PT  - JOURNAL ARTICLE
AU  - Daniel Strebinger
AU  - Cédric Deluz
AU  - Elias T. Friman
AU  - Subashika Govindan
AU  - Andrea B. Alber
AU  - David M. Suter
TI  - Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions
AID  - 10.1101/299073
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 299073
4099  - http://biorxiv.org/content/early/2019/05/13/299073.short
4100  - http://biorxiv.org/content/early/2019/05/13/299073.full
AB  - SOX2 and OCT4 are pioneer transcription factors playing a key role in embryonic stem (ES) cell self-renewal and differentiation. However, how temporal fluctuations in their expression levels bias lineage commitment is unknown. Here we generated knock-in reporter fusion ES cell lines allowing to monitor endogenous SOX2 and OCT4 protein fluctuations in living cells and to determine their impact on mesendodermal and neuroectodermal commitment. We found that small differences in SOX2 and OCT4 levels impact cell fate commitment in G1 but not in S phase. Elevated SOX2 levels modestly increased neuroectodermal commitment and decreased mesendodermal commitment upon directed differentiation. In contrast, elevated OCT4 levels strongly biased ES cell towards both neuroectodermal and mesendodermal fates. Using ATAC-seq on ES cells gated for different endogenous SOX2 and OCT4 levels, we found that high OCT4 levels increased chromatin accessibility at differentiation-associated enhancers. This suggests that small endogenous fluctuations of pioneer transcription factors can bias cell fate decisions by concentration-dependent priming of differentiation-associated enhancers.