OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms
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 b...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 3; pp. 1 - 11 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
19.01.2021
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| Subjects | |
| Online Access | Get full text |
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| Abstract | 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. |
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| AbstractList | 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. Significance We used single-cell whole-genome transcriptional profiling and protein quantification to investigate the role of OCT4 in establishing pluripotency in the murine embryo. Surprisingly, most pluripotency-associated factors are induced normally in OCT4 null early blastocysts, apart from members of the STAT3 signaling pathway. Coincidentally, certain trophectoderm markers are induced but not Cdx2 , which was previously implicated to repress Pou5f1 in vitro. This ectopic gene activation suggests a role for OCT4 in maintaining chromatin in a pluripotency-compatible state, likely via UTF1, a known OCT4 target. At implantation, OCT4 null inner cell masses morphologically resemble trophectoderm but exhibit molecular differences linking metabolic and physical stress responses to loss of OCT4. These effects correlate with reduced STAT3 signaling and consequent reduction of oxidative respiration. 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. We used single-cell whole-genome transcriptional profiling and protein quantification to investigate the role of OCT4 in establishing pluripotency in the murine embryo. Surprisingly, most pluripotency-associated factors are induced normally in OCT4 null early blastocysts, apart from members of the STAT3 signaling pathway. Coincidentally, certain trophectoderm markers are induced but not Cdx2 , which was previously implicated to repress Pou5f1 in vitro. This ectopic gene activation suggests a role for OCT4 in maintaining chromatin in a pluripotency-compatible state, likely via UTF1, a known OCT4 target. At implantation, OCT4 null inner cell masses morphologically resemble trophectoderm but exhibit molecular differences linking metabolic and physical stress responses to loss of OCT4. These effects correlate with reduced STAT3 signaling and consequent reduction of oxidative respiration. 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. |
| Author | Boroviak, Thorsten E. Stirparo, Giuliano G. Hladkou, Siarhei Silva, Jose C. R. Yanagida, Ayaka Kurowski, Agata Nichols, Jennifer Strawbridge, Stanley E. Stuart, Hannah T. Bates, Lawrence E. |
| Author_xml | – sequence: 1 givenname: Giuliano G. surname: Stirparo fullname: Stirparo, Giuliano G. – sequence: 2 givenname: Agata surname: Kurowski fullname: Kurowski, Agata – sequence: 3 givenname: Ayaka surname: Yanagida fullname: Yanagida, Ayaka – sequence: 4 givenname: Lawrence E. surname: Bates fullname: Bates, Lawrence E. – sequence: 5 givenname: Stanley E. surname: Strawbridge fullname: Strawbridge, Stanley E. – sequence: 6 givenname: Siarhei surname: Hladkou fullname: Hladkou, Siarhei – sequence: 7 givenname: Hannah T. surname: Stuart fullname: Stuart, Hannah T. – sequence: 8 givenname: Thorsten E. surname: Boroviak fullname: Boroviak, Thorsten E. – sequence: 9 givenname: Jose C. R. surname: Silva fullname: Silva, Jose C. R. – sequence: 10 givenname: Jennifer surname: Nichols fullname: Nichols, Jennifer |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33452132$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Copyright © 2021 the Author(s). Published by PNAS. Copyright © 2021 the Author(s). Published by PNAS. 2021 |
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| Keywords | OCT4 STAT3 pathway metabolism developmental biology single-cell profiling |
| Language | English |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Rudolf Jaenisch, Whitehead Institute for Biomedical Research, Cambridge, MA, and approved December 8, 2020 (received for review June 3, 2020) 1G.G.S. and A.K. contributed equally to this work. Author contributions: G.G.S., A.K., and J.N. designed research; A.K., A.Y., L.E.B., S.E.S., S.H., H.T.S., T.E.B., J.C.R.S., and J.N. performed research; G.G.S., A.Y., L.E.B., S.E.S., and J.N. contributed new reagents/analytic tools; G.G.S., A.K., L.E.B., S.E.S., and J.N. analyzed data; and G.G.S., A.K., and J.N. wrote the paper. |
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| Snippet | OCT4 is a fundamental component of the molecular circuitry governing pluripotency in vivo and in vitro. To determine how OCT4 establishes and protects the... Significance We used single-cell whole-genome transcriptional profiling and protein quantification to investigate the role of OCT4 in establishing pluripotency... We used single-cell whole-genome transcriptional profiling and protein quantification to investigate the role of OCT4 in establishing pluripotency in the... |
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| SubjectTerms | 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 |
| Title | OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms |
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