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


Type

Article

Change log

Authors

Goolam, Mubeen 
Scialdone, Antonio 
Graham, Sarah JL 
Macaulay, Iain C 
Jedrusik, Agnieszka 

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.

Description

Keywords

Animals, Blastocyst, CARD Signaling Adaptor Proteins, CDX2 Transcription Factor, Embryo, Mammalian, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Homeodomain Proteins, Mice, Octamer Transcription Factor-3, Pluripotent Stem Cells, SOXB1 Transcription Factors, SOXB2 Transcription Factors, Single-Cell Analysis, Transcription Factors

Journal Title

Cell

Conference Name

Journal ISSN

0092-8674
1097-4172

Volume Title

165

Publisher

Elsevier BV
Sponsorship
European Commission (657995)
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).