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Updated: Jan 25, 2026
09:07
Chemical Reversion of Conventional Human Pluripotent Stem Cells to a Naïve-like State with Improved Multilineage Differentiation Potency
Published on: June 10, 2018
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Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency
Tüzer Kalkan1, Susanne Bornelöv1, Carla Mulas2
1Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK.
Cell Stem Cell
|April 30, 2019
Summary
Gene regulatory networks in embryonic stem cells (ESCs) require specific transcription factors for lineage commitment. Deleting TCF3, ETV5, and RBPJ locks ESCs in self-renewal, halting differentiation.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Epigenetics
Background:
- Naive mouse embryonic stem cells (ESCs) possess a gene regulatory network (GRN) that must be reconfigured for lineage commitment.
- Transcription factor TCF3 suppresses ESC circuitry components, but its depletion only delays, not prevents, the transition to formative pluripotency.
Purpose of the Study:
- To investigate the roles of ETS-family transcription factor ETV5 and repressor RBPJ in ESC lineage commitment.
- To understand how ETV5 and RBPJ contribute to the exit from the naive ESC state.
Main Methods:
- Utilized genetic manipulation, specifically triple deletion of Etv5, Rbpj, and Tcf3 in mouse ESCs.
- Analyzed gene expression, genome relocation, and enhancer activity in response to ERK signaling.
Main Results:
- ETV5, upon ERK signaling, switches from self-renewal support to commissioning formative epiblast enhancers.
- RBPJ upregulation independently blocks naive factors (TBX3, NANOG) re-expression, securing exit from the naive state.
- Triple deletion of Etv5, Rbpj, and Tcf3 resulted in ESCs locked in self-renewal, resistant to differentiation stimuli.
Conclusions:
- ETV5 and RBPJ are crucial, complementary drivers of GRN transition during ESC lineage commitment.
- Simultaneous genetic elimination of TCF3, ETV5, and RBPJ stalls developmental progression, mimicking small-molecule inhibitor effects.
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