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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 embryonic stem cells (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, the 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 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.  Disclosure of potential conflicts of interest is found at the end of this article.

Tcf3 Functions as a Steady‐State Limiter of Transcriptional Programs of Mouse Embryonic Stem Cell Self‐Renewal