DAZL regulates Tet1 translation in murine embryonic stem cells |
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| Authors: | Javier Muñoz Michael U Musheev Lennart Kester Jan Philipp Junker Nikolai Mischerikow Mandana Arbab Ewart Kuijk Lev Silberstein Peter V Kharchenko Mieke Geens Christof Niehrs Hilde van de Velde Alexander van Oudenaarden Albert JR Heck Niels Geijsen |
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| Institution: | 1. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands;2. Netherlands Proteomics Centre, Utrecht, The Netherlands;3. Institute of Molecular Biology, Mainz, Germany;4. Hubrecht Institute–KNAW and University Medical Center Utrecht, Utrecht, The Netherlands;5. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA;6. Harvard Stem Cell Institute, Cambridge, MA, USA;7. Center for Biomedical Informatics, Harvard Medical School, Boston, MA, USA;8. Research Group Reproduction and Genetics, Vrije Universiteit Brussel, Brussels, Belgium;9. Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany;10. Department of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands |
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| Abstract: | Embryonic stem cell (ESC) cultures display a heterogeneous gene expression profile, ranging from a pristine naïve pluripotent state to a primed epiblast state. Addition of inhibitors of GSK3β and MEK (so‐called 2i conditions) pushes ESC cultures toward a more homogeneous naïve pluripotent state, but the molecular underpinnings of this naïve transition are not completely understood. Here, we demonstrate that DAZL, an RNA‐binding protein known to play a key role in germ‐cell development, marks a subpopulation of ESCs that is actively transitioning toward naïve pluripotency. Moreover, DAZL plays an essential role in the active reprogramming of cytosine methylation. We demonstrate that DAZL associates with mRNA of Tet1, a catalyst of 5‐hydroxylation of methyl‐cytosine, and enhances Tet1 mRNA translation. Overexpression of DAZL in heterogeneous ESC cultures results in elevated TET1 protein levels as well as increased global hydroxymethylation. Conversely, null mutation of Dazl severely stunts 2i‐mediated TET1 induction and hydroxymethylation. Our results provide insight into the regulation of the acquisition of naïve pluripotency and demonstrate that DAZL enhances TET1‐mediated cytosine hydroxymethylation in ESCs that are actively reprogramming to a pluripotent ground state. |
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| Keywords: | 2i conditions Dazl DNA hydroxymethylation naï ve pluripotency TET1 |
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