title: Pluripotency factors in embryonic stem cells regulate differentiation into germ layers.
abstract: Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells.
authors.affiliation: FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Thomson
authors.forename: Siyuan John
authors.initials: SJ
authors.lastname: Liu
authors.forename: Ling-Nan
authors.initials: LN
authors.lastname: Zou
authors.forename: Zack
authors.initials: Z
authors.lastname: Smith
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.forename: Sharad
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D005855:Germ Layers / Q000166:cytology*; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology; D055748:SOXB1 Transcription Factors / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse