Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in Four-Cell Mouse Embryos
Graham, Sarah JL
Macaulay, Iain C
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Goolam, M., Scialdone, A., Graham, S. J., Macaulay, I. C., Jedrusik, A., Hupalowska, A., Voet, T., et al. (2016). Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in Four-Cell Mouse Embryos. Cell, 165 61-74. https://doi.org/10.1016/j.cell.2016.01.047
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 characterise 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 cells with decreased Sox21 yield more extra-embryonic than pluripotent progeny. Consistently, decreasing Sox21 results in premature up-regulation of the differentiation regulator Cdx2, suggesting Sox21 helps safeguard pluripotency. Furthermore, Sox21 is elevated following increased expression of the histone H3R26-methylase CARM1, and 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.
We are grateful to the Wellcome Trust, EMBL and CRUK for supporting our work, and our colleagues : M.Shahbazi, D.Glover, F. Antonica for feedback and G. Recher for imaging assistance. Sequence data have been deposited in ArrayExpress (E-MTAB-3321).
European Commission (657995)
External DOI: https://doi.org/10.1016/j.cell.2016.01.047
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253486
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/