Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus
| Autor: | Anna Griego, Francesco Aulicino, Antonio del Sol, Aniello Cerrato, Maria Pia Cosma, Gökhan Ertaylan, Anchel de Jaime-Soguero, Frederic Lluis, Aravind Tallam |
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| Přispěvatelé: | ten Berge, Derk, TwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany., RS: FSE MaCSBio, RS: FPN MaCSBio, Maastricht Centre for Systems Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Somatic cell medicine.medical_treatment Gene Expression BETA-CATENIN Mice Animal Cells ENRICHMENT ANALYSIS Mouse Embryonic Stem Cells/metabolism TUMOR-SUPPRESSOR Hepatocyte Nuclear Factor 1-alpha Cell Cycle and Cell Division Promoter Regions Genetic Induced pluripotent stem cell Wnt Signaling Pathway Cells Cultured Genetics (clinical) Staining Genetics & Heredity Reverse Transcriptase Polymerase Chain Reaction Stem Cells Cell Cycle Wnt signaling pathway Cell Staining Mouse Embryonic Stem Cells Stem-cell therapy Cell cycle Cyclin-Dependent Kinase Inhibitor p15/genetics Cell staining TRANSCRIPTION FACTORS DIFFERENTIATION Cell Processes Gene Knockdown Techniques TCF3 Cell cycle inhibitors Cellular Types Life Sciences & Biomedicine Research Article G1 phase Cell division lcsh:QH426-470 Cell Potency Blotting Western DNA transcription Mice Transgenic Wnt/Tcf1 stem cell Ink4/Arf Biology Research and Analysis Methods PLURIPOTENCY Cell Proliferation/genetics 03 medical and health sciences Cyclin-Dependent Kinase Inhibitor p16/genetics Genetics medicine Animals Humans Cell Cycle/genetics Gene Regulation Wnt Signaling Pathway/genetics Hepatocyte Nuclear Factor 1-alpha/genetics Molecular Biology Techniques Cell Cycle Inhibitors Molecular Biology Cyclin-Dependent Kinase Inhibitor p16 Ecology Evolution Behavior and Systematics Cell Proliferation Cyclin-Dependent Kinase Inhibitor p15 REGULATORY CIRCUITRY Science & Technology Base Sequence Cell growth REPRESSION G1 Phase Biology and Life Sciences Cell Biology Promoter Regions Genetic/genetics Embryonic stem cell lcsh:Genetics SELF-RENEWAL HEK293 Cells 030104 developmental biology Gene Expression Regulation Specimen Preparation and Treatment Cancer research Cloning |
| Zdroj: | PLoS Genetics, Vol 13, Iss 3, p e1006682 (2017) PLOS genetics (Online) 13 (2017). doi:10.1371/journal.pgen.1006682 info:cnr-pdr/source/autori:De Jaime-Soguero A.; Aulicino F.; Ertaylan G.; Griego A.; Cerrato A.; Tallam A.; del Sol A.; Cosma M.P.; Lluis F./titolo:Wnt%2FTcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4%2FArf locus/doi:10.1371%2Fjournal.pgen.1006682/rivista:PLOS genetics (Online)/anno:2017/pagina_da:/pagina_a:/intervallo_pagine:/volume:13 PLoS Genetics Recercat. Dipósit de la Recerca de Catalunya instname Plos Genetics, 13(3):e1006682. Public Library of Science De Jaime-Soguero, A, Aulicino, F, Ertaylan, G, Griego, A, Cerrato, A, Tallam, A, Del Sol, A, Cosma, M P & Lluis, F 2017, ' Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus ', PLoS Genetics, vol. 13, no. 3, e1006682 . https://doi.org/10.1371/journal.pgen.1006682 |
| ISSN: | 1553-7390 |
| DOI: | 10.1371/journal.pgen.1006682 |
| Popis: | 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. Author summary Studying how to safely expand stem cells in culture is essential for regenerative medicine applications. Hence there is a clear need to decode how the cell cycle of mouse embryonic stem cells (mESCs) is regulated. Tcf3 and Tcf1 belong to the Tcf family of proteins. Tcf/Lef are effectors of the Wnt/β-catenin pathway and Tcf3 controls mESC pluripotency. Here we identified a recruitment site for Tcf1 embedded into a number of cell cycle repressor genes such as p15Ink4b, p16Ink4a and p19Arf. Tcf1-mediated activation of these genes drastically slows down proliferation of mESCs. In conclusion, here we showed that the Wnt pathway, besides controlling mESC pluripotency via Tcf3, also regulates mESC cell cycle through the recruitment of Tcf1 to the regulatory sites of key cell cycle genes. |
| Databáze: | OpenAIRE |
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