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Pluripotency Factors in Embryonic Stem Cells Regulate Differentiation into Germ Layers

Thomson, Matt and Liu, Siyuan John and Zou, Ling-Nan and Smith, Zack and Meissner, Alexander and Ramanathan, Sharad (2011) Pluripotency Factors in Embryonic Stem Cells Regulate Differentiation into Germ Layers. Cell, 145 (6). pp. 875-889. ISSN 0092-8674.

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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.

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Additional Information:© 2011 Elsevier Inc. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Received: October 15, 2010. Revised: March 3, 2011. Accepted: May 16, 2011. Published: June 9, 2011. We thank Doug Melton, Sean Eddy, Areez Mody, and Alexander Schier for scientific discussions and Rene Maehr, Masa Yamagata, and Dawen Cai for discussions and technical assistance. We thank Manfred Baetscher and the Harvard Genome Modification Facility for assistance with the cell line generation. We thank Bodo Stern, Nicole Francis, and in particular Sean Eddy and three anonymous referees for extensive comments on the manuscript. We thank the Harvard Stem Cell Institute Seed Grant (S.R.) and the Massachusetts Life Science Center (A.M.) for support. Microarray hybridization and measurements were performed by the Molecular Genetics Core Facility at Children’s Hospital Boston supported by NIH-P50-NS40828, and NIH-P30-HD18655. M.T. and S.R. conceived the project. M.T. established the experimental system and performed the immunofluorescence and perturbation experiments. S.J.L. and M.T. built the cell lines and performed microarray experiments. L.N.Z. performed the FACS experiments and established techniques for long term microscopy of ESCs on glass. M.T. and S.J.L. performed the time-lapse microscopy experiments. Z.S. and A.M. did the ChIP for Oct4 and Sox2. S.J.L., M.T., and S.R. performed the tiling qPCR experiments. M.T., S.R., and S.J.L. performed the data and mathematical analyses and wrote the manuscript. Accession Numbers: Microarray data are available in the Gene Expression Omnibus (GEO) database ( under the accession number GSE29005.
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Issue or Number:6
Record Number:CaltechAUTHORS:20170127-224411366
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73810
Deposited By: Donna Wrublewski
Deposited On:28 Jan 2017 19:45
Last Modified:03 Oct 2019 16:31

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