Zeb2 Regulates Cell Fate at the Exit from Epiblast State in Mouse Embryonic Stem Cells

Autor: Kathleen Coddens, Frank Grosveld, Geert Berx, Danny Huylebroeck, Steven Goossens, Annick Francis, Tim Pieters, Agata Stryjewska, Leo A. van Grunsven, Jody J. Haigh, Andrea Conidi, Griet Verstappen, Lieve Umans, Ruben Dries, Wilfred F. J. van IJcken
Přispěvatelé: Cell biology, Clinical Genetics, Basic (bio-) Medical Sciences, Liver Cell Biology, Translational Liver Cell Biology
Rok vydání: 2017
Předmět:
0301 basic medicine
Transcription
Genetic
Cellular differentiation
Embryoid body
RNA‐sequencing
Pluripotent
Embryonic Stem Cells/Induced Pluripotent Stem Cells
Neurons/cytology
Mice
Medicine and Health Sciences
Cell differentiation
Transcriptom
Induced pluripotent stem cell
Mice
Knockout
Neurons
Principal Component Analysis
DNA-Binding Proteins/metabolism
DNA‐methylation
Mouse Embryonic Stem Cells
Down-Regulation/genetics
Cell biology
DNA-Binding Proteins
Phenotype
GROUND-STATE
embryonic structures
Molecular Medicine
SIP1
Stem cell
Germ Layers
DNA Methylation/genetics
GERM-CELLS
Pluripotent Stem Cells
Embryonic stem cells
Repressors
RNA-sequencing
Down-Regulation
Cell fate determination
Biology
PLURIPOTENCY
03 medical and health sciences
stem cells
Proto-Oncogene Proteins
Transcription factors
Animals
Cell Lineage
Mouse Embryonic Stem Cells/cytology
Embryoid Bodies
Zinc Finger E-box Binding Homeobox 2
SMAD-INTERACTING PROTEIN-1
Neuroectoderm
Sequence Analysis
RNA
Repressor Proteins/metabolism
Biology and Life Sciences
Cell Biology
Pluripotent Stem Cells/cytology
HIRSCHSPRUNG-DISEASE
DNA
DNA Methylation
Proto-Oncogene Proteins/metabolism
Zinc Finger E-box Binding Homeobox 2/metabolism
Embryonic stem cell
Molecular biology
Germ Layers/cytology
NERVOUS-SYSTEM
Repressor Proteins
SELF-RENEWAL
030104 developmental biology
Epiblast
Embryoid Bodies/cytology
DNA-methylation
MENTAL-RETARDATION
Developmental Biology
Zdroj: Stem Cells (Dayton, Ohio)
Stem Cells, 35(3), 611-625. Wiley-Blackwell
STEM CELLS
ISSN: 1549-4918
1066-5099
Popis: In human embryonic stem cells (ESCs) the transcription factor Zeb2 regulates neuroectoderm versus mesendoderm formation, but it is unclear how Zeb2 affects the global transcriptional regulatory network in these cell-fate decisions. We generated Zeb2 knockout (KO) mouse ESCs, subjected them as embryoid bodies (EBs) to neural and general differentiation and carried out temporal RNA-sequencing (RNA-seq) and reduced representation bisulfite sequencing (RRBS) analysis in neural differentiation. This shows that Zeb2 acts preferentially as a transcriptional repressor associated with developmental progression and that Zeb2 KO ESCs can exit from their naïve state. However, most cells in these EBs stall in an early epiblast-like state and are impaired in both neural and mesendodermal differentiation. Genes involved in pluripotency, epithelial-to-mesenchymal transition (EMT), and DNA-(de)methylation, including Tet1, are deregulated in the absence of Zeb2. The observed elevated Tet1 levels in the mutant cells and the knowledge of previously mapped Tet1-binding sites correlate with loss-of-methylation in neural-stimulating conditions, however, after the cells initially acquired the correct DNA-methyl marks. Interestingly, cells from such Zeb2 KO EBs maintain the ability to re-adapt to 2i + LIF conditions even after prolonged differentiation, while knockdown of Tet1 partially rescues their impaired differentiation. Hence, in addition to its role in EMT, Zeb2 is critical in ESCs for exit from the epiblast state, and links the pluripotency network and DNA-methylation with irreversible commitment to differentiation.
Databáze: OpenAIRE
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