Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal

• Published in: Nature cell biology Vol. 13; no. 7; pp. 762 - 770
• Main Authors: Merrill, Bradley J, Yi, Fei, Pereira, Laura, Hoffman, Jackson A, Shy, Brian R, Yuen, Courtney M, Liu, David R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2011; Nature Publishing Group
• Subjects: 631/208/199; 631/532/2117; 631/532/2441; 631/80/86; Ablation; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell cycle; Cell Line; Cell Proliferation - drug effects; Chromatin; Developmental Biology; Embryonic stem cells; Embryonic Stem Cells - drug effects; Embryonic Stem Cells - metabolism; Gene expression; Gene Expression Regulation, Developmental; Genetic aspects; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Kinases; Life Sciences; Mice; Nanog Homeobox Protein; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Phosphatase; Physiological aspects; Protein Kinase Inhibitors - pharmacology; Proteins; RNA Interference; Signal Transduction - drug effects; Signal Transduction - genetics; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Stem Cells; Transcription factors; Transcription, Genetic; Transfection; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt3 Protein; Wnt3A Protein; United States; United States > US
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2283

The co-occupancy of Tcf3 with Oct4, Sox2 and Nanog on embryonic stem cell (ESC) chromatin indicated that Tcf3 has been suggested to play an integral role in a poorly understood mechanism underlying Wnt-dependent stimulation of mouse ESC self-renewal of mouse ESCs. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signalling suggested Tcf3–β-catenin activation of target genes would stimulate self-renewal, here we show that an antagonistic relationship between Wnt3a and Tcf3 on gene expression regulates ESC self-renewal. Genetic ablation of Tcf3 replaced the requirement for exogenous Wnt3a or GSK3 inhibition for ESC self-renewal, demonstrating that inhibition of Tcf3 repressor is the necessary downstream effect of Wnt signalling. Interestingly, both Tcf3–β-catenin and Tcf1–β-catenin interactions contributed to Wnt stimulation of self-renewal and gene expression, and the combination of Tcf3 and Tcf1 recruited Wnt-stabilized β-catenin to Oct4 binding sites on ESC chromatin. This work elucidates the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network. Inhibition of the repressor function of the Wnt3a effector β-catenin–TCF3 is shown to be required to maintain pluripotency in cooperation with the activating role of the second Wnt effector β-catenin–TCF1. Both Tcf3 and Tcf1 are involved in the recruitment of β-catenin to Oct4 binding sites in embryonic stem cell chromatin.