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

Cell. 2016 Mar 24;165(1):61-74. doi: 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • CARD Signaling Adaptor Proteins
  • CDX2 Transcription Factor
  • Card11 protein, mouse
  • Cdx2 protein, mouse
  • Homeodomain Proteins
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • SOXB1 Transcription Factors
  • SOXB2 Transcription Factors
  • Sox2 protein, mouse
  • Sox21 protein, mouse
  • Transcription Factors