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  3. Uncovering the role of TET2-mediated ENPEP activation in trophoblast cell fate determination

Uncovering the role of TET2-mediated ENPEP activation in trophoblast cell fate determination

  • Cell Mol Life Sci. 2024 Jun 17;81(1):270. doi: 10.1007/s00018-024-05306-z.
Wen Huang # 1 2,  Andy Chun Hang Chen # 1 2 3,  Xujin Wei 1,  Sze Wan Fong 1,  William Shu Biu Yeung 4 5 6,  Yin Lau Lee 7 8 9
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, China.
  • 2 Centre for Translational Stem Cell Biology, Science Park, Sha Tin , Hong Kong, Special Administrative Region, China.
  • 3 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 4 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, China. wsbyeung@hku.hk.
  • 5 Centre for Translational Stem Cell Biology, Science Park, Sha Tin , Hong Kong, Special Administrative Region, China. wsbyeung@hku.hk.
  • 6 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. wsbyeung@hku.hk.
  • 7 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, China. cherielee@hku.hk.
  • 8 Centre for Translational Stem Cell Biology, Science Park, Sha Tin , Hong Kong, Special Administrative Region, China. cherielee@hku.hk.
  • 9 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. cherielee@hku.hk.
  • # Contributed equally.
PMID: 38886218 DOI: 10.1007/s00018-024-05306-z
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.

Keywords

DNA methylation; Early trophoblast development; Glutamyl aminopeptidase; Human expanded potential stem cells; Ten-eleven translocation methylcytosine dioxygenase 2.

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