Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus

de Jaime Soguero, Anchel; Aulicino, Francesco, 1987-; Ertaylan, Gokhan; Griego, Anna; Cerrato, Aniello; Tallam, Aravind; del Sol, Antonio; Cosma, Maria Pia, 1970-; Lluis Vinas, Frederic

doi:http://dx.doi.org/10.1371/journal.pgen.1006682

Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus

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De Jaime-Soguero A, Aulicino F, Ertaylan G, Griego A, Cerrato A, Tallam A et al. Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. PLoS Genet. 2017 Mar 27;13(3):e1006682. DOI: 10.1371/journal.pgen.1006682

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.