OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms

Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):e2008890118. doi: 10.1073/pnas.2008890118.


OCT4 is a fundamental component of the molecular circuitry governing pluripotency in vivo and in vitro. To determine how OCT4 establishes and protects the pluripotent lineage in the embryo, we used comparative single-cell transcriptomics and quantitative immunofluorescence on control and OCT4 null blastocyst inner cell masses at two developmental stages. Surprisingly, activation of most pluripotency-associated transcription factors in the early mouse embryo occurs independently of OCT4, with the exception of the JAK/STAT signaling machinery. Concurrently, OCT4 null inner cell masses ectopically activate a subset of trophectoderm-associated genes. Inspection of metabolic pathways implicates the regulation of rate-limiting glycolytic enzymes by OCT4, consistent with a role in sustaining glycolysis. Furthermore, up-regulation of the lysosomal pathway was specifically detected in OCT4 null embryos. This finding implicates a requirement for OCT4 in the production of normal trophectoderm. Collectively, our findings uncover regulation of cellular metabolism and biophysical properties as mechanisms by which OCT4 instructs pluripotency.

Keywords: OCT4; STAT3 pathway; developmental biology; metabolism; single-cell profiling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blastocyst Inner Cell Mass / metabolism
  • Cell Lineage / genetics*
  • Embryo, Mammalian
  • Embryonic Development / genetics
  • Embryonic Development / immunology*
  • Gene Expression Regulation, Developmental / genetics
  • Glycolysis / genetics
  • Mice
  • Octamer Transcription Factor-3 / genetics*
  • Pluripotent Stem Cells / metabolism
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / genetics
  • Single-Cell Analysis


  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse