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Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in 4-Cell Mouse Embryos

Goolam, Mubeen and Scialdone, Antonio and Graham, Sarah J. L. and Macaulay, Iain C. and Jedrusik, Agnieszka and Hupalowska, Anna and Voet, Thierry and Marioni, John C. and Zernicka-Goetz, Magdalena (2016) Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in 4-Cell Mouse Embryos. Cell, 165 (1). pp. 61-74. ISSN 0092-8674. PMCID PMC4819611. http://resolver.caltech.edu/CaltechAUTHORS:20190405-170315162

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2016.01.047DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819611/PubMed CentralArticle
ORCID:
AuthorORCID
Zernicka-Goetz, Magdalena0000-0002-7004-2471
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.
Funders:
Funding AgencyGrant Number
Wellcome TrustUNSPECIFIED
European Molecular Biology Laboratory (EMBL)UNSPECIFIED
Cancer Research UKUNSPECIFIED
Katholieke Universiteit LeuvenPFV/10/016
PubMed Central ID:PMC4819611
Record Number:CaltechAUTHORS:20190405-170315162
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20190405-170315162
Official Citation:Mubeen Goolam, Antonio Scialdone, Sarah J.L. Graham, Iain C. Macaulay, Agnieszka Jedrusik, Anna Hupalowska, Thierry Voet, John C. Marioni, Magdalena Zernicka-Goetz, Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in 4-Cell Mouse Embryos, Cell, Volume 165, Issue 1, 2016, Pages 61-74, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2016.01.047. (http://www.sciencedirect.com/science/article/pii/S0092867416300617)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94538
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:09 Apr 2019 21:02
Last Modified:09 Apr 2019 21:02

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