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EMBRYONIC STEM CELLS |
1 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607
* To whom correspondence should be addressed. E-mail: merrillb{at}uic.edu.
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Abstract |
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Elucidating the underlying transcriptional control of pluripotent cells is necessary for the development of new methods of inducing and maintaining pluripotent cells in vitro. Three transcription factors, Nanog, Oct4, and Sox2, have been reported to form a feedforward circuit promoting pluripotent cell self renewal in embryonic stem cells (ESC). Previously, we found that a transcriptional repressor activity of Tcf3, a DNA-binding effector of Wnt signaling, reduced Nanog promoter activity and Nanog levels in mouse ESC (mESC). The objective of this study was to determine the scope of Tcf3 effects on gene expression and self renewal beyond the regulation of Nanog levels. We show that Tcf3 acts broadly on a genome-wide scale to reduce the levels of several promoters of self renewal (Nanog, Tcl1, Tbx3, Esrrb) while not affecting other ESC genes (Oct4, Sox2, Fgf4). Comparing effects of Tcf3 ablation with Oct4 or Nanog knockdown revealed that Tcf3 counteracted effects of both Nanog and Oct4. Interestingly, effects of Tcf3 were more strongly correlated with Oct4 than with Nanog, despite the normal levels of Oct4 in TCF3-/- mESC. The deranged gene expression allowed TCF3-/- mESC self renewal even in the absence of leukemia inhibitory factor (Lif) and delayed differentiation in embryoid bodies. These findings identify Tcf3 as a cell-intrinsic inhibitor of pluripotent cell self renewal that functions by limiting steady-state levels of self renewal factors.
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Author contributions: F.Y.: Conception and Design, Collection of data, Data analysis and interpretation, Manuscript writing; L.P.: Conception and design, Provision of study materials; B.M.: Concept and design, Financial support, Data analysis and interpretation, Manuscript writing.
Key Words. Embryo, Embryonic stem cell, In vitro culture, Gene expression
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M.F. Cole and R.A. Young Mapping Key Features of Transcriptional Regulatory Circuitry in Embryonic Stem Cells Cold Spring Harb Symp Quant Biol, November 6, 2008; (2008) sqb.2008.73.027v1. [Abstract] [PDF]
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 N. P. Hoverter and M. L. Waterman A Wnt-fall for Gene Regulation: Repression Sci. Signal., September 30, 2008; 1(39): pe43 - pe43. [Abstract] [Full Text] [PDF]
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