DAZL regulates Tet1 translation in murine embryonic stem cells

Autor: Welling, Maaike, Chen, Hsu Hsin, Munoz Peralta, Javier, Musheev, Michael U., Kester, Lennart, Junker, Jan Philipp, Mischerikow, Nikolai, Arbab, Mandana, Kuijk, Ewart, Silberstein, Lev, Kharchenko, Peter V., Geens, Mieke, Niehrs, Christof, Van De Velde, Hilde, Van Oudenaarden, Alexander, Heck, Albert J R, Geijsen, Niels, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Faculty of Veterinary Medicine Research Groups, CSCA TR1
Přispěvatelé: Reproduction and Genetics, Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, Reproductive immunology and implantation, Oral Health, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Biomol.Mass Spect. and Proteomics, Faculty of Veterinary Medicine Research Groups, CSCA TR1, Hubrecht Institute for Developmental Biology and Stem Cell Research
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Cellular differentiation
Biochemistry
DAZL
Mice
DNA hydroxymethylation
PRIMORDIAL GERM-CELLS
Induced pluripotent stem cell
Non-U.S. Gov't
IN-VIVO
Genetics
Research Support
Non-U.S. Gov't
METHYLATION
Gene Expression Regulation
Developmental
RNA-Binding Proteins
Cell Differentiation
Mouse Embryonic Stem Cells
Cellular Reprogramming
Cell biology
DNA-Binding Proteins
DIFFERENTIATION
DNA methylation
Reprogramming
Germ Layers
DNA Hydroxymethylation
Pluripotent Stem Cells
naïve pluripotency
Biology
Research Support
Cytosine
DNA DEMETHYLATION
SINGLE-CELL
Proto-Oncogene Proteins
2i conditions
Journal Article
Animals
5-METHYLCYTOSINE
RNA
Messenger
Molecular Biology
Scientific Reports
naive pluripotency
Dazl
DNA Methylation
Embryonic stem cell
TET1
SELF-RENEWAL
Epiblast
Protein Biosynthesis
Transcriptome
GROUND-STATE PLURIPOTENCY
Zdroj: EMBO Reports, 16(7), 791-802. Nature Publishing Group
EMBO Reports, 16(7), 791. Nature Publishing Group
ISSN: 1469-221X
Popis: 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. Synopsis This study reports that by enhancing Tet1 mRNA translation, the RNA-binding protein DAZL regulates TET1-mediated cytosine hydroxymethylation in ESCs during active reprogramming to a pluripotent ground state. DAZL marks ESCs actively transitioning to a naïve pluripotent state. DAZL enhances Tet1 mRNA translation. DAZL overexpression results in increased hydroxymethylation. This study reports that by enhancing Tet1 mRNA translation, the RNA-binding protein DAZL regulates TET1-mediated cytosine hydroxymethylation in ESCs during active reprogramming to a pluripotent ground state.
Databáze: OpenAIRE
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