现，Plet1在胚胎干细胞中被DNA甲基化紧密抑制，但在胚胎干细胞和滋养层巨细胞的细胞表面表达。在容易获得某些滋养细胞特征的低甲基化ESCs中，Plet1需要提供滋养细胞特有的基因表达模式，包括ELF5的上调。Plet1在TSC分化过程中表现出不寻常的双相表达，因此可能在平衡滋养层细胞自我更新和分化中起关键作用。此外，在TSCs中过表达和CRISPR/Cas9介导的基因敲除表明，高水平的Plet1有利于向滋养层巨细胞分化，而缺乏Plet1则优先诱导合体滋养层细胞的形成。因此，Plet1表达的内源性动态通过促进Plet1-low和Plet1-High细胞向合体滋养细胞或巨细胞途径的分化，在滋养层间隔内建立了重要的模式线索。
Gene loci that are hypermethylated and repressed in embryonic (ESCs) but hypomethylated and expressed in trophoblast (TSCs) stem cells are very rare and may have particularly important roles in early developmental cell fate decisions, as previously shown for Elf5. Here, we assessed another member of this small group of genes, Placenta Expressed Transcript 1 (Plet1), for its function in establishing trophoblast lineage identity and modulating trophoblast differentiation. We find that Plet1 is tightly repressed by DNA methylation in ESCs but expressed on the cell surface of TSCs and trophoblast giant cells. In hypomethylated ESCs that are prone to acquire some trophoblast characteristics, Plet1 is required to confer a trophoblast-specific gene expression pattern, including up-regulation of Elf5. Plet1 displays an unusual biphasic expression profile during TSC differentiation and thus may be pivotal in balancing trophoblast self-renewal and differentiation. Furthermore, overexpression and CRISPR/Cas9-mediated knockout in TSCs showed that high Plet1 levels favour differentiation towards the trophoblast giant cell lineage, whereas lack of Plet1 preferentially induces syncytiotrophoblast formation. Thus, the endogenous dynamics of Plet1 expression establish important patterning cues within the trophoblast compartment by promoting differentiation towards the syncytiotrophoblast or giant cell pathway in Plet1-low and Plet1-high cells, respectively.