Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions
| Autor: | David M. Suter, Daniel Strebinger, Elias T. Friman, Subashika Govindan, Cédric Deluz, Andrea B. Alber |
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| Rok vydání: | 2018 |
| Předmět: |
Medicine (General)
SOX2 OCT4 Regenerative Medicine Mice 0302 clinical medicine Gene Knock-In Techniques Biology (General) Induced pluripotent stem cell reproductive and urinary physiology Neural Plate 0303 health sciences Applied Mathematics Endoderm Cell Differentiation Articles differentiation embryonic stem cells endogenous protein fluctuations Chromatin Cell biology Enhancer Elements Genetic Computational Theory and Mathematics embryonic structures biological phenomena cell phenomena and immunity General Agricultural and Biological Sciences Information Systems Pluripotent Stem Cells QH301-705.5 Recombinant Fusion Proteins Cell fate determination Biology Article General Biochemistry Genetics and Molecular Biology Cell Line Cell fate commitment 03 medical and health sciences Directed differentiation R5-920 Animals Enhancer Transcription factor 030304 developmental biology General Immunology and Microbiology SOXB1 Transcription Factors fungi Embryonic stem cell Developmental biology Octamer Transcription Factor-3 Development & Differentiation 030217 neurology & neurosurgery |
| Zdroj: | Molecular Systems Biology, Vol 15, Iss 9, Pp n/a-n/a (2019) Molecular Systems Biology |
| DOI: | 10.13140/rg.2.2.36000.89604 |
| Popis: | The SOX2 and OCT4 transcription factors are key regulators of embryonic stem (ES) cell self-renewal and differentiation, but how temporal fluctuations in their endogenous expression levels bias lineage commitment is unknown. We generated knock-in reporter fusion ES cell lines allowing to measure endogenous SOX2 and OCT4 protein fluctuations and determine their impact on mesendodermal and neuroectodermal commitment. Surprisingly, small differences in endogenous SOX2 and OCT4 levels impacted cell fate commitment in G1 but not in S phase. While SOX2 fluctuations had a minor impact on neuroectodermal commitment, elevated OCT4 levels at the onset of differentiation strongly biased ES cell towards both neuroectoderm and mesendoderm at the expense of self-renewal and primitive endoderm. Genome-wide measurements of chromatin accessibility revealed OCT4 level-dependent priming of differentiation-associated enhancers. Finally, CRISPR-Cas9 knock-out of an OCT4 binding site in a key Eomes enhancer abolished the ability of OCT4 to promote mesendodermal differentiation. Our study demonstrates how small endogenous fluctuations of transcription factors prime cell fate decisions in a cell cycle-specific manner by modulating chromatin accessibility at regulatory regions, and thus represent a major source of heterogeneity in the ability of individual ES cells to respond to differentiation cues. |
| Databáze: | OpenAIRE |
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