Sox17-mediated XEN cell conversion identifies dynamic networks controlling cell-fate decisions in embryo-derived stem cells.
Little is known about the gene regulatory networks (GRNs) distinguishing extraembryonic endoderm (ExEn) stem (XEN) cells from those that maintain the extensively characterized embryonic stem cell (ESC). An intriguing network candidate is Sox17, an essential transcription factor for XEN derivation and self-renewal. Here, we show that forced Sox17 expression drives ESCs toward ExEn, generating XEN cells that contribute to ExEn when placed back into early mouse embryos. Transient Sox17 expression is sufficient to drive this fate change during which time cells transit through distinct intermediate states prior to the generation of functional XEN-like cells. To orchestrate this conversion process, Sox17 acts in autoregulatory and feedforward network motifs, regulating dynamic GRNs directing cell fate. Sox17-mediated XEN conversion helps to explain the regulation of cell-fate changes and reveals GRNs regulating lineage decisions in the mouse embryo.
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada.
Angela C H
AC
McDonald
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
Steffen
S
Biechele
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON M5G 0A4, Canada. Electronic address: janet.rossant@sickkids.ca.
Janet
J
Rossant
Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada; Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1L 8L6, Canada; Cellular and Molecular Medicine, Faulty of Medicine, University of Ottawa, 75 Laurier Avenue East, Ottawa, ON K1N 6N5, Canada. Electronic address: wstanford@ohri.ca.
William L
WL
Stanford
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004707:Endoderm / Q000166:cytology; D053263:Gene Regulatory Networks; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism*
D024002:HMGB Proteins; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse