Journal
STEM CELLS
Volume 26, Issue 8, Pages 2019-2031Publisher
WILEY
DOI: 10.1634/stemcells.2007-1115
Keywords
embryonic stem cells; differentiation; T-cell factor 3; transcription; Wnt signaling
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Funding
- NIAID NIH HHS [AI54973, R01 AI054973] Funding Source: Medline
- NIDDK NIH HHS [R01 DK047636-13, DK04763] Funding Source: Medline
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The Wnt signaling pathway is necessary both for maintaining undifferentiated stem cells and for directing their differentiation. In mouse embryonic stem cells (ESCs), Wnt signaling preferentially maintains stemness under certain permissive conditions. T-cell factor 3 (Tcf3) is a component 4 of the Wnt signaling and a dominant downstream effector in ESCs. Despite the wealth of knowledge regarding the importance of Writ signaling underlying stem cells functions, the precise mechanistic explanation by which the effects are mediated is unknown. In this study, we identified new regulatory targets of Tcf3 using a whole-genome approach and found that Tcf3 transcriptionally represses many genes important for maintaining pluripotency and self-renewal, as well as those involved in lineage commitment and stem cell differentiation. This effect is in part mediated by the core-pressors transducin-like enhancer of split 2 and C-terminal Binding Protein (CtBP). Notably, Tcf3 binds to and represses the Oct4 promoter, and this repressive effect requires both the Groucho and CtBP interacting domains of Tcf3. Interestingly, we find that in mouse preimplantation development embryos, Tcf3 expression is coregulated with Oct4 and Nanog and becomes localized to the inner cell mass of the blastocyst. These data demonstrate an important role for Tcf3 in modulating the appropriate level of gene transcription in ESCs and during embryonic development.
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