OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 3; pp. 1 - 11
• Main Authors: Stirparo, Giuliano G., Kurowski, Agata, Yanagida, Ayaka, Bates, Lawrence E., Strawbridge, Stanley E., Hladkou, Siarhei, Stuart, Hannah T., Boroviak, Thorsten E., Silva, Jose C. R., Nichols, Jennifer
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.01.2021
• Subjects: Animals; Biological Sciences; 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; Signal Transduction - genetics; Single-Cell Analysis; STAT3 Transcription Factor - genetics; OCT4; STAT3 pathway; metabolism; developmental biology; single-cell profiling
• ISSN: 0027-8424; 1091-6490
• 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.