Epigenetic regulation limits competence of pluripotent stem cell‐derived oocytes

  • Aizawa E
  • Ozonov E
  • Kawamura Y
  • et al.
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Abstract

Recent studies have reported the differentiation of pluripotent cells into oocytes in vitro . However, the developmental competence of in vitro ‐generated oocytes remains low. Here, we perform a comprehensive comparison of mouse germ cell development in vitro over all culture steps versus in vivo with the goal to understand mechanisms underlying poor oocyte quality. We show that the in vitro differentiation of primordial germ cells to growing oocytes and subsequent follicle growth is critical for competence for preimplantation development. Systematic transcriptome analysis of single oocytes that were subjected to different culture steps identifies genes that are normally upregulated during oocyte growth to be susceptible for misregulation during in vitro oogenesis. Many misregulated genes are Polycomb targets. Deregulation of Polycomb repression is therefore a key cause and the earliest defect known in in vitro oocyte differentiation. Conversely, structurally normal in vitro ‐derived oocytes fail at zygotic genome activation and show abnormal acquisition of 5‐hydroxymethylcytosine on maternal chromosomes. Our data identify epigenetic regulation at an early stage of oogenesis limiting developmental competence and suggest opportunities for future improvements. image Generation of female germ cells from pluripotent stem cells (PSCs) has extensive potential, but these oocytes often show low developmental competence. This study that reveals deregulation of Polycomb repression during the early oogenesis is a key cause of defects in in vitro ‐generated mouse oocytes. Stage‐specific single‐cell transcriptomics and functional assessment of PSC‐derived oocytes provides a comprehensive resource for comparisons to oogenesis in vivo . Culture steps for growth and differentiation of reconstituted follicles are critical for defining embryonic competence of in vitro ‐generated oocytes. Failure of zygotic genome activation and epigenetic impairment are hallmarks of in vitro ‐generated oocytes that fail to develop after fertilization or parthenogenetic activation. Computational analysis of gene expression and chromatin modification changes identifies Polycomb‐mediated repression as a key vulnerability during in vitro oocyte development.

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Aizawa, E., Ozonov, E. A., Kawamura, Y. K., Dumeau, C., Nagaoka, S., Kitajima, T. S., … Wutz, A. (2023). Epigenetic regulation limits competence of pluripotent stem cell‐derived oocytes. The EMBO Journal, 42(23). https://doi.org/10.15252/embj.2023113955

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