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Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions

View ORCID ProfileDaniel Strebinger, Cédric Deluz, Elias T. Friman, Subashika Govindan, Andrea B. Alber, View ORCID ProfileDavid M. Suter
doi: https://doi.org/10.1101/299073
Daniel Strebinger
1Sponsored Stem Cells Research Chair (UPSUTER), The Institute of Bioengineering (IBI), School of Life Sciences, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland
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Cédric Deluz
1Sponsored Stem Cells Research Chair (UPSUTER), The Institute of Bioengineering (IBI), School of Life Sciences, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland
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Elias T. Friman
1Sponsored Stem Cells Research Chair (UPSUTER), The Institute of Bioengineering (IBI), School of Life Sciences, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland
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Subashika Govindan
1Sponsored Stem Cells Research Chair (UPSUTER), The Institute of Bioengineering (IBI), School of Life Sciences, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland
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Andrea B. Alber
1Sponsored Stem Cells Research Chair (UPSUTER), The Institute of Bioengineering (IBI), School of Life Sciences, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland
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David M. Suter
1Sponsored Stem Cells Research Chair (UPSUTER), The Institute of Bioengineering (IBI), School of Life Sciences, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland
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  • For correspondence: david.suter@epfl.ch
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Abstract

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.

Footnotes

  • This is an extensively revised version of our manuscript. We have streamlined the story and included validation experiments on the fusion proteins, knock-in cell lines and additional differentiation experiments.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 13, 2019.
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Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions
Daniel Strebinger, Cédric Deluz, Elias T. Friman, Subashika Govindan, Andrea B. Alber, David M. Suter
bioRxiv 299073; doi: https://doi.org/10.1101/299073
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Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions
Daniel Strebinger, Cédric Deluz, Elias T. Friman, Subashika Govindan, Andrea B. Alber, David M. Suter
bioRxiv 299073; doi: https://doi.org/10.1101/299073

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