title: Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells.
abstract: Nanog, Oct4, and Sox2 are the core regulators of mouse (m)ESC pluripotency. Although their basic importance in human (h)ESCs has been demonstrated, the mechanistic functions are not well defined. Here, we identify general and cell-line-specific requirements for NANOG, OCT4, and SOX2 in hESCs. We show that OCT4 regulates, and interacts with, the BMP4 pathway to specify four developmental fates. High levels of OCT4 enable self-renewal in the absence of BMP4 but specify mesendoderm in the presence of BMP4. Low levels of OCT4 induce embryonic ectoderm differentiation in the absence of BMP4 but specify extraembryonic lineages in the presence of BMP4. NANOG represses embryonic ectoderm differentiation but has little effect on other lineages, whereas SOX2 and SOX3 are redundant and repress mesendoderm differentiation. Thus, instead of being panrepressors of differentiation, each factor controls specific cell fates. Our study revises the view of how self-renewal is orchestrated in hESCs.
authors.affiliation: Yale Stem Cell Center, Department of Genetics, Yale University, New Haven, CT 06520, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Efrat
authors.initials: E
authors.lastname: Oron
authors.forename: Brynna
authors.initials: B
authors.lastname: Nelson
authors.forename: Spiro
authors.initials: S
authors.lastname: Razis
authors.forename: Natalia
authors.initials: N
authors.lastname: Ivanova
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage / Q000502:physiology*; D004475:Ectoderm / Q000166:cytology / Q000196:embryology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors