A novel role of Tet1/2 proteins in cell cycle progression of trophoblast stem cells
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PROVIDER: PRJNA431364 | ENA |
REPOSITORIES: ENA
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Project description:The ten-eleven translocation (Tet) proteins are well known for their role in maintaining naive pluripotency of embryonic stem cells. Here, we demonstrate that jointly, Tet1 and Tet2 also safeguard the self-renewal potential of trophoblast stem cells (TSCs) and have partially redundant roles in maintaining their epithelial integrity. For the more abundantly expressed Tet1, we demonstrate that this is achieved by binding to critical epithelial genes, notably E-Cadherin, which becomes hyper-methylated and down-regulated in the absence of Tet1. This epithelial-to-mesenchymal transition phenotype is accompanied by centrosome duplication and separation defects. Moreover, we identify a novel role of Tet1 in stabilizing Cyclin B1, thereby acting as a facilitator of mitotic cell cycle progression. As a result, Tet1/2 mutant TSCs are prone to undergo endoreduplicative cell cycles leading to the formation of polyploid trophoblast giant cells. Taken together, our data reveal essential functions of Tet proteins in the trophoblast lineage.
2018-05-02 | GSE109545 | GEO
Project description:The ten-eleven translocation (TET) proteins are well known for their role in maintaining naive pluripotency of embryonic stem cells. Here, we demonstrate that, jointly, TET1 and TET2 also safeguard the self-renewal potential of trophoblast stem cells (TSCs) and have partially redundant roles in maintaining the epithelial integrity of TSCs. For the more abundantly expressed TET1, we show that this is achieved by binding to critical epithelial genes, notably E-cadherin, which becomes hyper-methylated and downregulated in the absence of TET1. The epithelial-to-mesenchymal transition phenotype of mutant TSCs is accompanied by centrosome duplication and separation defects. Moreover, we identify a role of TET1 in maintaining cyclin B1 stability, thereby acting as facilitator of mitotic cell-cycle progression. As a result, Tet1/2 mutant TSCs are prone to undergo endoreduplicative cell cycles leading to the formation of polyploid trophoblast giant cells. Taken together, our data reveal essential functions of TET proteins in the trophoblast lineage.
| S-EPMC5998911 | biostudies-literature
Project description:5-hydroxymethylcytosine (5hmC) is a recently discovered epigenetic modification that is lost in human cancers. Formation of 5hmC is catalysed by the Ten eleven translocation (TET) proteins that mediate the sequential oxidation of 5-methylcytosine (5mC) to 5hmC, leading to eventual DNA demethylation. Several mechanisms can lead to loss of 5hmC in cancers, including mutations in IDH or TET2 genes. However, little is known about the role of TET proteins and 5hmC in adult cells. Here, we report that TET1 downmodulation is required to permit adult cells to proliferate. TET1 is rapidly downmodulated in proliferating primary cells and in regenerating liver. TET1 silencing accelerates cell cycle progression while its constitutive expression inhibits cell growth. TET1 is a negative regulator of cell proliferation and it is regulated during development in tissue specific manner. These findings enlarge our knowledge on how one epigenetic modification such as the DNA hydroxymethylation mediated by TET1 is a key player on the control of cell proliferation. Examination of 5hmC in MEF at passage 0 and at passage 5.
2015-08-04 | E-GEOD-57250 | biostudies-arrayexpress
Project description:5-hydroxymethylcytosine (5hmC) is a recently discovered epigenetic modification that is lost in human cancers. Formation of 5hmC is catalysed by the Ten eleven translocation (TET) proteins that mediate the sequential oxidation of 5-methylcytosine (5mC) to 5hmC, leading to eventual DNA demethylation. Several mechanisms can lead to loss of 5hmC in cancers, including mutations in IDH or TET2 genes. However, little is known about the role of TET proteins and 5hmC in adult cells. Here, we report that TET1 downmodulation is required to permit adult cells to proliferate. TET1 is rapidly downmodulated in proliferating primary cells and in regenerating liver. TET1 silencing accelerates cell cycle progression while its constitutive expression inhibits cell growth. TET1 is a negative regulator of cell proliferation and it is regulated during development in tissue specific manner. These findings enlarge our knowledge on how one epigenetic modification such as the DNA hydroxymethylation mediated by TET1 is a key player on the control of cell proliferation.
2015-08-04 | GSE57250 | GEO
Project description:TET-family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem (ES) cells. ES cells depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1, and display hyperactive Nodal signalling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions that favor derivation of trophoblast stem (TS) cells, Tet1-depleted ES cells activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in mid-gestation embryo chimeras. Consistent with these findings, Tet1-depleted ES cells form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm and ectopic appearance of trophoblastic giant cells. Thus Tet1 functions to regulate the lineage differentiation potential of ES cells. Here, we performed whole-genome transcriptome profiling of ES cells stably depleted of Tet1 by shRNA knockdown (Tet1-kd) cultured in either standard ES cell or in TS cell culture conditions. Gene expression changes in Tet1-kd ES cells were fairly modest compared to control (GFP-kd) cells, although gene ontology (GO) analysis of differentially expressed genes yielded many terms related to embryonic development and cell cycle regulation. In TS cell culture conditions, a core set of genes defining trophectodermal cell differentiation, including Cdx2, Eomes and Tead4, was enriched in Tet1-kd compared to GFP-kd cells. A total of 27 samples were analysed with at least 3 replicates in each group. Control/reference samples comprise ES cells cultured in standard ES cell media (true ES cells) and TS cells cultured in Fgf4/heparin-supplemented (TS) media (true TS cells). We compared Tet1-kd ES cells with GFP-kd ES cells cultured in either ES or TS cell media. In addition, we included a set of Tet1-kd subclones (Tet1-kd-sc) cultured in TS cell condition and a set of untransfected ES cells (parental control) cultured in TS cell condition.
2011-02-07 | E-GEOD-26900 | biostudies-arrayexpress
Project description:Precise regulation of DNA methylation in mammals is critical for genome stability and epigenetic regulation. The discovery of the ten-eleven translocation (TET) proteins catalyzing the oxidation from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) revolutionized the perspective on the complexity and regulation of DNA modifications. Despite accumulating knowledge about the role of TET1, it remains unclear to what extent these can be attributed to its catalytic activity. Here, we use genome engineering and quantitative multi-omics approaches to dissect the role and mechanism of TET1 in mESCs. Our study identifies TET1 as an essential interaction hub for multiple chromatin modifying complexes and as a global regulator of histone modifications. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. Moreover, we show that the establishment of H3K9me3 and H4K20me3 at ERV1, ERVK, and ERVL is mediated by TET1 independent of DNA demethylation. We provide evidence that repression of endogenous retroviruses depends on the interaction between TET1 and SIN3A. In summary, we demonstrate that the non-catalytic functions of TET1 are critical for regulation of gene expression and the silencing of endogenous retroviruses in mESCs.
2022-08-31 | PXD028850 | Pride
Project description:Polymerase II pausing licenses cell-cycle progression
| PRJNA393887 | ENA
Project description:TET-family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem (ES) cells. ES cells depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1, and display hyperactive Nodal signalling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions that favor derivation of trophoblast stem (TS) cells, Tet1-depleted ES cells activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in mid-gestation embryo chimeras. Consistent with these findings, Tet1-depleted ES cells form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm and ectopic appearance of trophoblastic giant cells. Thus Tet1 functions to regulate the lineage differentiation potential of ES cells. Here, we performed whole-genome transcriptome profiling of ES cells stably depleted of Tet1 by shRNA knockdown (Tet1-kd) cultured in either standard ES cell or in TS cell culture conditions. Gene expression changes in Tet1-kd ES cells were fairly modest compared to control (GFP-kd) cells, although gene ontology (GO) analysis of differentially expressed genes yielded many terms related to embryonic development and cell cycle regulation. In TS cell culture conditions, a core set of genes defining trophectodermal cell differentiation, including Cdx2, Eomes and Tead4, was enriched in Tet1-kd compared to GFP-kd cells.
2011-02-07 | GSE26900 | GEO
Project description:TET1 and 5-hydroxymethylation preserve the stem cell state of mouse trophoblast
| PRJNA578148 | ENA
Project description:TET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, whether and how TET1 exerts catalytic activity-independent functions in regulating bivalent genes is not well understood. Therefore, we mapped the TET1 interactome in mouse ESCs using a SILAC IP-MS proteomics approach.
2022-06-10 | PXD033587 | Pride