FoxO transcription factors actuate the formative pluripotency specific gene expression programme

Laura Santini, Saskia Kowald, Luis Miguel Cerron-Alvan, Michelle Huth, Anna Philina Fabing, Giovanni Sestini, Nicolas Rivron and Martin Leeb ()
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Laura Santini: University of Vienna, Vienna BioCenter
Saskia Kowald: University of Vienna, Vienna BioCenter
Luis Miguel Cerron-Alvan: University of Vienna, Vienna BioCenter
Michelle Huth: University of Vienna, Vienna BioCenter
Anna Philina Fabing: University of Vienna, Vienna BioCenter
Giovanni Sestini: Doctoral School of the University of Vienna, Medical University of Vienna
Nicolas Rivron: Vienna BioCenter
Martin Leeb: University of Vienna, Vienna BioCenter

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Naïve pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naïve pluripotency-specific transcription factors (TFs). Upon exiting naïve pluripotency, embryonic stem cells (ESCs) transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage choice. However, the mechanisms underlying disengagement from the naïve GRN and initiation of the formative GRN are unclear. Here, we demonstrate that phosphorylated AKT acts as a gatekeeper that prevents nuclear localisation of FoxO TFs in naïve ESCs. PTEN-mediated reduction of AKT activity upon exit from naïve pluripotency allows nuclear entry of FoxO TFs, enforcing a cell fate transition by binding and activating formative pluripotency-specific enhancers. Indeed, FoxO TFs are necessary and sufficient for the activation of the formative pluripotency-specific GRN. Our work uncovers a pivotal role for FoxO TFs in establishing formative post-implantation pluripotency, a critical early embryonic cell fate transition.

Date: 2024
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DOI: 10.1038/s41467-024-51794-9

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