OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms.
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Stuart, Hannah T
Rebelo Da Silva, Jose
Proceedings of the National Academy of Sciences of the United States of America
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Stirparo, G. G., Kurowski, A., Yanagida, A., Bates, L., Strawbridge, S., Hladkou, S., Stuart, H. T., et al. (2021). OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms.. Proceedings of the National Academy of Sciences of the United States of America, 118 (3)https://doi.org/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 signalling machinery. Concurrently, OCT4 null inner cell masses ectopically activate a subset of trophectoderm-associated genes. Inspection of metabolic pathways implicates regulation of rate-limiting glycolytic enzymes by OCT4, consistent with a role in sustaining glycolysis. Furthermore, upregulation of the lysosomal pathway was specifically detected in OCT4 null embryos. This finding implicates a requirement for OCT4 in production of normal trophectoderm. Collectively, our findings uncover regulation of cellular metabolism and biophysical properties as mechanisms by which OCT4 instructs pluripotency.
Pluripotent Stem Cells, Animals, Mice, Signal Transduction, Gene Expression Regulation, Developmental, Glycolysis, Cell Lineage, Embryonic Development, STAT3 Transcription Factor, Octamer Transcription Factor-3, Blastocyst Inner Cell Mass, Embryo, Mammalian, Single-Cell Analysis
This work was supported by the University of Cambridge, BBSRC project grant RG74277, BB/R018588/1 and MR/R017735/1 to HS and LB respectively, MRC PhD studentship for AK and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute.
Wellcome Trust (101861/Z/13/Z)
External DOI: https://doi.org/10.1073/pnas.2008890118
This record's URL: https://www.repository.cam.ac.uk/handle/1810/315955
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