title: A heterogeneous expression pattern for Nanog in embryonic stem cells.
abstract: Nanog is a critical homeodomain factor responsible for maintaining embryonic stem (ES) cell self-renewal and pluripotency. Of interest, Nanog expression is not homogeneous in the conventional culture of murine ES cells. A Nanog-high population expresses markers for pluripotent ES cells, whereas a Nanog-low population expresses markers for primitive endoderm, such as Gata6. Since the inner cell mass of early blastocysts has recently been reported to be heterogeneous in terms of Nanog and Gata6 expression, ES cells appear to closely resemble the developing stage from which they originate. We further demonstrate that Nanog can directly repress Gata6 expression through its binding to the proximal promoter region of the Gata6 gene and that overexpression of Nanog reduces heterogeneity during ES cell maintenance. Interestingly, Nanog heterogeneity does not correlate with the heterogeneous expression of stage-specific embryonic antigen-1, suggesting that multiple but overlapping levels of heterogeneity may exist in ES cells. These findings provide insight into the factors that control ES cell self-renewal and the earliest lineage commitment to primitive endoderm while also suggesting methods to promote homogeneity during ES cell maintenance. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Department of Pathology, University of Florida College of Medicine, Box 100275, Gainesville, Florida 32610, USA.
authors.forename: Amar M
authors.initials: AM
authors.lastname: Singh
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamazaki
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hankowski
authors.forename: Naohiro
authors.initials: N
authors.lastname: Terada
mesh_terms: D000818:Animals; D002460:Cell Line / Q000378:metabolism; D019070:Cell Lineage; D002469:Cell Separation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004475:Ectoderm / Q000166:cytology; D053595:Embryonic Stem Cells / Q000145:classification / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology; D050993:GATA6 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse