Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in 4-Cell Mouse Embryos
Abstract
The major and essential objective of pre-implantation development is to establish embryonic and extra-embryonic cell fates. To address when and how this fundamental process is initiated in mammals, we characterize transcriptomes of all individual cells throughout mouse pre-implantation development. This identifies targets of master pluripotency regulators Oct4 and Sox2 as being highly heterogeneously expressed between blastomeres of the 4-cell embryo, with Sox21 showing one of the most heterogeneous expression profiles. Live-cell tracking demonstrates that cells with decreased Sox21 yield more extra-embryonic than pluripotent progeny. Consistently, decreasing Sox21 results in premature upregulation of the differentiation regulator Cdx2, suggesting that Sox21 helps safeguard pluripotency. Furthermore, Sox21 is elevated following increased expression of the histone H3R26-methylase CARM1 and is lowered following CARM1 inhibition, indicating the importance of epigenetic regulation. Therefore, our results indicate that heterogeneous gene expression, as early as the 4-cell stage, initiates cell-fate decisions by modulating the balance of pluripotency and differentiation.
Additional Information
© 2016 The Authors. Published by Elsevier Inc. Under a Creative Commons license (Attribution 4.0 International (CC BY 4.0)) Received 9 June 2015, Revised 10 November 2015, Accepted 22 January 2016, Available online 24 March 2016. We are grateful to the Wellcome Trust, EMBL, and CRUK for supporting our work and our colleagues: M. Shahbazi, D. Glover, and F. Antonica for feedback and G. Recher for imaging assistance. T.V. also acknowledges KU Leuven SymBioSys (PFV/10/016). Author Contributions: M.G. carried out the majority of the experiments with help from S.J.L.G. and A.H. S.J.L.G., M.G., and A.J. scored cell divisions and collected individual cells. A.S. analyzed the single-cell transcriptomics data and performed all downstream analyses using these data. I.C.M. prepared the cDNA libraries and performed and analyzed the deep sequencing data. T.V. supervised the cDNA library preparation. J.C.M. oversaw the computational analysis and supervised the study. M.Z.-G. conceived the project, designed and oversaw experiments, and supervised the study. All authors contributed to writing the manuscript. Accession Numbers: The accession number for the sequencing data reported in this paper is ArrayExpress: E-MTAB-3321.Attached Files
Published - 1-s2.0-S0092867416300617-main.pdf
Supplemental Material - 1-s2.0-S0092867416300617-mmc1.pdf
Supplemental Material - 1-s2.0-S0092867416300617-mmc2.xlsx
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Additional details
- PMCID
- PMC4819611
- Eprint ID
- 94538
- Resolver ID
- CaltechAUTHORS:20190405-170315162
- Wellcome Trust
- European Molecular Biology Laboratory (EMBL)
- Cancer Research UK
- PFV/10/016
- Katholieke Universiteit Leuven
- Created
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2019-04-09Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field