Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, SELF-RENEWAL, BETA-CATENIN, TRANSCRIPTION FACTORS, REGULATORY CIRCUITRY, ENRICHMENT ANALYSIS, TUMOR-SUPPRESSOR, PLURIPOTENCY, DIFFERENTIATION, TCF3, REPRESSION, Animals, Base Sequence, Blotting, Western, Cell Cycle, Cell Proliferation, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, Gene Expression Regulation, Gene Knockdown Techniques, HEK293 Cells, Hepatocyte Nuclear Factor 1-alpha, Humans, Mice, Mice, Transgenic, Mouse Embryonic Stem Cells, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Wnt Signaling Pathway, C14/16/078#53765171, 0604 Genetics, Developmental Biology, 3105 Genetics

Abstract:

Understanding the mechanisms regulating cell cycle, proliferation and potency of pluripotent stem cells guarantees their safe use in the clinic. Embryonic stem cells (ESCs) present a fast cell cycle with a short G1 phase. This is due to the lack of expression of cell cycle inhibitors, which ultimately determines naïve pluripotency by holding back differentiation. The canonical Wnt/β-catenin pathway controls mESC pluripotency via the Wnt-effector Tcf3. However, if the activity of the Wnt/β-catenin controls the cell cycle of mESCs remains unknown. Here we show that the Wnt-effector Tcf1 is recruited to and triggers transcription of the Ink4/Arf tumor suppressor locus. Thereby, the activation of the Wnt pathway, a known mitogenic pathway in somatic tissues, restores G1 phase and drastically reduces proliferation of mESCs without perturbing pluripotency. Tcf1, but not Tcf3, is recruited to a palindromic motif enriched in the promoter of cell cycle repressor genes, such as p15Ink4b, p16Ink4a and p19Arf, which mediate the Wnt-dependent anti-proliferative effect in mESCs. Consistently, ablation of β-catenin or Tcf1 expression impairs Wnt-dependent cell cycle regulation. All together, here we showed that Wnt signaling controls mESC pluripotency and proliferation through non-overlapping functions of distinct Tcf factors.