A genome-wide screen reveals new regulators of the 2-cell-like cell state

Defossez Pierre-Antoine and Gupta Nikhil and Yakhou Lounis and Albert Julien Richard and Miura Fumihito and Ferry Laure and Kirsh Olivier and Azogui Anaelle and Yamaguchi Kohsuke and Laisné Marthe and Domrane Cécilia and Bonhomme Frédéric

In mammals, only the zygote and blastomeres of the early embryo are fully totipotent. This totipotency is mirrored in vitro by mouse "2-cell-like cells" (2CLCs), which appear at low frequency in cultures of Embryonic Stem cells (ESCs). Because totipotency is incompletely understood, we carried out a genomewide CRISPR KO screen in mouse ESCs, searching for mutants that reactivate the expression of Dazl, a robust 2-cell-like marker. Using secondary screens, we identify four mutants that reactivate not just Dazl, but also a broader 2-cell-like signature: the E3 ubiquitin ligase adaptor SPOP, the Zinc Finger transcription factor ZBTB14, MCM3AP, a component of the RNA processing complex TREX-2, and the lysine demethylase KDM5C. Functional experiments show how these factors link to known players of the 2 celllike state. These results extend our knowledge of totipotency, a key phase of organismal life.

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June, 2022



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