title: Gata6 potently initiates reprograming of pluripotent and differentiated cells to extraembryonic endoderm stem cells.
abstract: Transcription factor-mediated reprograming is a powerful method to study cell fate changes. In this study, we demonstrate that the transcription factor Gata6 can initiate reprograming of multiple cell types to induced extraembryonic endoderm stem (iXEN) cells. Intriguingly, Gata6 is sufficient to drive iXEN cells from mouse pluripotent cells and differentiated neural cells. Furthermore, GATA6 induction in human embryonic stem (hES) cells also down-regulates pluripotency gene expression and up-regulates extraembryonic endoderm (ExEn) genes, revealing a conserved function in mediating this cell fate switch. Profiling transcriptional changes following Gata6 induction in mES cells reveals step-wise pluripotency factor disengagement, with initial repression of Nanog and Esrrb, then Sox2, and finally Oct4, alongside step-wise activation of ExEn genes. Chromatin immunoprecipitation and subsequent high-throughput sequencing analysis shows Gata6 enrichment near pluripotency and endoderm genes, suggesting that Gata6 functions as both a direct repressor and activator. Together, this demonstrates that Gata6 is a versatile and potent reprograming factor that can act alone to drive a cell fate switch from diverse cell types.
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, United Kingdom;
authors.forename: Sissy E
authors.initials: SE
authors.lastname: Wamaitha
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, United Kingdom;
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Valle
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, United Kingdom;
authors.forename: Lily T Y
authors.initials: LT
authors.lastname: Cho
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA;
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, United Kingdom;
authors.forename: Norah M E
authors.initials: NM
authors.lastname: Fogarty
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, United Kingdom;
authors.forename: Paul
authors.initials: P
authors.lastname: Blakeley
authors.affiliation: Brigham and Women's Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Sherwood
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA;
authors.forename: Hongkai
authors.initials: H
authors.lastname: Ji
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, United Kingdom;
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Niakan
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D065150:Cellular Reprogramming / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology*; D004707:Endoderm / Q000166:cytology*; D051519:Fibroblast Growth Factor 4 / Q000235:genetics / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology*; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C484171:Gata4 protein, mouse; C494760:Gata6 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse
keywords: Gata6; extraembryonic endoderm; human embryonic stem cells; mouse embryonic stem cells; pluripotency; reprograming