1. FoxO transcription factors actuate the formative pluripotency specific gene expression programme.
- Author
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Santini L, Kowald S, Cerron-Alvan LM, Huth M, Fabing AP, Sestini G, Rivron N, and Leeb M
- Subjects
- Animals, Mice, Cell Differentiation genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-akt genetics, PTEN Phosphohydrolase metabolism, PTEN Phosphohydrolase genetics, Forkhead Transcription Factors metabolism, Forkhead Transcription Factors genetics, Forkhead Box Protein O1 metabolism, Forkhead Box Protein O1 genetics, Phosphorylation, Mouse Embryonic Stem Cells metabolism, Embryonic Stem Cells metabolism, Gene Expression Regulation, Developmental, Pluripotent Stem Cells metabolism, Gene Regulatory Networks
- 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., (© 2024. The Author(s).)
- Published
- 2024
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