ArticleCellular and molecular life sciences : CMLS2024
Uncovering the role of TET2-mediated ENPEP activation in trophoblast cell fate determination.
Article in Cellular and molecular life sciences : CMLS, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Perifollicular stromal cells sustain folliculogenesis via MDK-NCL signaling in mice and humans.Cell discovery · 2026Article
- VGLL1 contributes to both the transcriptome and epigenome of the developing trophoblast compartment.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Combinatorial profiling of multiple histone modifications and transcriptome in single cells using scMTR-seq.Science advances · 2025Article
- Maternal plasma extracellular vesicles tsRNA as potential biomarkers for assessing preterm labor risk.BMC pregnancy and childbirth · 2025Article
- Host-Microbiota Interactions in the Pathogenesis of Porcine Fetal Mummification.Microorganisms · 2025Article
- TET1-mediated DNA demethylation suppresses migration of goat placental trophoblast cells.Journal of animal science · 2025Article
- Nuclear transfer leads to aberrant cell cycle regulation and translation, as determined by gene expression, and selection of mitochondrial DNA in porcine blastocysts.NAR molecular medicine · 2024Article
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Authors and funding
6 authors.
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Abstract
Early trophoblast differentiation is crucial for embryo implantation, placentation and fetal development. Dynamic changes in DNA methylation occur during preimplantation development and are critical for cell fate determination. However, the underlying regulatory mechanism remains unclear. Recently, we derived morula-like expanded potential stem cells from human preimplantation embryos (hEPSC-em), providing a valuable tool for studying early trophoblast differentiation. Data analysis on published datasets showed differential expressions of DNA methylation enzymes during early trophoblast differentiation in human embryos and hEPSC-em derived trophoblastic spheroids. We demonstrated downregulation of DNA methyltransferase 3 members (DNMT3s) and upregulation of ten-eleven translocation methylcytosine dioxygenases (TETs) during trophoblast differentiation. While DNMT inhibitor promoted trophoblast differentiation, TET inhibitor hindered the process and reduced implantation potential of trophoblastic spheroids. Further integrative analysis identified that glutamyl aminopeptidase (ENPEP), a trophectoderm progenitor marker, was hypomethylated and highly expressed in trophoblast lineages. Concordantly, progressive loss of DNA methylation in ENPEP promoter and increased ENPEP expression were detected in trophoblast differentiation. Knockout of ENPEP in hEPSC-em compromised trophoblast differentiation potency, reduced adhesion and invasion of trophoblastic spheroids, and impeded trophoblastic stem cell (TSC) derivation. Importantly, TET2 was involved in the loss of DNA methylation and activation of ENPEP expression during trophoblast differentiation. TET2-null hEPSC-em failed to produce TSC properly. Collectively, our results illustrated the crucial roles of ENPEP and TET2 in trophoblast fate commitments and the unprecedented TET2-mediated loss of DNA methylation in ENPEP promoter.
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